@article {pmid41061323,
year = {2025},
author = {Zhang, J and Zhang, L and Sun, X and Yang, Y and Kong, L and Lu, C and Lv, G and Wang, T and Wang, H and Fu, F},
title = {Corrigendum to "Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation" [The Journal of Pharmacology and Experimental Therapeutics 359 (2016) 374-382].},
journal = {The Journal of pharmacology and experimental therapeutics},
volume = {392},
number = {10},
pages = {103699},
doi = {10.1016/j.jpet.2025.103699},
pmid = {41061323},
issn = {1521-0103},
}

@article {pmid41058018,
year = {2025},
author = {Pascual-Lucas, M and Lacosta, AM and Montañés, M and Canudas, J and Loscos, J and Monleón, I and Allué, JA and Sarasa, L and Fandos, N and Romero, J and Sarasa, M and Torres, M and Whyms, D and Terencio, J and Piñol-Ripoll, G and Boada, M},
title = {Safety, tolerability, immunogenicity, and efficacy of ABvac40 active immunotherapy against Aβ40 in patients with mild cognitive impairment or very mild Alzheimer's disease: A randomized, double-blind, placebo-controlled phase 2 study.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70776},
doi = {10.1002/alz.70776},
pmid = {41058018},
issn = {1552-5279},
support = {//Araclon Biotech-Grifols/ ; },
mesh = {Humans ; Double-Blind Method ; *Alzheimer Disease/therapy/immunology/drug therapy ; Male ; *Amyloid beta-Peptides/immunology ; Female ; Aged ; *Cognitive Dysfunction/therapy/immunology/drug therapy ; *Immunotherapy, Active/methods ; Treatment Outcome ; *Peptide Fragments/immunology ; *Alzheimer Vaccines/therapeutic use/adverse effects ; Middle Aged ; Aged, 80 and over ; },
abstract = {INTRODUCTION: ABvac40 is an investigational active immunotherapy (vaccine) targeting Aβ40. This study assessed the safety and immunogenicity of ABvac40 in patients with amnestic mild cognitive impairment or very mild Alzheimer's disease.

METHODS: AB1601 was a multicenter, randomized, double-blind, placebo-controlled phase 2 study. Patients (n = 124) received five monthly injections plus a 10-month booster of ABvac40 or placebo, with 18-24 months of follow-up. Primary endpoints included safety, tolerability, and immunogenicity. Secondary endpoints assessed immune response, neuropsychological changes, and disease biomarkers.

RESULTS: Treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable between ABvac40 (90.6% and 26.6%) and placebo (93.3% and 26.7%). Amyloid-related imaging abnormalities-hemorrhage (ARIA-H) were similar (12.5% ABvac40; 15.0% placebo), with no ARIA-edema (ARIA-E) or meningoencephalomyelitis. ABvac40 induced a specific, sustained immune response in plasma, with detectable antibodies in CSF.

DISCUSSION: These findings support further investigation of ABvac40 as a potential disease-modifying therapy.

NCT03461276 (ClinicalTrials.gov) HIGHLIGHTS: ABvac40 was safe and well-tolerated in early-stage Alzheimer's disease patients. No amyloid-related imaging abnormalities-edema (ARIA-E) or encephalitis observed; ARIA-hemorrhage (ARIA-H) rates were similar across groups. Specific, sustained immune response to ABvac40 in plasma, with cerebrospinal fluid (CSF) antibody penetration. Cognitive scales and magnetic resonance imaging (MRI) volumetric data favored ABvac40 over placebo. Results support further development of ABvac40 as a disease-modifying therapy.},
}

Humans
Double-Blind Method
*Alzheimer Disease/therapy/immunology/drug therapy
Male
*Amyloid beta-Peptides/immunology
Female
Aged
*Cognitive Dysfunction/therapy/immunology/drug therapy
*Immunotherapy, Active/methods
Treatment Outcome
*Peptide Fragments/immunology
*Alzheimer Vaccines/therapeutic use/adverse effects
Middle Aged
Aged, 80 and over

@article {pmid41057918,
year = {2025},
author = {Erichsen, JM and Register, TC and Sutphen, C and Ma, D and Gaussoin, SA and Rudolph, M and Rundle, M and Bateman, JT and Lockhart, SN and Sai, KKS and Whitlow, C and Craft, S},
title = {A phase 2A/B randomized trial of metabolic modulators intranasal insulin and empagliflozin for MCI and early AD.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70704},
doi = {10.1002/alz.70704},
pmid = {41057918},
issn = {1552-5279},
support = {P30 AG072947/AG/NIA NIH HHS/United States ; T32 AG033534/AG/NIA NIH HHS/United States ; //Kulynych Center for Memory and Cognition/ ; //Aptar Pharma/ ; //Kulynych Cente for Memory and and Cognition/ ; T32 AG0333534/AG/NIA NIH HHS/United States ; //National Institute of Aging/ ; PTC-22-975243/ALZ/Alzheimer's Association/United States ; },
mesh = {Humans ; *Glucosides/administration & dosage/therapeutic use ; *Cognitive Dysfunction/drug therapy ; *Benzhydryl Compounds/administration & dosage/therapeutic use ; Male ; Administration, Intranasal ; Female ; *Alzheimer Disease/drug therapy ; *Insulin/administration & dosage/therapeutic use ; Aged ; Double-Blind Method ; *Sodium-Glucose Transporter 2 Inhibitors/administration & dosage/therapeutic use ; Biomarkers/cerebrospinal fluid ; Treatment Outcome ; },
abstract = {INTRODUCTION: Agents targeting metabolic/vascular disorders are promising candidates to treat Alzheimer's disease (AD) and enhance safety and efficacy of other therapies.

METHODS: In a 2×2 factorial double-blinded randomized trial, participants with mild cognitive impairment (MCI), early AD, or who were amyloid positive received intranasal insulin (INI; 40 IU q.i.d.), the sodium-glucose cotransporter-2 inhibitor empagliflozin (10 mg q.d. oral tablet), both, or placebo for 4 weeks. The primary outcome was treatment-related adverse events (TRAEs). Secondary outcomes included the modified Preclinical Alzheimer's Cognitive Composite-5 (mPACC5), fluid biomarkers, cerebral blood flow (CBF), and fractional anisotropy (FA).

RESULTS: TRAEs were mild and similar for all groups. INI increased mPACC5, modulated FA and CBF, and reduced plasma glial fibrillary acidic protein. Empagliflozin lowered cerebrospinal fluid tau and modulated CBF. Both agents moderated immune/inflammatory/neurovascular markers.

DISCUSSION: INI and empagliflozin treatment was safe with promising effects on cognition, fluid, and imaging biomarkers. A longer and larger trial is needed to confirm these results.

CLINICAL TRIAL REGISTRATION: NCT05081219 HIGHLIGHTS: Agents targeting metabolic or vascular disorders are promising candidates to prevent or treat Alzheimer's disease (AD). Intranasal insulin and empagliflozin were safe alone or in combination for mild cognitive impairment/AD. Insulin improved cognition and markers of inflammation and immune function. Empagliflozin reduced markers of vascular injury and neurodegeneration. A longer, larger trial is needed to validate these results.},
}

Humans
*Glucosides/administration & dosage/therapeutic use
*Cognitive Dysfunction/drug therapy
*Benzhydryl Compounds/administration & dosage/therapeutic use
Male
Administration, Intranasal
Female
*Alzheimer Disease/drug therapy
*Insulin/administration & dosage/therapeutic use
Aged
Double-Blind Method
*Sodium-Glucose Transporter 2 Inhibitors/administration & dosage/therapeutic use
Biomarkers/cerebrospinal fluid
Treatment Outcome

@article {pmid41056473,
year = {2025},
author = {Crump, C and Wei, J and Vickrey, BG and Edwards, AC and Schulz, PE and Sieh, W and Sundquist, J and Sundquist, K},
title = {Risk of major depression in partners of people with Alzheimer's disease: a national cohort study.},
journal = {Age and ageing},
volume = {54},
number = {10},
pages = {},
doi = {10.1093/ageing/afaf283},
pmid = {41056473},
issn = {1468-2834},
mesh = {Humans ; *Alzheimer Disease/psychology/epidemiology/diagnosis ; Female ; *Depressive Disorder, Major/epidemiology/psychology/diagnosis ; Male ; Aged ; Sweden/epidemiology ; Risk Factors ; Incidence ; Aged, 80 and over ; Middle Aged ; Cohort Studies ; Risk Assessment ; *Spouses/psychology ; *Caregivers/psychology ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) may cause significant psychosocial distress not only in the patient but also their partner. However, long-term risks of major depression in partners of AD patients are largely unknown.

METHODS: A national cohort study was conducted of all 145 289 partners of people diagnosed with all-cause dementia, including 57 113 partners of people diagnosed with AD, in Sweden during 1998-2017, and 1 300 561 population-based controls. Cox regression was used to compute hazard ratios (HRs) for subsequent risk of major depression identified from nationwide outpatient and inpatient diagnoses through 2018, adjusting for sociodemographic factors and prior mental disorders.

RESULTS: The 10-year cumulative incidence of major depression was 5.4% in partners of people with AD, 5.6% in partners of people with all-cause dementia, and 3.9% in controls. The adjusted relative rate of major depression was increased ~1.5-fold in partners of people with AD (HR, 1.53; 95% CI, 1.35-1.72) or all-cause dementia (1.45; 1.34-1.57), compared with controls. These risks were elevated among both women (AD: HR, 1.41; 95% CI, 1.22-1.64; all-cause dementia: 1.36; 1.24-1.50) and men (AD: 1.81; 1.46-2.25; all-cause dementia: 1.73; 1.48-2.01). Risks remained significantly elevated ≥3 years later in both women (1.3- to 1.5-fold) and men (1.5-fold). Risks were generally highest in partners aged ≥85 years.

CONCLUSIONS: In this large national cohort, partners of people diagnosed with AD or all-cause dementia had ~1.5-fold risks of major depression, which remained elevated several years later. Partners of people with dementia need psychosocial support and long-term follow-up for timely detection and treatment of depression.},
}

Humans
*Alzheimer Disease/psychology/epidemiology/diagnosis
Female
*Depressive Disorder, Major/epidemiology/psychology/diagnosis
Male
Aged
Sweden/epidemiology
Risk Factors
Incidence
Aged, 80 and over
Middle Aged
Cohort Studies
Risk Assessment
*Spouses/psychology
*Caregivers/psychology

@article {pmid41056389,
year = {2025},
author = {Sharma, M and Deshmukh, S and Thakre, T and Waskar, R and Pardhekar, A},
title = {Ayurvedic Management of Alzheimer's Disease: A Clinical Case Study.},
journal = {Alternative therapies in health and medicine},
volume = {},
number = {},
pages = {},
pmid = {41056389},
issn = {1078-6791},
abstract = {ABSTRACT: Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects memory, cognition, and behavior, often leading to severe functional decline. A 55-year-old male patient came with complaints of confusion in daily activities, forgetting names, misplacing objects, frequent episodes of crying, and loss of communication skills for the past 1 year. He was clinically diagnosed with Alzheimer's Disease. The patient was treated with an Ayurvedic treatment protocol, involving internal administration of Brahmi ghrit, Saraswatarishta with gold, Ashwagandha powder, and Rasona Ksheerpaka, along with Panchakarma therapies including Nasya with Panchendriya taila, Shirobasti, and Abhyanga with Balashwagandha taila. After the treatment, the patient showed marked improvements in memory retention, orientation, and mood stability. This case showed that Ayurvedic interventions aid in slowing cognitive decline and improving daily functioning in Alzheimer's patients, highlighting the need for integrative and individualized treatment approaches in neurodegenerative disorders.

KEYWORDS: neurodegeneration, Alzheimer's disease, Dementia, Ayurvedic medicines, Brahmi ghrit, case report.},
}

@article {pmid41055317,
year = {2025},
author = {Li, J and Sun, W and Wang, X and Ding, F and Li, L and Lin, X and Zhao, Y},
title = {Astaxanthin Suppresses Amyloid-Beta-Induced Toxicity in AD Transgenic Caenorhabditis elegans via Promoting Skn-1-Dependent Proteasomal Activity.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00130},
pmid = {41055317},
issn = {1948-7193},
abstract = {Astaxanthin is a ketocarotenoid that exhibits a variety of bioactivities, including neuroprotection, but the detailed mechanisms by which astaxanthin exerts neuroprotection remain unclear. In the present study, the effects of astaxanthin on amyloid-beta (Abeta)-induced toxicity were investigated in a Caenorhabditis elegans (C. elegans) model of Alzheimer's disease (AD). It is demonstrated that astaxanthin treatment significantly alleviated the Abeta-induced paralytic phenotype in AD C. elegans while reducing the production of reactive oxygen species and restoring the level of glutathione. Further analyses revealed that astaxanthin treatment resulted in a decrease in Abeta accumulation in AD C. elegans. Moreover, astaxanthin restored the proteasomal activity in AD C. elegans by elevating the expression of genes encoding the central subunits of the 20S proteasome. Therefore, astaxanthin might reduce Abeta accumulation via promoting proteasomal function. In addition, astaxanthin treatment increased the expression of skinhead-1 (skn-1), while knockdown of skn-1 expression by RNA interference diminished the inhibition of astaxanthin on Abeta-induced toxicity in AD C. elegans. The elevation of the expression of proteasome subunit genes and the enhancement of proteasomal activity by astaxanthin were also dependent on SKN-1. Overall, these findings indicated that astaxanthin exerted its protection against Abeta-induced toxicity in AD C. elegans via maintaining redox balance and promoting SKN-1-mediated proteasomal activity.},
}

@article {pmid41054805,
year = {2025},
author = {Teipel, S and Singh, D and Dubbelman, MA and Pan, G and Tang, Y and König, A},
title = {Early detection of Alzheimer's disease: From multiplex assays and imaging to point of care devices and AI-based functional monitoring.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251383339},
doi = {10.1177/13872877251383339},
pmid = {41054805},
issn = {1875-8908},
abstract = {The advent of disease-modifying treatments and risk-reduction strategies in the clinic have increased the demand for biomarkers for early disease detection, prediction of clinical course of disease, individual risk prediction and monitoring of treatment effects. The studies in this special issue span ultra-sensitive fluid assays and automated laboratory platforms, structural and molecular neuroimaging, electrophysiology, digital cognitive and behavioral monitoring, multi-omics, neuromodulation, and the computational frameworks necessary to integrate these diverse data.},
}

@article {pmid41054216,
year = {2025},
author = {Sánchez de Muniain, L and Escalada, P and Ramírez, MJ and Solas, M},
title = {Astrocytes as Metabolic Sensors Orchestrating Energy-Driven Brain Vulnerability in Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {169},
number = {10},
pages = {e70252},
doi = {10.1111/jnc.70252},
pmid = {41054216},
issn = {1471-4159},
support = {PID2021-128737NB-I00//MCIN/AEI/10.13039/501100011033/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology ; Humans ; *Astrocytes/metabolism/pathology ; *Energy Metabolism/physiology ; *Brain/metabolism/pathology ; Animals ; Oxidative Stress/physiology ; },
abstract = {Alzheimer's disease (AD), the leading neurodegenerative disorder linked to aging, emerges within a paradoxical metabolic landscape. Despite rising cellular energy demands due to accumulated damage and stress, overall energy expenditure remains stable or declines with age. The brain, acting as the central regulator, responds to hypermetabolic signals from aged tissues by activating energy-conserving mechanisms. In this scenario, astrocytes, strategically located between blood vessels and neurons, play a pivotal role as energy sensors, adapting to systemic stress and modulating brain metabolism. This review explores how astrocytes undergo metabolic reprogramming in the early stages, potentially becoming maladaptive over time, fueling neuroinflammation, oxidative stress, and accelerating AD. By understanding astrocyte energetics, we uncover new avenues for biomarkers and therapies that could transform AD treatment.},
}

*Alzheimer Disease/metabolism/pathology
Humans
*Astrocytes/metabolism/pathology
*Energy Metabolism/physiology
*Brain/metabolism/pathology
Animals
Oxidative Stress/physiology

@article {pmid41053519,
year = {2025},
author = {Amiri, M and Afshary, H and Bezaatpour, A and Hatamikia, S and Wei, J and Boukherroub, R and Szunerits, S},
title = {A critical review on neurodegenerative biomarker diagnostics: where is the field heading to?.},
journal = {Analytical and bioanalytical chemistry},
volume = {},
number = {},
pages = {},
pmid = {41053519},
issn = {1618-2650},
abstract = {Neurodegenerative diseases (NDD), a collection of disorders with different underlying causes and clinical presentations, are recognized as a major area of concern of our society today. The most common NDD are Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Huntington's disease, each one of them being characterized by the progressive degradation of nerve cells and accumulation of misfolded and aggregated proteins in the affected brain region. Diagnosing NDD is challenging, due to the heterogeneity of the disease and the overlap of symptoms. Yet, early detection and accurate diagnosis are crucial for effective NDD management. With the emergence of disease-modifying therapies for AD, monitoring disease progression and treatment success is becoming essential. The future of NND diagnostics is focusing on developing less invasive, cost-effective strategies that enable early NDD identification and detection with improved patient outcomes. The integration of biotechnology and nanotechnology is seen as crucial for advancing the analytical science aspect of NDD. The creation of these innovative tools and methodologies is on the verge of enabling new possibilities for clinical diagnostics, but is also faced with several hurdles that will be critically evaluated.},
}

@article {pmid41053038,
year = {2025},
author = {Ficchì, S and Cauzzi, E and La Barbera, L and De Paolis, ML and Loffredo, G and Spoleti, E and Ferrari, I and Saba, L and Biamonte, F and Nobili, A and Krashia, P and D'Amelio, M},
title = {Optogenetic stimulation of midbrain dopaminergic neurons rescues hippocampal synaptic plasticity deficits in a mouse model of Alzheimer's disease.},
journal = {Translational psychiatry},
volume = {15},
number = {1},
pages = {371},
pmid = {41053038},
issn = {2158-3188},
support = {AARG-21-851219/ALZ/Alzheimer's Association/United States ; },
mesh = {Animals ; *Alzheimer Disease/physiopathology/therapy ; *Dopaminergic Neurons/physiology ; *Optogenetics ; Disease Models, Animal ; Mice ; *Mesencephalon/physiopathology ; *Neuronal Plasticity/physiology ; *Hippocampus/physiopathology ; Mice, Inbred C57BL ; Mice, Transgenic ; Oxidopamine ; *Long-Term Potentiation/physiology ; Male ; Synaptic Transmission ; },
abstract = {We previously demonstrated that the Tg2576 mouse model of Alzheimer's Disease (AD) exhibits degeneration of midbrain dopaminergic neurons, resulting in reduced dopamine (DA) outflow in the hippocampus. These impairments temporally coincide with synaptic plasticity deficits at CA3-CA1 synapses. Notably, systemic administration of dopaminergic agents/drugs rescues the hippocampal deficits in Tg2576 mice. However, whether direct stimulation of the remaining midbrain dopaminergic neurons can restore glutamatergic transmission and rescue plasticity dysfunctions in the context of AD remains unexplored. Here, using both 6-hydroxydopamine (6-OHDA) neurotoxic lesion and optogenetic stimulation in C57BL/6N and DATCre/Tg2576 mice, respectively, we demonstrate that midbrain DA is essential for hippocampal High-Frequency Stimulation-induced Long-Term Potentiation (HFS-LTP) in CA3-CA1 synapses. Indeed, lesioning midbrain DA neurons with 6-OHDA abolishes HFS-LTP and impairs novel object recognition memory. Conversely, optogenetic activation of the midbrain-hippocampal dopaminergic pathway in DATCre/Tg2576 mice enhances glutamatergic transmission and rescues plasticity deficits. Our results highlight the phase-specific role of DA in HFS-LTP, since 6-OHDA lesion affects the late but not the early phase, aligning with prior studies on D1/D5 receptor involvement in protein synthesis-dependent plasticity. Furthermore, we provide novel insights into midbrain DA neuron regulation, demonstrating that phasic, but not prolonged, optogenetic stimulation effectively engages DA neuron activity, restoring hippocampal function in Tg2576 mice. Notably, phasic DA release induces "DA-LTP" via D1/D5 receptors, and restores HFS-LTP in CA3-CA1 synapses of AD mice, underscoring a potential compensatory mechanism counteracting plasticity deficits induced by DA neuron degeneration in Tg2576 mice. These findings support targeting the dopaminergic midbrain as a promising strategy for AD treatment, complementing pharmacological and non-invasive neuromodulatory approaches.},
}

Animals
*Alzheimer Disease/physiopathology/therapy
*Dopaminergic Neurons/physiology
*Optogenetics
Disease Models, Animal
Mice
*Mesencephalon/physiopathology
*Neuronal Plasticity/physiology
*Hippocampus/physiopathology
Mice, Inbred C57BL
Mice, Transgenic
Oxidopamine
*Long-Term Potentiation/physiology
Male
Synaptic Transmission

@article {pmid41052971,
year = {2025},
author = {Chen, J and Xiang, P and Duro-Castano, A and Cai, H and Guo, B and Liu, X and Yu, Y and Lui, S and Luo, K and Ke, B and Ruiz-Pérez, L and Gong, Q and Tian, X and Battaglia, G},
title = {Rapid amyloid-β clearance and cognitive recovery through multivalent modulation of blood-brain barrier transport.},
journal = {Signal transduction and targeted therapy},
volume = {10},
number = {1},
pages = {331},
pmid = {41052971},
issn = {2059-3635},
support = {769798 CheSSTag//EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)/ ; },
mesh = {Animals ; *Blood-Brain Barrier/metabolism/drug effects ; *Amyloid beta-Peptides/genetics/metabolism ; Mice ; *Alzheimer Disease/genetics/drug therapy/pathology/metabolism ; Humans ; *Low Density Lipoprotein Receptor-Related Protein-1/genetics ; *Cognition/drug effects ; Receptors, LDL/genetics ; Disease Models, Animal ; Transcytosis ; },
abstract = {The blood‒brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimer's disease (AD), contributing to the accumulation of amyloid-β (Aβ) plaques. We present a novel therapeutic strategy that targets low-density lipoprotein receptor-related protein 1 (LRP1) on the BBB. Our design leverages the multivalent nature and precise size of LRP1-targeted polymersomes to modulate receptor-mediated transport, biasing LRP1 trafficking toward transcytosis and thereby upregulating its expression to promote efficient Aβ removal. In AD model mice, this intervention significantly reduced brain Aβ levels by nearly 45% and increased plasma Aβ levels by 8-fold within 2 h, as measured by ELISA. Multiple imaging techniques confirmed the reduction in brain Aβ signals after treatment. Cognitive assessments revealed that treated AD mice exhibited significant improvements in spatial learning and memory, with performance levels comparable to those of wild-type mice. These cognitive benefits persisted for up to 6 months post-treatment. This work pioneers a new paradigm in drug design, where function arises from the supramolecular nature of the nanomedicine, harnessing multivalency to elicit biological action at the membrane trafficking level. Our findings also reaffirm the critical role of the BBB in AD pathogenesis and demonstrate that targeting the BBB can make therapeutic interventions significantly more effective. We establish a compelling case for BBB modulation and LRP1-mediated Aβ clearance as a transformative foundation for future AD therapies.},
}

Animals
*Blood-Brain Barrier/metabolism/drug effects
*Amyloid beta-Peptides/genetics/metabolism
Mice
*Alzheimer Disease/genetics/drug therapy/pathology/metabolism
Humans
*Low Density Lipoprotein Receptor-Related Protein-1/genetics
*Cognition/drug effects
Receptors, LDL/genetics
Disease Models, Animal
Transcytosis

@article {pmid41052930,
year = {2025},
author = {Emami Naeini, S and Bhandari, B and Hill, B and Perez-Morales, N and Rogers, HM and Khodadadi, H and Young, N and Maciel, LM and Yu, JC and Hess, DC and Morgan, JC and Lopes Salles, É and Wang, LP and Baban, B},
title = {Rethinking Alzheimer's: Harnessing Cannabidiol to Modulate IDO and cGAS Pathways for Neuroinflammation Control.},
journal = {eNeuro},
volume = {},
number = {},
pages = {},
doi = {10.1523/ENEURO.0114-25.2025},
pmid = {41052930},
issn = {2373-2822},
abstract = {Alzheimer's disease (AD) has traditionally been associated with amyloid-β plaques, but growing evidence underscores the role of neuroinflammation in disease progression. The autoinflammatory hypothesis of AD suggests chronic immune dysfunction contributes to neuronal damage, making immune modulation a promising therapeutic strategy.Cannabidiol (CBD), a phytocannabinoid with anti-inflammatory properties, may offer therapeutic potential. This study investigates how CBD independently influences two key neuroinflammatory regulators in AD: the Indoleamine 2,3-dioxygenase (IDO) pathway and the cyclic GMP-AMP synthase (cGAS) pathway. Though mechanistically distinct, both shape CNS immune responses. Targeting these immune-metabolic axes provides a mechanistic alternative to amyloid- or tau-based approaches by addressing upstream drivers of neuroinflammation and immune dysregulation. Using the male 5XFAD transgenic AD mouse model, we administered CBD via inhalation and assessed IDO and cGAS expression using flow cytometry, immunofluorescence, and gene expression analysis. We evaluated cytokine levels and used STRING-based bioinformatics to identify CBD-target interactions. CBD treatment significantly reduced IDO and cGAS expression, correlating with decreased pro-inflammatory cytokines, including TNF-α, IL-1β, and IFN-γ. Bioinformatics identified potential interactions between CBD and immune targets such as AKT1, TRPV1, and GPR55. These targets were prioritized based on their roles in neuroinflammatory signaling and high-confidence interactions with CBD. AKT1 regulates inflammatory signaling and cell survival, TRPV1 modulates nociception and neuroinflammation, and GPR55 influences immune cell activation. These findings support CBD as a potential monotherapy or adjunctive treatment for AD by targeting distinct neuroinflammatory pathways, including IDO and cGAS. Further studies are warranted to fully explore its therapeutic potential.Significance statement This study highlights the therapeutic potential of cannabidiol (CBD) in targeting neuroinflammation, a major driver of Alzheimer's disease (AD) progression. By modulating the IDO and cGAS pathways-critical regulators of CNS immune responses-CBD reduces pro-inflammatory cytokines and ameliorates immune dysfunction. These findings support the emerging autoinflammatory hypothesis of AD, which posits that chronic inflammation underlies neuronal damage. The IDO/cGAS signaling axis, located at the intersection of innate immunity and metabolic regulation, remains underexplored in AD and represents a key intervention point to disrupt neuroinflammatory loops. This study positions CBD as a promising mono- or adjunctive therapy and reinforces the need to consider multi-targeted strategies that address upstream immune mechanisms in neurodegenerative disease.},
}

@article {pmid41052547,
year = {2025},
author = {Ajoolabady, A and Kim, B and Abdulkhaliq, AA and Ren, J and Bahijri, S and Tuomilehto, J and Borai, A and Khan, J and Pratico, D},
title = {Dual role of microglia in neuroinflammation and neurodegenerative diseases.},
journal = {Neurobiology of disease},
volume = {},
number = {},
pages = {107133},
doi = {10.1016/j.nbd.2025.107133},
pmid = {41052547},
issn = {1095-953X},
abstract = {Microglia are the principal innate immune cells of the central nervous system, playing cardinal roles in regulating immunity and mediating neuroinflammation - a chronic inflammatory response occurring in the brain and spinal cord. Microglia exhibit a dual role in this process: they can suppress neuroinflammation through anti-inflammatory polarization or inhibition of proinflammatory intracellular signaling, or conversely, they can exacerbate neuroinflammation via activation of proinflammatory pathways and phenotypes. This seemingly binary behavior is further complicated by a network of internal and external molecular effectors that influence microglial polarization and function, guiding them toward either neuroprotection or neurotoxicity. In this narrative review, we aimed to elucidate the dual role of microglia in neuroinflammation, particularly in the context of neurodegenerative diseases and other brain pathologies. Special emphasis is placed on the most recent findings related to key proteins such as TREM2 (triggering receptor expressed on myeloid cells 2) and HMGB1 (high mobility group box 1 protein). By examining the molecular mechanisms and pathways involving these proteins, we highlight promising therapeutic targets for modulating neuroinflammation and advancing developing novel treatment strategies for neurodegenerative and other brain-related disorders.},
}

@article {pmid41052542,
year = {2025},
author = {Hansen, N and Wiltfang, J},
title = {[Disease-modifying therapy with lecanemab for early Alzheimer's dementia].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2681-4558},
pmid = {41052542},
issn = {1439-3522},
abstract = {Alzheimer's disease (AD) is a severe and progressive neurodegenerative disease of the brain that has so far been treated with symptomatic drug and non-drug therapies as standard treatment. Following the approval of the monoclonal anti-amyloid antibody by the FDA, AD therapy has changed, as this therapy has made it possible to attenuate the biological disease process of AD. Lecanemab has been recommended by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for approval in patients with early AD under two conditions. Firstly, homozygous ApoE4 carriers and secondly, patients receiving oral anticoagulants should not receive lecanemab. The following narrative review explains the mechanism of action, safety and side effects of lecanemab. Furthermore, risk factors for side effects are described. Finally, the first experiences with lecanemab are reported and the efficacy and financial aspects are discussed. Lecanemab leads to a temporary reduction in amyloid-ß deposits and to a benefit that can be reflected in everyday competence, cognition and quality of life and can be described as a breakthrough in AD's therapy due to its demonstrable biological and clinical efficacy.},
}

@article {pmid41051912,
year = {2025},
author = {Hickman, LB and Pandey, B and Fish, A and Bandla, M and Husein, A and Allas, C and Kottakota, H and Herzog, L and Vossel, K and Stern, JM},
title = {Late-onset epilepsy of unknown etiology is more treatment-responsive than acquired lesional late-onset epilepsy.},
journal = {Epilepsia open},
volume = {},
number = {},
pages = {},
doi = {10.1002/epi4.70156},
pmid = {41051912},
issn = {2470-9239},
support = {UE5 NS065723-16/NS/NINDS NIH HHS/United States ; R01 NS033310/NS/NINDS NIH HHS/United States ; R01 AG058820/NS/NINDS NIH HHS/United States ; R01 AG075955/NS/NINDS NIH HHS/United States ; R56 AG074473/NS/NINDS NIH HHS/United States ; UH2 AG083254/NS/NINDS NIH HHS/United States ; },
abstract = {OBJECTIVE: Late-onset epilepsy of unknown etiology (LOEU) carries an elevated risk of dementia, suggesting that it may represent an early manifestation of neurodegenerative or cerebrovascular disease. Direct comparisons between LOEU and acquired lesional late-onset epilepsy (LOE) may elucidate clinical features specific to LOEU.

METHODS: We performed a retrospective chart review of patients with LOE, with first documented seizure at age 55 or older, whose evaluation included an epilepsy-protocol brain MRI and/or inpatient video-EEG evaluation. Etiology was determined from neuroimaging lesions and medical history. Patients without an identified etiology were categorized as LOEU. Analyses were performed controlling for sex, age of onset, and epilepsy duration.

RESULTS: We identified 75 LOEU (mean onset: 64.9 years, 38.7% female) and 57 acquired lesional LOE cases with etiologies including cortical stroke, hemorrhage, neoplasm, trauma, or infection (mean onset: 66.5 years, 36.8% female). LOEU was less likely to have a history of status epilepticus (6.7% vs. 21.1%, aOR: 0.28, p < 0.03) or to have undergone inpatient video-EEG monitoring (13.3% vs. 24.6%, aOR: 0.34, p < 0.04). LOEU was prescribed fewer ASMs compared to acquired lesional LOE (aOR: 0.43, p < 0.02), and LOEU patients prescribed multiple ASMs had lower average 12-month seizure frequency than acquired lesional LOE (median: 0.2 vs. 1.0, p < 0.01). LOEU had lower rates of vascular comorbidities than acquired lesional LOE, though rates of subsequent dementia were not significantly different (5-year risk: 16.6% vs. 17.7%). An exploratory cluster analysis demonstrated an LOEU subgroup with older onset, higher prevalence of white matter hyperintensities, cerebral atrophy, epileptiform discharges, and greater epilepsy severity.

SIGNIFICANCE: LOEU was associated with fewer proxies for epilepsy severity, signifying that LOEU is more often treatment-responsive than acquired lesional LOE. LOEU has lower rates of comorbid vascular disease compared to acquired lesional LOE, suggesting that occult cerebrovascular disease is not overrepresented in LOEU relative to other forms of LOE.

PLAIN LANGUAGE SUMMARY: People who develop epilepsy after age 55 without a known cause usually respond well to treatment and need fewer antiseizure medications than people with epilepsy from a known brain injury. In this study, they had fewer hospital stays for seizure monitoring and fewer vascular problems. Dementia risk was high in patients with late-onset epilepsy, both when the cause was known and when it was unknown. Late-onset epilepsy without a known cause is often less severe but still needs regular monitoring for memory and thinking problems.},
}

@article {pmid41051689,
year = {2025},
author = {Azam, HMH and Mumtaz, M and Rödiger, S and Schierack, P and Hussain, N and Aisha, A},
title = {MicroRNAs in neurodegenerative diseases: from molecular mechanisms to clinical biomarkers, detection methods and therapeutic strategies-advances and challenges.},
journal = {Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology},
volume = {},
number = {},
pages = {},
pmid = {41051689},
issn = {1590-3478},
abstract = {Neurodegenerative diseases (NDDs) pose significant challenges in early detection and treatment due to their complex pathophysiology and heterogeneous clinical presentations. MicroRNAs (miRNAs), small noncoding RNAs that regulate gene expression, have emerged as promising diagnostic biomarkers and therapeutic targets in NDDs. Pathological examination of affected tissues reveals early synaptic dysfunction, protein misfolding, and neuroinflammation occur prior to overt clinical symptoms, highlighting the importance of sensitive diagnostics approaches in prodromal stages. This review summarizes for researchers on the role of miRNAs in NDDs by examining their diagnostic potential in biofluids such as blood and cerebrospinal fluid, and their therapeutic applicability through inhibition or replacement strategies. Literature from peer-reviewed databases was assessed with a focus on recent advances in molecular detection platforms, computational modeling of miRNA-mRNA interactions, and preclinical/clinical investigations.More than 2600 human miRNAs have been identified, collectively regulating over half of mammalian protein-coding genes. Quantitative methodologies, particularly reverse transcription quantitative PCR (RT-qPCR), enable reliable miRNA profiling, facilitating early diagnosis and prognosis of NDDs. Therapeutic strategies, including antagomirs, mimics, sponges and viral or non-viral delivery systems, show promise in modulating disease pathways. However, significant challenges remain, including variability in miRNA extraction and quantification protocols, off-target effects, delivery barriers across the blood brain barrier and limited reproducibility across studies. MiRNAs represent a class of molecular tools with potential to transform diagnostics and therapeutics in NDDs. Future research should prioritize methodological standardization, validation in large multicenter cohorts, and improved computational approaches to elucidate miRNA-mediated regulatory networks in NDDs. Replication studies and translational research are essential harnessing the the full clinical utility of miRNAs in the management of Alzheimer disease, Parkinson disease and other NDDs. Graphical Abstract.},
}

@article {pmid41051550,
year = {2025},
author = {Yang, T},
title = {Molecular Mechanisms of EDC-Induced Alzheimer's Disease and of Traditional Chinese Medicine Active Substances in Treating AD and Antagonizing EDC-Induced Effects.},
journal = {Neurochemical research},
volume = {50},
number = {5},
pages = {319},
pmid = {41051550},
issn = {1573-6903},
mesh = {*Alzheimer Disease/chemically induced/drug therapy/metabolism ; Molecular Docking Simulation/methods ; *Medicine, Chinese Traditional/methods ; Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; Animals ; Network Pharmacology ; Ginsenosides/therapeutic use/pharmacology ; Protein Interaction Maps/drug effects ; },
abstract = {AD, a progressive neurodegenerative disorder, imposes an increasingly heavy burden on global public health, with its pathogenesis remaining incompletely understood. Meanwhile, EDCs-widely present in the environment, food, and consumer products-have emerged as a significant public health concern due to their diverse health risks, including potential contributions to neurodegenerative processes such as AD by disrupting neurohomeostasis. Furthermore, as natural compounds, ginsenosides and other AS have been the focus of numerous studies exploring their role in treating AD, thanks to their advantages of multi-target properties and low side effects. However, the specific molecular pathways through which EDCs induce AD, as well as the mechanisms by which AS may counteract EDC-induced toxicity and intervene in AD, remain unclear. Against this background, this study sought to: (1) explore the molecular pathways through which EDCs may induce AD by disrupting neurohomeostasis; (2) preliminarily investigate the potential of AS in treating AD and antagonizing EDC-induced AD at the molecular level. To achieve these goals, we integrated network toxicology, network pharmacology, and molecular docking to construct a multi-dimensional interaction network among EDCs, AD, and AS. By establishing intersecting target sets for EDCs-AD and AS-AD, core targets were identified via topology analysis of protein-protein interaction (PPI) networks. GO and KEGG enrichment analyses highlighted key pathways, including serotonergic synapse and neuroactive ligand-receptor interaction. Molecular docking further explored interactions between EDCs/AS and core target proteins. The results suggest that EDCs may drive neurodegeneration in AD by impairing synaptic function, while AS may counteract these effects by enhancing synaptic activity, stabilizing membrane microenvironments, inhibiting Aβ aggregation, alleviating neuroinflammation, and restoring metabolic homeostasis. Further analysis indicated that AS exhibit stronger binding ability to core targets compared to EDCs, implying a potential antagonistic effect of AS against EDCs. This study provides insights into the molecular mechanisms underlying EDC-induced AD and establishes a multi-target theoretical framework for AS-mediated antagonism of EDC toxicity, offering a reference for the prevention and treatment of neurodegenerative diseases.},
}

*Alzheimer Disease/chemically induced/drug therapy/metabolism
Molecular Docking Simulation/methods
*Medicine, Chinese Traditional/methods
Humans
*Drugs, Chinese Herbal/therapeutic use/pharmacology
Animals
Network Pharmacology
Ginsenosides/therapeutic use/pharmacology
Protein Interaction Maps/drug effects

@article {pmid41051385,
year = {2025},
author = {Xie, D and Zheng, Q and Lv, J and Zhang, Q and Cui, Z and Huang, S and Yu, W and Chen, B and Que, W and Fu, S and Xi, Y and Chen, J and Ye, X and Chen, S and Zhao, H and Yamamoto, T and Koyama, H and Wang, X and Cheng, J},
title = {Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
volume = {},
number = {},
pages = {e10270},
doi = {10.1002/advs.202510270},
pmid = {41051385},
issn = {2198-3844},
support = {2022Y4007//Fujian Provincial Industry-University-Research Collaborative Innovation Project Plan/ ; U01 AG024904/AG/NIA NIH HHS/United States ; W81XWH-12-2-0012//DOD ADNI/ ; 2020J01018//Natural Science Foundation of Fujian Province/ ; 82260163//National Natural Science Foundation of China/ ; 82370895//National Natural Science Foundation of China/ ; 82271451//National Natural Science Foundation of China/ ; },
abstract = {Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.},
}

@article {pmid41051231,
year = {2025},
author = {Paul, S and Guruprasad, L},
title = {Hexagonal Boron Nitride Nanoparticles for Inhibition of Small Fragment Tau Aggregation.},
journal = {The journal of physical chemistry. B},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jpcb.5c04935},
pmid = {41051231},
issn = {1520-5207},
abstract = {The aberrant folding of the Tau protein is correlated with several neurodegenerative diseases, such as Alzheimer's and other tauopathies. Recent studies on the neurotoxic species of Tau have identified some smaller nucleating domains of the full-length protein to initiate Tau aggregation and are shown as potential therapeutic targets in Tau pathology. Two hexapeptides, namely, PHF6 ([306]VQIVYK[311]) and PHF6* ([275]VQIINK[280]), have been recognized as the most important aggregation-prone Tau fragments among all. Currently, low-dimensional nanomaterials have shown a plethora of applications in bionanomedicine, including the treatment of amyloid diseases. Hexagonal boron nitride (h-BN) nanoparticles, analogous to carbon nanomaterials, have become potential candidates in this field due to their lower cytotoxicity compared to carbon nanoparticles and biocompatibility. In this study, we have explored the aggregation pattern of PHF6 and PHF6* and the effects of a two-dimensional (2D) h-BN nanosheet (BNNS) on these peptide oligomerizations. Atomistic simulations reveal that the PHF6-PHF6 homomer aggregation is highly favored due to the aromatic π-π interaction between the Tyr residues; furthermore, the heteromeric interaction between PHF6 and PHF6* is stronger than the self-association of PHF6* homomers. In the presence of BNNS, the peptides get absorbed on the nanosurface through weak hydrophobic interactions and aromatic π-π stacking and remain in their monomeric random coil structure. Also, the h-BN nanosheet can destabilize the preformed oligomers of the hexapeptides, hence providing a new direction toward the use of h-BN and other related nanomaterials as potential antiaggregating agents against amyloid deposition.},
}

@article {pmid41051040,
year = {2025},
author = {Agarwal, U and Paliwal, S and Yadav, V and Pannu, A and Tonk, RK and Verma, S},
title = {Pathological Insights into Neurodegenerative and Neurodevelopmental Disorders: Perspectives for the Development of Novel Treatment Approaches.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273402657250905055635},
pmid = {41051040},
issn = {1996-3181},
abstract = {Neurodegenerative and neurodevelopmental disorders represent a significant global health burden, characterized by progressive neuronal dysfunction and loss. Both diseases, despite their diverse etiologies and mechanisms, share a complex interplay of genetic, environmental, and biological factors. Neurodegenerative diseases are caused by multiple factors, including aging, mitochondrial dysfunction, oxidative stress, inflammation, genetic mutations, and protein misfolding. In contrast, neurodevelopmental disorders are primarily influenced by epigenetic alterations, neurotransmitter imbalances, early brain damage, environmental factors, and genetic variations. Despite extensive research, effective treatments remain unavailable due to the complexity of their pathologies and the biochemical pathways involved. A deep understanding of the complexities and individual differences associated with these disorders is crucial for developing effective treatments. In this background, this review provides a comprehensive overview of neurodegenerative and neurodevelopmental disorders, including their clinical symptoms, etiology, pathogenesis, underlying mechanisms, potential drug targets, reported drugs, advanced treatment options, and challenges in the drug discovery process. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to April 2025. By understanding the complexities of these disorders, researchers can develop novel therapeutic approaches, including potential drugs and advanced treatment methods, to mitigate their devastating impact.},
}

@article {pmid41050964,
year = {2025},
author = {Zhou, Z and Chen, X and Kou, W and Meng, F and Yu, L and Wen, J and Boey, J and Shah, V and Malagón, P},
title = {Modified Dynamic Lymphaticovenular Anastomosis for Surgical Management of Alzheimer Disease.},
journal = {Plastic and reconstructive surgery. Global open},
volume = {13},
number = {10},
pages = {e7082},
pmid = {41050964},
issn = {2169-7574},
abstract = {Alzheimer disease (AD) is a neurodegenerative disorder that frequently results in progressive cognitive decline. Despite the extensive research conducted on AD, there is presently no solution available due to its increasing prevalence. Recent research has suggested cervical lymphaticovenular anastomosis (LVA) as a therapeutic strategy to improve lymphatic outflow and potentially reduce AD symptoms. We established an amended LVA protocol to mitigate the risk of venous reflux, a prevalent issue associated with the original LVA methodology. A 64-year-old man of Chinese descent exhibited the typical signs and symptoms of AD. The absence of substantial progress with standard medical treatment led to the consideration of LVA. We used a lower limb vein graft for the LVA, anastomosing it to the cervical lymphatic vessels and external jugular vein. The cognitive function of the patient got better after LVA, as shown by higher Mini Mental State Examination and Montreal Cognitive Assessment scores. Fewer β-amyloid and tau protein deposits were observed on positron emission tomography/computed tomography scans. No adverse occurrences or issues were observed. The success in this case demonstrated the potential role of LVA in the management of AD. However, further thorough research is required to evaluate the efficacy of our technique.},
}

@article {pmid41050469,
year = {2025},
author = {Wang, Y and Liu, T and He, Y and Tang, Y and Tan, P and Huang, L and Huang, D and Wen, T and Shao, L and Wang, J and Wang, Y and Han, Z},
title = {Identifying Alzheimer's disease-related pathways based on whole-genome sequencing data.},
journal = {Computational and structural biotechnology journal},
volume = {27},
number = {},
pages = {4132-4144},
pmid = {41050469},
issn = {2001-0370},
abstract = {Alzheimer's disease (AD) is a highly inheritable neurodegenerative disorder for which pathway-specific genetic profiling provides insights into its key biological mechanisms and potential treatment targets. Traditional disease-pathway analyses for AD have certain limitations, such as environmental interference and arbitrary sample division. We present a comprehensive framework that starts with genome data, avoiding these drawbacks and offering intrinsic pathway-specific genetic profiling for AD. Whole genome sequencing data from 173 individuals were used to quantify transcriptomes in 14 brain regions, estimate individual-level pathway variant scores, and analyze AD risk for each patient. These results were combined to identify AD-related pathways and quantify their interactions. The predicted expression levels were consistent with previous findings, and the estimated AD risk showed a significant correlation with Braak/Thal scores. A total of 3798 pathways were identified as potentially associated with AD, with about 19.7 % previously reported. The pathways identified as AD risk related primarily address six core biological themes, including: Immunity and inflammation, Metabolism, Protein homeostasis, DNA/RNA and Epigenetics, Synapse and structure, Cell cycle. Specifically, key pathways, such as NF-κB signaling and GSK3β activation, were linked to AD pathogenesis. The interactions among pathways highlighted shared gene functions in AD. In summary, we provided an effective framework for disease-pathway analysis, revealing the interdependence or compensatory effects of pathways in AD.},
}

@article {pmid41050397,
year = {2025},
author = {Liu, W and Zhao, Y and Liu, T and Wang, Y and Yin, D and Zou, S and Zou, C and Zhang, Z and Zhi, H and Wang, Y},
title = {Kaixin San Jiawei granule improves cognitive function and alleviates neuronal damage in Alzheimer's disease via multi-component and multi-target mechanisms.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1650534},
pmid = {41050397},
issn = {1663-9812},
abstract = {BACKGROUND: Kaixin San Jiawei Granule (KSG) is a traditional Chinese medicine formulation derived from classical prescriptions. Although it has shown promise in treating Alzheimer's disease (AD), its precise mechanisms of action remain unclear. This study aimed to systematically investigate the molecular mechanisms underlying KSG's therapeutic effects on AD through an integrative approach combining network pharmacology with experimental validation.

METHODS: An in vivo AD model was established in male KM mice via intraperitoneal injection of scopolamine. Cognitive function was assessed using the Morris water maze, and hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE), glutathione peroxidase (GSH-Px), and reactive oxygen species (ROS) were measured using ELISA. In vitro, PC12 cells were exposed to Aβ25-35 to induce apoptosis. Immunofluorescence staining, Western blotting, and qPCR were used to assess the expression of amyloid-beta (Aβ), apoptosis-related protein caspase-3, and inflammatory cytokines (TNF-α, IL-1β). Active components of KSG and their potential targets and pathways were identified using mass spectrometry and network pharmacology, while partial validation was performed using molecular docking and Western blotting.

RESULTS: In vivo, KSG significantly alleviated scopolamine-induced cognitive deficits in mice. Treatment increased hippocampal levels of ACh and GSH-Px while reducing AChE and ROS. In vitro, KSG mitigated Aβ25-35-induced cytotoxicity in PC12 cells, decreased Aβ accumulation, and downregulated the expression of TNF-α and IL-1β. However, KSG had no significant effect on telomerase activity, telomere length, or the expression of the telomere-associated protein POT1. Mass spectrometry and network pharmacology analyses identified genistein, quercetin, and apigenin as key active compounds with TP53, AKT1, PTGS2, and CNR2 identified as core targets. Molecular docking validation confirmed the favorable binding activity between them. The calcium signaling, PI3K-Akt, and MAPK pathways emerged as the primary enriched pathways.

CONCLUSION: KSG improves cognitive function and attenuates Aβ-induced neuronal damage in AD through multi-component, multi-target synergistic mechanisms. These effects appear to be mediated by modulation of the cholinergic system, inhibition of oxidative stress and inflammation, and suppression of neuronal apoptosis. These findings provide a theoretical basis and experimental support for developing novel AD therapies based on traditional Chinese medicine.},
}

@article {pmid41049759,
year = {2025},
author = {Meden, A and Žnidaršič, N and Knez, D and Wang, Y and Xu, Z and Yang, H and Zhang, W and Pišlar, A and Perdih, A and Brezar, SK and Grgurevič, N and Pajk, S and Sun, H and Gobec, S},
title = {Pleiotropic prodrugs for both symptomatic and disease-modifying treatment of Alzheimer's disease.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4807-4828},
pmid = {41049759},
issn = {2211-3835},
abstract = {The inherent complexity of Alzheimer's disease (AD) and failed clinical trials have spiked the interest in multifunctional ligands that target at least two key disease-associated macromolecules in AD pathology. Here we present a focused series of pleiotropic N-carbamoylazole prodrugs with dual mechanism of action. Pseudo-irreversible inhibition of the first therapeutic target, human butyrylcholinesterase (hBChE), enhances cholinergic transmission, and thereby provides symptomatic treatment, same as the standard therapeutics in use for AD. Simultaneously, this step also functions as a metabolic activation that liberates a nanomolar selective α 2-adrenergic antagonist atipamezole, which blocks pathological amyloid β (Aβ)-induced and noradrenaline-dependent activation of GSK3β that ultimately leads to hyperphosphorylation of tau, thus achieving a disease-modifying effect. Lead compound 8 demonstrated long-term pseudo-irreversible hBChE inhibition, metabolic activation in human plasma, blood-brain barrier permeability, and p.o. bioavailability in mice. Multi-day in vivo treatment with 8 in an Aβ-induced AD murine model revealed a significant alleviation of cognitive deficit that was comparable to rivastigmine, the current drug of choice for AD therapy. Furthermore, decreased GSK3β activation and lowered tau phosphorylation were observed in APP/PS1 mice. This surpasses the symptomatic-only treatment with cholinesterase inhibitors, as it directly blocks an essential pathological cascade in AD. Therefore, these multifunctional α 2-adrenergic antagonists-butyrylcholinesterase inhibitors, exemplified by lead compound 8, present an innovative, small molecule-based, disease-modifying approach to treatment of AD.},
}

@article {pmid41049755,
year = {2025},
author = {Yang, Y and Diao, Y and Jiang, L and Li, F and Chen, L and Ni, M and Wang, Z and Fang, H},
title = {A computational medicine framework integrating multi-omics, systems biology, and artificial neural networks for Alzheimer's disease therapeutic discovery.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4411-4426},
pmid = {41049755},
issn = {2211-3835},
abstract = {The translation of genetic findings from genome-wide association studies into actionable therapeutics persists as a critical challenge in Alzheimer's disease (AD) research. Here, we present PI4AD, a computational medicine framework that integrates multi-omics data, systems biology, and artificial neural networks for therapeutic discovery. This framework leverages multi-omic and network evidence to deliver three core functionalities: clinical target prioritisation; self-organising prioritisation map construction, distinguishing AD-specific targets from those linked to neuropsychiatric disorders; and pathway crosstalk-informed therapeutic discovery. PI4AD successfully recovers clinically validated targets like APP and ESR1, confirming its prioritisation efficacy. Its artificial neural network component identifies disease-specific molecular signatures, while pathway crosstalk analysis reveals critical nodal genes (e.g., HRAS and MAPK1), drug repurposing candidates, and clinically relevant network modules. By validating targets, elucidating disease-specific therapeutic potentials, and exploring crosstalk mechanisms, PI4AD bridges genetic insights with pathway-level biology, establishing a systems genetics foundation for rational therapeutic development. Importantly, its emphasis on Ras-centred pathways-implicated in synaptic dysfunction and neuroinflammation-provides a strategy to disrupt AD progression, complementing conventional amyloid/tau-focused paradigms, with the future potential to redefine treatment strategies in conjunction with mRNA therapeutics and thereby advance translational medicine in neurodegeneration.},
}

@article {pmid41049729,
year = {2025},
author = {Ren, F and Wei, J and Chen, Q and Hu, M and Yu, L and Mi, J and Zhou, X and Qin, D and Wu, J and Wu, A},
title = {Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions.},
journal = {Acta pharmaceutica Sinica. B},
volume = {15},
number = {9},
pages = {4327-4385},
pmid = {41049729},
issn = {2211-3835},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss, with few effective treatments currently available. The multifactorial nature of AD, shaped by genetic, environmental, and biological factors, complicates both research and clinical management. Recent advances in artificial intelligence (AI) and multi-omics technologies provide new opportunities to elucidate the molecular mechanisms of AD and identify early biomarkers for diagnosis and prognosis. AI-driven approaches such as machine learning, deep learning, and network-based models have enabled the integration of large-scale genomic, transcriptomic, proteomic, metabolomic, and microbiomic datasets. These efforts have facilitated the discovery of novel molecular signatures and therapeutic targets. Methods including deep belief networks and joint deep semi-non-negative matrix factorization have contributed to improvements in disease classification and patient stratification. However, ongoing challenges remain. These include data heterogeneity, limited interpretability of complex models, a lack of large and diverse datasets, and insufficient clinical validation. The absence of standardized multi-omics data processing methods further restricts progress. This review systematically summarizes recent advances in AI-driven multi-omics research in AD, highlighting achievements in early diagnosis and biomarker discovery while discussing limitations and future directions needed to advance these approaches toward clinical application.},
}

@article {pmid41048559,
year = {2025},
author = {Ma, X and Wang, F and Wang, G and Zhao, M and Zheng, Y and Guo, Y and Wu, J and Liu, Y and Liu, Y and He, G and Ren, L and Gong, Z and Wang, J and Chen, L and Hu, S and Chu, Q and Li, Z and Wu, J and Li, R and Zhang, X and Shi, Q and Lian, H and Ye, J},
title = {A surgical therapy for Alzheimer's disease with lymphaticovenular anastomosis.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251384244},
pmid = {41048559},
issn = {2542-4823},
abstract = {BACKGROUND: Deep cervical lymphaticovenular anastomosis (dcLVA) surgery is able to control aging-associated Alzheimer's disease in patients. However, the efficacy rate remains unknown.

OBJECTIVE: This study is designed to test the surgery efficacy in the treatment of mild-to-moderate AD patients.

METHODS: This is a single-center retrospective study of dcLVA treatment of mild-to-moderate AD for 3 months. A total of 41 patients received the surgery, in which lymph vessels and lymph nodes in the district III of cervical area were identified using indocyanine fluorescence dye. The afferent lymphatics of the obstructed lymph nodes were connected to the jugular vein to fix the lymphatic blockage under a fluorescent microscope. The efficacy rate was examined at 3-month post-surgery by clinical scores and biomarkers.

RESULTS: Lymph flow obstruction was observed on both sides of cervical area in the AD patients. The obstruction was successfully resolved through the surgery, and AD progression was attenuated or even reversed in the patients according to improvement in the scales of MMSE, ADL, NPI, CDR-SB, and CGI-EI. The average effectiveness rate was 50% by the CDR-SB score improvement. The efficacy was higher with shorter disease duration but not influenced by age and APOE4 genotype. Aβ42/40 ratio and p-tau181 were improved in more than 67% patients. There were 2 cases of mild adverse reactions that were controlled immediately by regular treatments.

CONCLUSIONS: The data demonstrate that dcLVA surgery is an effective and safe therapy for AD in mild-to-moderate patients with 50% efficacy rate as measured by improvement of the CDR-SB score.},
}

@article {pmid41048557,
year = {2025},
author = {Jeong, H and Kang, D and Kim, JE and Lim, J and Lee, HW},
title = {Preliminary study on the feasibility of virtual reality-based cognitive training on patients with mild to moderate Alzheimer's disease.},
journal = {Journal of Alzheimer's disease reports},
volume = {9},
number = {},
pages = {25424823251385901},
pmid = {41048557},
issn = {2542-4823},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease that causes a decline in cognitive functions, considerably affecting a patient's life. Recently, virtual reality (VR) technology has emerged as a new tool used in the cognitive training of patients with AD.

OBJECTIVE: This study aimed to investigate the safety, feasibility, and clinical efficacy of VR-based cognitive training for patients with mild to moderate AD.

METHODS: Thirteen participants diagnosed with mild to moderate AD underwent VR training sessions by using the MentiTree software. Each session was conducted for 30 min twice a week for 9 weeks (total of 540 min). Cognitive functions were assessed before and after the intervention.

RESULTS: Although 1 of the 13 participants experienced adverse effects, the 9-week cognitive training was well tolerated and had a high feasibility of 93%±24.65%. A tendency toward improvement was observed in the visual recognition memory of the participants (p = 0.034), but other domains did not significantly change.

CONCLUSIONS: VR-based cognitive training is safely accepted by patients with mild to moderate AD. The potential of VR in AD treatment should be further explored using a randomized control group.},
}

@article {pmid41048330,
year = {2025},
author = {Puducheri, S and Zhou, OT and Kapadia, K and Romano, MF and Yalamanchili, S and Agrawal, A and Carlota Andreu-Arasa, V and Farris, CW and Mian, AZ and Paul, AB and Rohatgi, S and Setty, BN and Small, JE and Kolachalama, VB},
title = {Augmenting radiological assessment of imaging evident dementias with radiomic analysis.},
journal = {NPJ dementia},
volume = {1},
number = {1},
pages = {27},
pmid = {41048330},
issn = {3005-1940},
abstract = {Accurate differential diagnosis of dementia is essential for guiding timely treatment, particularly as anti-amyloid therapies become more widely available and require precise patient characterization. Here, we developed a radiomics-based machine learning (ML) approach to enhance neuroimaging assessments in distinguishing Alzheimer's disease (AD) from other imaging-evident dementias (OIED). We retrospectively analyzed 1041 individuals from the National Alzheimer's Coordinating Center with confirmed dementia diagnoses and at least one T1 or T2/FLAIR MRI scan. Using FastSurfer and a Lesion Prediction Algorithm, we extracted volumetric and lesion features, which were then used to train ML models. Model performance was compared to the independent evaluations of seven fellowship-trained neuroradiologists. The classifier achieved an AUROC of 0.79 ± 0.01 for AD and 0.66 ± 0.03 for OIED, performing comparably to expert assessments. Interpretation using SHAP values showed strong alignment with imaging features known to align with AD or OIED, respectively. These findings highlight the potential of radiomics to augment neuroimaging workflows.},
}

@article {pmid41047765,
year = {2025},
author = {Jayarathne, H and Manchanayake, DH and Sullivan, R and Chimienti, N and Kadri, O and Gurdziel, K and Kim, S and Jang, H and Ginsburg, BC and Miller, RA and Yakar, S and Sadagurski, M},
title = {Canagliflozin Reprograms the Aging Hippocampus in Genetically Diverse UM-HET3 Mice and Attenuates Alzheimer's-Like Pathology.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70255},
doi = {10.1111/acel.70255},
pmid = {41047765},
issn = {1474-9726},
support = {P30ES020957/ES/NIEHS NIH HHS/United States ; R01ES033171/ES/NIEHS NIH HHS/United States ; RF1AG078170/AG/NIA NIH HHS/United States ; //Impetus Grants for Longevity Research/ ; },
abstract = {Aging is the strongest risk factor for cognitive decline and Alzheimer's disease (AD), yet the mechanisms underlying brain aging and their modulation by pharmacological interventions remain poorly defined. The hippocampus, essential for learning and memory, is particularly vulnerable to metabolic stress and inflammation. Canagliflozin (Cana), an FDA-approved sodium-glucose co-transporter 2 inhibitor (SGLT2i) for type 2 diabetes, extends lifespan in male but not female mice, but its impact on brain aging is unknown. Here, we used a multi-omics strategy integrating transcriptomics, proteomics, and metabolomics to investigate how chronic Cana treatment reprograms brain aging in genetically diverse UM-HET3 mice. In males, Cana induced mitochondrial function, insulin and cGMP-PKG signaling, and suppressed neuroinflammatory networks across all molecular layers, resulting in improved hippocampal-dependent learning and memory. In females, transcriptional activation of neuroprotective pathways did not translate to protein or metabolite-level changes and failed to rescue cognition. In the 5xFAD AD model, Cana reduced amyloid plaque burden, microgliosis, and memory deficits in males only, despite comparable peripheral glucose improvements in both sexes. Our study reveals sex-specific remodeling of hippocampal aging by a clinically available SGLT2i, with implications for AD pathology and lifespan extension, and highlights Cana's potential to combat brain aging and AD through sex-specific mechanisms.},
}

@article {pmid41047763,
year = {2025},
author = {Pinto, A and Haytural, H and Loss, CM and Alvarez, C and Ertas, A and Curtis, O and Williams, AR and Murphy, G and Salleng, KJ and Gografe, S and Visavadiya, NP and Khamoui, AV and Altıntaş, A and Kafri, T and Barres, R and Deshmukh, AS and van Praag, H},
title = {Muscle Cathepsin B Treatment Improves Behavioral and Neurogenic Deficits in a Mouse Model of Alzheimer's Disease.},
journal = {Aging cell},
volume = {},
number = {},
pages = {e70242},
doi = {10.1111/acel.70242},
pmid = {41047763},
issn = {1474-9726},
support = {NNF19SA0059305//Novo Nordisk Fonden/ ; NNF23SA0084103//Novo Nordisk Fonden/ ; NNF18CC0034900//Novo Nordisk Fonden/ ; RO1HL155986/HL/NHLBI NIH HHS/United States ; 9AZ02//Florida Department of Health/ ; },
abstract = {Increasing evidence indicates skeletal muscle function is associated with cognition. Muscle-secreted protease Cathepsin B (Ctsb) is linked to memory in animals and humans, but has an unclear role in neurodegenerative diseases. To address this question, we utilized an AAV-vector-mediated approach to express Ctsb in skeletal muscle of APP/PS1 Alzheimer's disease (AD) model mice. Mice were treated with Ctsb at 4 months of age, followed by behavioral analyses 6 months thereafter. Here we show that muscle-targeted Ctsb treatment results in long-term improvements in motor coordination, memory function, and adult hippocampal neurogenesis, while plaque pathology and neuroinflammation remain unchanged. Additionally, in AD mice, Ctsb treatment normalizes hippocampal, muscle, and plasma proteomic profiles to resemble that of wildtype (WT) controls. In AD mice, Ctsb increases the abundance of hippocampal proteins involved in mRNA metabolism and protein synthesis, including those relevant to adult neurogenesis and memory function. Furthermore, Ctsb treatment enhances plasma metabolic and mitochondrial processes. In muscle, Ctsb treatment elevates protein translation in AD mice, whereas in WT mice mitochondrial proteins decrease. In WT mice, Ctsb treatment causes memory deficits and results in protein profiles across tissues that are comparable to AD control mice. Overall, the biological changes in the treatment groups are consistent with effects on memory function. Thus, skeletal muscle Ctsb application has potential as an AD therapeutic intervention.},
}

@article {pmid41047679,
year = {2025},
author = {Wang, R and Yang, X},
title = {Research Progress on the Pathogenesis, Therapeutic Strategies, and Phthalocyanine Compounds for Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050406141250822082635},
pmid = {41047679},
issn = {1875-5828},
abstract = {Alzheimer's disease (AD) is a formidable and complex neurodegenerative disorder driven by multifactorial interactions, including amyloid-beta (Aβ) aggregation, neurofibrillary tangles, and neuroinflammation etc. Current therapies mainly consist of cholinesterase inhibitors and NMDA receptor antagonists, which can alleviate symptoms but fail to reverse disease progression. In recent years, emerging approaches such as immunotherapy and gene therapy have shown potential but remain in clinical exploration. Phthalocyanine (Pc) compounds, with their ability to inhibit Aβ fibril formation, favorable biocompatibility, and optical properties, have demonstrated potential in AD diagnosis and treatment. This review discusses the pathogenesis, therapeutic strategies, and research progress of Pc compounds in AD. Furthermore, the elucidation of their mechanisms of action, the optimization of blood-brain barrier penetration, and the promotion of clinical translation are needed to provide new directions for AD therapy.},
}

@article {pmid41047654,
year = {2025},
author = {Shichijo, F},
title = {[Precautions for Neurosurgeons in Administering Anti-Amyloid β Antibody Therapy].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {1000-1012},
doi = {10.11477/mf.030126030530051000},
pmid = {41047654},
issn = {0301-2603},
mesh = {Humans ; *Amyloid beta-Peptides/immunology ; *Alzheimer Disease/drug therapy/therapy ; *Neurosurgeons ; *Antibodies, Monoclonal/therapeutic use ; },
abstract = {In Japan, anti-amyloid β (Aβ) monoclonal antibodies, including lecanemab and donanemab, have recently been approved as disease-modifying therapies for early-stage Alzheimer's disease (AD). These drugs, developed based on the amyloid cascade hypothesis, target toxic Aβ aggregates: lecanemab selectively binds to soluble protofibrils, while donanemab targets Aβ plaques. The Ministry of Health, Labour and Welfare (MHLW) has issued Optimal Use Guidelines that specify criteria for administration: informed consent from both patients and caregivers; cognitive assessments (MMSE and CDR); confirmation of Aβ pathology via amyloid PET or cerebrospinal fluid (CSF) testing; and MRI screening to assess the risk of amyloid-related imaging abnormalities (ARIA). ARIA is a significant adverse event and requires regular MRI monitoring. Initial administration is limited to certified facilities staffed by experienced specialists and equipped with the necessary diagnostic infrastructure. After six months, treatment may be continued at collaborating institutions. The APOEε4 genotype is a known risk factor for ARIA but is not covered by insurance. Caution is advised when co-administering anticoagulants or antiplatelet agents. The guidelines also require the use of official treatment cards to inform healthcare providers. This article summarizes the clinical precautions, diagnostic requirements, and facility standards necessary for implementing anti-Aβ antibody therapy in accordance with current MHLW Guidelines in Japan.},
}

Humans
*Amyloid beta-Peptides/immunology
*Alzheimer Disease/drug therapy/therapy
*Neurosurgeons
*Antibodies, Monoclonal/therapeutic use

@article {pmid41047650,
year = {2025},
author = {Miyajima, M and Kawai, Y and Bandai, H},
title = {[Hydrocephalus and Dementia].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {969-974},
doi = {10.11477/mf.030126030530050969},
pmid = {41047650},
issn = {0301-2603},
mesh = {Humans ; *Dementia/etiology/diagnosis/surgery ; *Hydrocephalus, Normal Pressure/complications/surgery/diagnosis ; Neuropsychological Tests ; },
abstract = {Idiopathic normal pressure hydrocephalus (iNPH), also known as Hakim's disease, is a major cause of reversible dementia in adults. iNPH primarily affects frontal lobe-related cognitive functions, including attention, executive function, and working memory, even in early stages. Although memory impairment is also present, recognition memory is often preserved, distinguishing iNPH from Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD), especially apathy, depression, and anxiety, are common in iNPH and are generally less active than those seen in AD. Neuropsychological assessments reveal significant impairments in frontal lobe tests such as the Frontal Assessment Battery and Trail Making Test-B. Shunt surgery leads to substantial improvement in attention and executive function, reflecting the reversible nature of iNPH. However, memory functions, particularly delayed recall, show limited recovery, indicating possible overlap with neurodegenerative mechanisms. Early surgical intervention is associated with better outcomes, while delayed treatment or advanced brain atrophy may reduce effectiveness. Comprehensive cognitive evaluation is essential for assessing treatment response, planning rehabilitation, and providing appropriate patient and family guidance.},
}

Humans
*Dementia/etiology/diagnosis/surgery
*Hydrocephalus, Normal Pressure/complications/surgery/diagnosis
Neuropsychological Tests

@article {pmid41047647,
year = {2025},
author = {Ota, M and Arai, T},
title = {[Pharmacological Interventions in Dementia].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {943-950},
doi = {10.11477/mf.030126030530050943},
pmid = {41047647},
issn = {0301-2603},
mesh = {Humans ; *Dementia/drug therapy ; Cholinesterase Inhibitors/therapeutic use ; },
abstract = {Pharmacological interventions for dementia include medications aimed at alleviating its core symptom: cognitive dysfunction. These medicines are known as anti-dementia drugs. As our understanding of Alzheimer's disease (AD) has advanced, the amyloid hypothesis stating that amyloid proteins are involved in the pathogenesis of AD has been proposed. To date, anti-dementia drugs such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists have focused on symptomatic treatment. In recent years, based on the amyloid hypothesis, the development of medicines that target either (1) the enzyme that produces amyloid beta (Aβ) or (2) Aβ itself, has been promoted as a treatment strategy for AD. In 2021, the first drug targeting Aβ, aducanumab, was launched in the USA. In Japan, lecanemab and donanemab are now available as monoclonal antibodies targeting Aβ. Additionally, medications have been used to manage the behavioral and psychological symptoms of dementia (BPSD), Parkinsonism, and rapid eye movement sleep behavior disorder. Furthermore, dementia is a major risk factor for delirium, which often occurs during the course of dementia. In this study, we introduce pharmacotherapy with anti-dementia drugs, BPSD treatment, and delirium.},
}

Humans
*Dementia/drug therapy
Cholinesterase Inhibitors/therapeutic use

@article {pmid41047645,
year = {2025},
author = {Ishiguro, T and Kasuga, K},
title = {[Current Status and Future Perspectives of Biomarkers in Alzheimer's Disease Diagnosis].},
journal = {No shinkei geka. Neurological surgery},
volume = {53},
number = {5},
pages = {923-931},
doi = {10.11477/mf.030126030530050923},
pmid = {41047645},
issn = {0301-2603},
mesh = {Humans ; *Alzheimer Disease/diagnosis/metabolism ; *Biomarkers/cerebrospinal fluid/blood ; Amyloid beta-Peptides ; tau Proteins/blood ; },
abstract = {Alzheimer's disease (AD) is the most common cause of dementia, characterized by the pathological accumulation of amyloid-β (Aβ) and phosphorylated tau in the brain. Recent advances in biomarker technology have significantly improved AD diagnosis and treatment. Cerebrospinal fluid biomarkers and amyloid positron emission tomography imaging are now available in clinical settings and serve as key tools in identifying early-stage AD, especially when considering anti-Aβ monoclonal antibody therapies. In 2024, the Alzheimer's Association proposed revised diagnostic criteria that integrate both biomarker-based and clinical staging systems. This framework introduces a classification of "core biomarkers" that reflect AD-specific pathology and defines biological and clinical symptom stages. Furthermore, blood-based biomarkers, such as plasma p-tau217 and MTBR-tau243, are gaining attention as minimally invasive tools for early diagnosis and disease staging. As these biomarkers become more accessible, proper interpretation within a clinical context remains essential. In Japan, biomarker testing is currently recommended only for symptomatic individuals, and its use requires careful judgment regarding indications and relevance to the clinical setting. This review outlines the evolution of diagnostic criteria, current and emerging biomarkers, and their implications for personalized AD care while emphasizing the need for expert clinical interpretation to ensure responsible and patient-centric use.},
}

Humans
*Alzheimer Disease/diagnosis/metabolism
*Biomarkers/cerebrospinal fluid/blood
Amyloid beta-Peptides
tau Proteins/blood

@article {pmid41047224,
year = {2025},
author = {Graham, N and Zimmerman, K and Hain, J and Rooney, E and Lee, Y and Del Giovane, M and Parker, T and Wilson, M and Patel, M and Veleva, E and Swann, O and Heslegrave, AJ and Li, LM and Zetterberg, H and Friedland, D and Sylvester, R and Sharp, D},
title = {Midlife plasma proteomic profiles indicate altered amyloid and tau processing in former elite rugby players.},
journal = {Journal of neurology, neurosurgery, and psychiatry},
volume = {},
number = {},
pages = {},
doi = {10.1136/jnnp-2025-336593},
pmid = {41047224},
issn = {1468-330X},
abstract = {BACKGROUND: Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment.

METHODS: Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA - NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES).

RESULTS: 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau181 (p-tau181). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES.

CONCLUSIONS: Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau-181 more so than p-tau217 points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.},
}

@article {pmid41047041,
year = {2025},
author = {Fan, X and Wang, H and Ping, J and Li, M and Gu, J and Qian, W},
title = {Synaptic scaffold protein PSD-95: a therapeutic target for Alzheimer's disease.},
journal = {Biochemical pharmacology},
volume = {},
number = {},
pages = {117401},
doi = {10.1016/j.bcp.2025.117401},
pmid = {41047041},
issn = {1873-2968},
abstract = {Alzheimer's disease (AD) is a chronic neurodegenerative disorder marked by gradual cognitive deterioration and distinct neuropathological characteristics. The abnormal accumulation of amyloid-β (Aβ) and neurofibrillary tangles (NFTs) are the hallmarks of AD. In fact, synaptic loss and damage occur earlier than amyloid plaques and NFTs in the progression of AD and are most closely associated with the cognitive deficits exhibited by AD patients. In this review, we discuss the expression level, localization, posttranslational modification and interaction proteins of PSD-95, as well as their roles in synaptic plastisity. We also review the mechanisms through which PSD-95 contributes to synaptic dysfunction in AD. Moreover, the potential of PSD-95 as an early biomarker for AD is also discussed, along with the therapeutic approaches that target PSD-95 for patients afflicted with the disease. The objective of this review is to offer comprehensive insights into the early pathogenesis of Alzheimer's disease and to aid in the development of novel diagnostic and treatment methodologies grounded in this understanding.},
}

@article {pmid41046825,
year = {2025},
author = {Manful, EE and Adu-Amankwaah, F and Madhvi, A and Bubb, K and Pietersen, RD and Baker, B},
title = {Therapeutic potential of IFIT2 in human diseases.},
journal = {Cytokine},
volume = {196},
number = {},
pages = {157049},
doi = {10.1016/j.cyto.2025.157049},
pmid = {41046825},
issn = {1096-0023},
abstract = {The interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) is a crucial member of the interferon-stimulated gene (ISG) family, widely acknowledged for its antiviral activity. IFIT2 functions primarily through AU-rich RNA binding, aiding in viral suppression by inhibiting protein translation and promoting apoptosis via mitochondrial pathways. While traditionally known for its role in antiviral defence, emerging research highlights its broader significance in cancer, bacterial and fungal infections, autoimmune diseases, neurological disorders, and metabolic and cardiovascular conditions. Notably, IFIT2 is the only IFIT family member with established tumour suppressor properties, demonstrating anti-proliferative effects in multiple cancers, including lung, renal, colorectal, breast, and gallbladder cancers. Beyond oncology, IFIT2 has been implicated in the host response to Mycobacterium tuberculosis, Plasmodium spp., Candida albicans, and Treponema pallidum, where it modulates immune responses and infection outcomes. It is upregulated in several autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, and multiple sclerosis, suggesting its potential as a diagnostic and therapeutic biomarker. Furthermore, transcriptomic analyses have linked IFIT2 to disease progression and treatment response in conditions like diabetic ulcers, gestational diabetes, ischaemic cardiomyopathy, schizophrenia, and Alzheimer's disease. This review thoroughly examines the molecular structure, regulatory mechanisms, and diverse roles of IFIT2 in human diseases. It addresses its interaction with key immune pathways, its ability to modulate apoptosis and inflammation, and its potential as a prognostic marker and therapeutic target. Although its mechanistic functions in numerous diseases remain only partly understood, IFIT2 emerges as a versatile immune effector with considerable translational promise. Further investigation into its biological roles will be crucial for utilising its therapeutic potential across infectious, inflammatory, metabolic, and neoplastic diseases.},
}

@article {pmid41046632,
year = {2025},
author = {Fuh, JL and Wang, SJ and Wang, PN and Wu, HM and Su, WS and Lin, HM and Yang, FY},
title = {Safety and efficacy of transcranial ultrasound stimulation for the treatment of Alzheimer's disease: A randomized, double-blind, placebo-controlled trial.},
journal = {Ultrasonics},
volume = {159},
number = {},
pages = {107844},
doi = {10.1016/j.ultras.2025.107844},
pmid = {41046632},
issn = {1874-9968},
abstract = {Transcranial ultrasound stimulation (TUS) has emerged as a potential neuromodulatory intervention for Alzheimer's disease (AD). This pilot randomized, double-blind, placebo-controlled trial evaluated TUS's safety and preliminary efficacy in patients with mild AD. Patients aged 50-90 years were enrolled and randomly assigned at a 2:1 ratio to receive TUS treatment for 30 sessions (15 min/day, 5 days/week for 6 weeks) or a placebo procedure. Safety was monitored through magnetic resonance imaging, adverse event reporting, and laboratory assessments. Efficacy was assessed with the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini-Mental State Examination (MMSE). Nine of 30 patients screened were enrolled (six TUS, three placebo). All patients completed the study, and no serious clinical or radiographic adverse events related to TUS were observed. At 52 weeks, the change in ADAS-cog score from baseline remained relatively stable in the TUS group compared to worsening in the placebo group (0.5 ± 4.7 vs. 5.0 ± 4.0, p = 0.237), particularly in the memory domain. The change in MMSE score from baseline showed a significant benefit in the TUS group at 24 weeks compared to placebo (2.2 ± 2.2 vs. -3.0 ± 2.6, p < 0.05), and this improvement persisted to 52 weeks. This study demonstrates the safety and feasibility of repeated TUS sessions in AD and suggests potential benefits in preserving cognitive function. Larger, adequately powered trials are required to validate these preliminary findings and further define the therapeutic potential of TUS in AD.},
}

@article {pmid41046322,
year = {2025},
author = {Wu, KC and Lin, CY and Tran, T and Lin, JH and Yeh, HH and Ho, CJ and Chern, Y and Lin, CJ},
title = {Preclinical Evaluation of a Novel Molecule Targeting Nucleoside Homeostasis to Restore Energy Metabolism and Cognitive Function in Alzheimer's Disease.},
journal = {Pharmacology research & perspectives},
volume = {13},
number = {5},
pages = {e70176},
doi = {10.1002/prp2.70176},
pmid = {41046322},
issn = {2052-1707},
support = {AS-BRPT-110-11//Academia Sinica, Taiwan/ ; AS-KPQ-111-KNT//Academia Sinica, Taiwan/ ; MOST 110-3111-Y-001-002//Ministry of Science and Technology, Taiwan/ ; MOST 110-3111-Y-001-003//Ministry of Science and Technology, Taiwan/ ; },
mesh = {Animals ; *Alzheimer Disease/drug therapy/metabolism ; *Energy Metabolism/drug effects ; Mice ; Disease Models, Animal ; *Nucleosides/metabolism ; Homeostasis/drug effects ; Brain/metabolism/drug effects ; Mice, Transgenic ; *Cognition/drug effects ; Male ; Equilibrative Nucleoside Transporter 1/metabolism ; Mice, Inbred C57BL ; Humans ; Cognitive Dysfunction/drug therapy ; Positron-Emission Tomography ; },
abstract = {Alzheimer's disease (AD) is the most prevalent cause of dementia, characterized by progressive cognitive decline and cerebral metabolic impairment. Yet, the therapeutic options for addressing the disease pathogenesis are limited. Here, we report an approach by targeting brain nucleoside homeostasis and energy metabolism to alleviate AD-associated cognitive deficits. A compound, J4, was designed to modulate nucleoside homeostasis by interacting with the equilibrative nucleoside transporter-1 (ENT1). The effects of J4 on brain nucleoside homeostasis and energy metabolism were examined in mice. Two AD animal models, THY-Tau22 and APP/PS1 mice, were used to evaluate the translational potential of J4 for the treatment of AD. Cognitive function and functional ability were assessed using the Morris water maze, Y-maze, and nesting behavior tests. The pharmacodynamic marker was explored, and the pharmacokinetic and safety properties of J4 were evaluated. As a result, being administered after disease onset, oral J4 administration rescued memory and cognitive dysfunction in both tau and amyloid AD mouse models. Metabolomic analysis showed that J4 increased brain nucleoside levels and facilitated brain primary metabolism, including glucose metabolism and the pentose phosphate pathway. The [[18]F]-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging further demonstrated that glucose metabolism can be used as a pharmacodynamic biomarker for the target engagement of J4 on ENT1. The nonclinical studies also demonstrated the ideal pharmacokinetic and safety profiles of J4, supporting that targeting nucleoside homeostasis can improve brain energy metabolism and is a promising approach for AD treatment.},
}

Animals
*Alzheimer Disease/drug therapy/metabolism
*Energy Metabolism/drug effects
Mice
Disease Models, Animal
*Nucleosides/metabolism
Homeostasis/drug effects
Brain/metabolism/drug effects
Mice, Transgenic
*Cognition/drug effects
Male
Equilibrative Nucleoside Transporter 1/metabolism
Mice, Inbred C57BL
Humans
Cognitive Dysfunction/drug therapy
Positron-Emission Tomography

@article {pmid41046244,
year = {2025},
author = {Chatterjee, S and Soria, M and Norville, ZC and Thompson, KR and Lillie, J and Kreitzer, AC and Wood, MW},
title = {Preclinical efficacy of the muscarinic agonist ML-007 in psychosis models depends on both M1 and M4 receptors.},
journal = {Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {41046244},
issn = {1740-634X},
abstract = {Muscarinic agonists represent a new class of treatments for psychosis with a mechanism distinct from typical and atypical antipsychotics. The muscarinic subtype M4 has been proposed as the primary mediator of efficacy but results from recent clinical trials with M4-selective compounds have drawn this hypothesis into question. Instead, activation of both M1 and M4 receptor subtypes may be required for robust treatment effects. Here, we characterize the clinical-stage muscarinic agonist ML-007 in preclinical models and explore its therapeutic potential for treating psychosis in schizophrenia and Alzheimer's disease. ML-007 is a potent brain-penetrant agonist at both M1 and M4 muscarinic receptors that has demonstrated compelling efficacy across a range of preclinical models of psychosis in schizophrenia including amphetamine-induced hyperlocomotion, PCP-induced hyperlocomotion, and conditioned avoidance response. Moreover, ML-007 is approximately ten-fold more potent than the comparator xanomeline in all animal models. Dose-response experiments in M1 and M4 knockout mice reveal that the efficacy of ML-007 is dependent on both M1 and M4 receptors. Taken together, our data suggest that both M1 and M4 receptors contribute to the potent efficacy of ML-007 in preclinical rodent models of psychosis.},
}

@article {pmid41046022,
year = {2025},
author = {Zhou, X and Lin, X and He, Y and Huang, N and Luo, Y},
title = {TDP-43 in Alzheimer's disease: pathophysiology and therapeutic strategies.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {107977},
doi = {10.1016/j.phrs.2025.107977},
pmid = {41046022},
issn = {1096-1186},
abstract = {Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the dysregulation of multiple molecular mechanisms. In recent years, transactive response DNA-binding protein 43kDa (TDP-43) has increasingly been recognized as a critical pathological protein and has become a prominent focus in AD research. TDP-43 is involved not only in physiological processes such as RNA metabolism, protein quality control, and mitochondrial regulation but also in AD pathology through abnormal aggregation, dysregulated nucleocytoplasmic transport, and aberrant posttranslational modifications, leading to neurotoxicity, mitochondrial dysfunction, and disrupted protein homeostasis. Studies have shown that TDP-43 closely interacts with two core pathological hallmarks of AD, β-amyloid (Aβ) and tau. By promoting Aβ oligomerization and tau hyperphosphorylation, TDP-43 accelerates the pathological progression of this disease. Given the multifaceted role of TDP-43 in AD, therapeutic strategies targeting TDP-43 have shown great potential. Approaches such as modulating its RNA splicing activity, inhibiting pathological aggregation, restoring the balance of nucleocytoplasmic transport, and preventing its mitochondrial localization offer new avenues for AD treatment. This review systematically summarizes the pathological mechanisms of TDP-43 in AD and its interactions with Aβ and tau and discusses the feasibility of targeting TDP-43 as a therapeutic strategy. Future studies should further elucidate the role of TDP-43 in the early stages of AD and develop specific therapeutic agents that target TDP-43, with the aim of providing new insights for precision treatment of AD.},
}

@article {pmid41045719,
year = {2025},
author = {Swerdlow, NR and Sprock, J and Gonzalez, CE and Din, JM and Minhas, J and Talledo, J and Molina, JL and Joshi, YB and Léger, GC and Powell, L and Rana, B and Delano-Wood, L and Light, GA},
title = {Do cognitive and neurophysiological effects of acute memantine "challenge" predict its clinical benefits in Alzheimer's Disease?.},
journal = {Psychiatry research},
volume = {353},
number = {},
pages = {116740},
doi = {10.1016/j.psychres.2025.116740},
pmid = {41045719},
issn = {1872-7123},
abstract = {"Personalized" interventions based on patients' "biomarkers" may be valuable for treatments that benefit only subsets of patients. The NMDA antagonist, memantine, slows clinical progression of Alzheimer's disease (AD); this effect is heterogeneous in magnitude and duration. This study tested whether acute cognitive or neurophysiological responses to memantine challenge predicted sensitivity to memantine's therapeutic effects. Thirty individuals with mild-to-moderate severity AD (M:F = 13:17) and 24 comparably aged healthy subjects (HCS) (M:F = 12:12) were enrolled. Participants with AD were characterized on 9 experimental measures and their changes after acute memantine "challenge" (20 mg). We then assessed whether acute memantine effects on these measures predicted clinical change over a 24-week open-label trial of memantine. Baseline cognitive (Repeatable Battery for the Assessment of Neuropsychological Status) and neurophysiological measures (prepulse inhibition, P3a latency and auditory steady state response power and coherence) were impaired in participants with AD (p's<0.05-0.0001); neurophysiological deficits were modestly reduced by acute memantine challenge. As a group, participants with AD showed no significant clinical changes across 24 weeks of memantine treatment; subgroups exhibited either small gains or deterioration. With one exception (mismatch negativity latency, p < 0.017), sensitivity of experimental measures to acute memantine challenge did not significantly predict clinical sensitivity to memantine. In summary, a challenge dose design identified neurophysiological measures sensitive to memantine in mild-to-moderate severity AD; acute memantine effects on one measure weakly predicted clinical outcomes over 24 weeks. Impairment in specific measures among participants with AD, and their opposition by memantine, might inform future efforts to identify treatment biomarkers in AD.},
}

@article {pmid41045350,
year = {2025},
author = {Alsaadi, T and Almadani, A and AlRukn, S and Hassan, A and Sarathchandran, P and Shatila, A and Szolics, M and Benito, D and Ince, S and Krieger, DW},
title = {Expert Guidance on Cognitive Impairment in Alzheimer's Disease: A Practical Seven-Step Approach from the United Arab Emirates.},
journal = {Neurology and therapy},
volume = {},
number = {},
pages = {},
pmid = {41045350},
issn = {2193-8253},
abstract = {INTRODUCTION: Cognitive impairment (CI) spans a spectrum from mild CI to severe dementia, with Alzheimer's disease (AD) the most prevalent cause of CI and dementia. Although dementia burden and prevalence in Arab countries reflect general global trends, the United Arab Emirates (UAE) differs from Western countries both culturally and regarding management resources. Further guidance is therefore needed for the diagnosis and management of CI in the UAE.

METHODS: A task force of eight neurologists and two non-voting collaborators with special dementia expertise was convened to develop evidence-based position statements/recommendations to guide the diagnosis and management of AD, including the use of amyloid-targeting therapies (ATTs), in the UAE clinical setting. A modified Delphi survey method was chosen to obtain a consensus, ensuring that drafted expert statements reflected diverse perspectives and experiences. Discordance was predefined as > 25% of panelists rating an expert statement as ≤ 3 on the Likert scale. Consensus was predefined as a median rating ≥ 7 without discordance. Expert statements achieving consensus were adopted.

RESULTS: A seven-step framework for diagnosing and managing CI in the UAE was developed, with consensus achieved on all statements. Recommendations largely aligned with international guidelines on AD dementia management and treatment, combined with UAE-specific guidance. The framework spans the full patient journey from initial symptoms to diagnosis (including biomarker use), initial treatment (including ATTs where appropriate), and subsequent monitoring and management as the disease progresses.

CONCLUSIONS: Management of CI and dementia in UAE requires consideration of international guidelines in the context of regional and local cultural sensitivities and healthcare resources. A holistic approach is recommended, combining appropriate pharmacological treatment with lifestyle interventions, education, and support for patients and care partners. Patients require ongoing monitoring to ensure the approach is tailored to the disease stage and provides optimal quality of life and reduced burden for patients and care partners.},
}

@article {pmid41044993,
year = {2025},
author = {Yan, Q and Qin, Q and Zhang, S and Chen, F and Ru, Y and Zhong, Y and Wu, G},
title = {Glial cell nutrient sensing: mechanisms of nutrients regulating Alzheimer's pathogenesis and precision intervention.},
journal = {Critical reviews in food science and nutrition},
volume = {},
number = {},
pages = {1-17},
doi = {10.1080/10408398.2025.2568606},
pmid = {41044993},
issn = {1549-7852},
abstract = {Modern nutrition is a core element of clinical treatment. Although some literature addresses neuro-nutrition's effects on Alzheimer's disease (AD), a systematic discussion of how the body's six essential nutrients impact AD is lacking. Moreover, neural glial cells directly participate in the pathological regulation of AD. A novel conceptual framework linking "essential nutrients - glial cells - AD" needs to be summarized. Therefore, this review examines the regulatory roles of glial cells (astrocytes, microglia, and their networks) in AD and explores how essential nutrients impact AD via glial cells. Specifically, vitamins (NR, NMN, etc.), minerals (copper, iron, selenium, etc.), proteins and amino acids (arginine, citrulline, methionine, etc.), lipids (fatty acids, phosphatidylinositol, etc.), and carbohydrates (trehalose, oligosaccharides, plant polysaccharides, etc.) can influence important functions such as brain energy metabolism remodeling, inflammatory factor secretion, and phagocytic clearance by regulating microglia and astrocytes. Moreover, a significant strength of this review is its clear exposition of nutrient alterations observed in AD patients, coupled with detailed recommendations for nutritional interventions targeting AD prevention and management. Furthermore, it also investigated beneficial dietary patterns for improving AD. In conclusion, this review explores the "essential nutrients -glial cell" molecular interactions, laying the foundation for precision nutrition-based AD strategies.},
}

@article {pmid41042852,
year = {2025},
author = {Bellaflor, S and Barfoot, MK and Boddy, J and Wallace, PJ and Baranowski, RW and Cheung, SS and Fajardo, VA and MacPherson, REK},
title = {Heat therapy increases brain HSP-70 and BDNF content in male mice.},
journal = {Journal of neurophysiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/jn.00301.2025},
pmid = {41042852},
issn = {1522-1598},
support = {2017-03904//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2019-05833//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; 2018-04077//Canadian Government | Natural Sciences and Engineering Research Council of Canada (NSERC)/ ; },
abstract = {Heat shock proteins (HSPs) are molecular chaperones that play important roles in protein homeostasis, with HSP70 linked to a role in neuroprotection. HSP70 is upregulated in response to various stressors, such as heat therapy (HT), which has been shown to increase brain-derived neurotrophic factor (BDNF) content. BDNF reduces the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the rate-limiting enzyme responsible for the generation of amyloid-β (Aβ) peptides that form the characteristic Aβ plaques observed in Alzheimer's disease brains. The current pilot study examined whether 4 weeks of HT can increase HSP70 and BDNF content (pro and mature forms) in the brain, as well as alter markers of amyloid precursor protein (APP) processing. Male mice had their core temperature maintained between 37.0-38.0° in Control (CON, n = 16) and 40.5-41.5° in Heat Therapy (HT, n = 16) for 20-minutes every 72 hours over 4-weeks. 72 hours after the last treatment, the prefrontal cortex (PFC) and hippocampus (HIP) were collected. HT significantly increased HSP70 levels in both the hippocampus and prefrontal cortex compared to controls (p = 0.0007, PFC CON=1.001 [0.314], PFC HT=1.546 [0.948], HIP CON=1.000 [0.356], HIP HT=2.207 [0.756]). In the HIP, proBDNF levels were also higher in the HT group relative to both the control group and the PFC (p < 0.05, PFC CON=1.000 [0.156], PFC HT = 0.984 [0.607], HIP CON=1.001 [0.242], HIP HT=1.575 [0.482]. There were no differences in mature BDNF in either PFC or HIP regions (p>0.05, PFC CON=1.000 [0.273], PFC HT=1.174 [0.266], HIP CON=0.999 [0.130], HIP HT=0.971 [0.207]), The findings from our pilot study suggest that HT enhances the expression of HSP70 and BDNF, indicating the potential to modulate key neuroprotective proteins. Future studies in dedicated preclinical mouse models of Alzheimer's disease using heat therapy regimen are warranted.},
}

@article {pmid41039568,
year = {2025},
author = {Wu, H and Qiu, Z and Mu, J and Wang, Y and Wang, J and Han, Y and Yang, R and Yuan, S and Yuan, M and Yang, R and Chen, X and Sun, Q and Li, F and Xiao, L and Zhang, M and Xu, J},
title = {Salt-sensitive hypertension promotes neuronal mitochondrial stress and neurodegenerative alterations via neuro-vascular metabolic reprogramming and local RAS signaling.},
journal = {Journal of neuroinflammation},
volume = {22},
number = {1},
pages = {220},
pmid = {41039568},
issn = {1742-2094},
support = {XJTU1AF-CRF-2023-021//The First Affiliated Hospital of Xi'an Jiaotong University/ ; 32271016//National Natural Science Foundation of China/ ; 81803026//National Natural Science Foundation of China/ ; 82071879//National Natural Science Foundation of China/ ; 82100454//National Natural Science Foundation of China/ ; 2023PT-09//the Health Research and Innovation Capacity Strengthening Platform Program of Shaanxi Province/ ; },
abstract = {UNLABELLED: Hypertension increases risks for cognitive impairment and Alzheimer’s disease (AD). In renal patients with both hypertension and cognitive decline, via rest-state fMRI, their cerebral cortical region showed maintained cerebral blood flow (CBF), but reduced signals of blood-oxygen-level-dependent (BOLD). In mice, although CBF was unchanged, deoxycorticosterone acetate (DOCA)-salt treatment markedly reduced cerebrovascular reactivity, with altered transcriptomic pattern in cortical endothelial cells (ECs) and astrocytes, showing downregulated expression of glucose transport 1 (GluT1) but upregulated metabolic reprogramming. Lipidomic analysis using prefrontal cortex (PFC) further revealed enhanced catabolism of glycerophospholipids and accumulation of free fatty acids. In the PFC of hypertensive mice, neurodegenerative alterations were observed, including reduced number of neuronal dendritic spines and more expression of phosphorylated Tau (p-Tau). Via both morphological and molecular tests, we identified that DOCA-salt hypertension was associated with significant mitochondrial injury and upregulated lysine succinylation in the PFC neurons. Upregulated lysine succinylation was largely mitochondria-located, and they were functionally enriched in gluconeogenesis-related energy metabolic pathways, the tricarboxylic acid (TCA) cycle, oxidative stress, and neurodegenerative diseases. In hypertensive mice, angiotensinogen (Agt) expression was markedly upregulated in most astrocytes, together with neuronal expression of Agtr1a. In cultured neuronal cells, angiotensin II (ang II) elevated mitochondrial membrane potential and ATP biosynthesis. In mice with neuronal AT1aR knockout (AT1N), DOCA-salt failed to induce cognitive impairment. Additionally, DOCA-salt-associated reduction of acetylcholine, accumulation of p-Tau, and upregulation of lysine succinylation were not observed in AT1N mice. Direct anti-hypertensive treatment did not abolish DOCA-salt-related pathological phenotypes, and enhanced lysine succinylation was not detected in hypertension models induced by norepinephrine or L-NAME. Our data provide evidence that hypertension induced metabolic rearrangement (enhanced energy metabolism from non-glucose source and upregulated mitochondrial oxidative phosphorylation) in the neuro-vascular unit, due to downregulated glucose uptake in ECs. Increased neuronal energy consumption, via local ang II/AT1R signaling, further exacerbated mitochondrial stress and neurodegenerative alterations. Together, by multi-omics analysis, this study provided novel insights regarding how hypertension increases the risk for age-related cognitive impairment.

GRAPHICAL ABSTRACT: [Image: see text]

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-025-03533-0.},
}

@article {pmid41042837,
year = {2025},
author = {Boongird, C and Anothaisintawee, T and Tearneukit, W and Wongpipathpong, W and Suthutvoravut, U and Thongpan, M and Pongsettakul, N and Attia, J and McKay, GJ and Rattanasiri, S and Thakkinstian, A},
title = {Bridging the gap: Efficacy of combined therapies for cognitive, behavioral, and functional outcomes in Alzheimer's disease - results from a systematic review and network meta-analysis.},
journal = {Journal of Alzheimer's disease : JAD},
volume = {},
number = {},
pages = {13872877251378354},
doi = {10.1177/13872877251378354},
pmid = {41042837},
issn = {1875-8908},
abstract = {BackgroundEvidence regarding efficacy of combined pharmaco- and non-pharmacotherapies and their comparative effectiveness for Alzheimer's disease (AD) is limited.ObjectiveTo estimate the comparative efficacy of pharmacotherapies, non-pharmacotherapies, and combined therapies for improving cognitive, behavioral, and functional outcomes in patients with AD.MethodsRelevant studies were identified from Medline via PubMed and Scopus databases (March 2021-December 2022). Randomized-controlled trials were eligible if they assessed the efficacy of pharmacotherapies, non-pharmacotherapies, or combined therapies in patients aged 60 years or older, and measuring cognitive, behavioral, or functional outcomes. A network meta-analysis was conducted to estimate relative treatment effects, and interventions were ranked using surface under the cumulative ranking (SUCRA) curve. Confidence in the findings was evaluated using the Confidence in Network Meta-Analysis (CINeMA) framework.ResultsA total of 153 randomized-controlled trials were analyzed. Compared to placebo/usual care, donepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation significantly improved Mini-Mental State Examination scores. Behavioral outcomes were improved by rivastigmine plus cognitive stimulation, brain stimulation plus exercise, and occupational therapy. Functional status improved significantly with rivastigmine plus cognitive stimulation and exercise. Based on SUCRA ranking, rivastigmine plus cognitive rehabilitation ranked highest for cognitive improvement (92.8%), brain stimulation plus exercise ranked highest for the behavioral outcome (93.1%), and rivastigmine plus cognitive stimulation ranked highest for functional improvement (94.1%).ConclusionsDonepezil plus cognitive therapy and rivastigmine plus cognitive rehabilitation were the most effective treatments for improving cognitive outcomes. Rivastigmine plus cognitive stimulation ranked highest for both behavioral and functional outcomes, while exercise remains an important strategy for supporting daily functioning in patients with AD.},
}

@article {pmid41042700,
year = {2025},
author = {Xu, X and Tan, H and Yin, K and Xu, S and Wang, Z and Serrano, GE and Beach, TG and Wang, X and Peng, J and Wu, R},
title = {Comprehensive and Site-Specific Characterization of Protein N-Glycosylation in AD Samples Reveals Its Potential Roles in Protein Aggregation and Synaptic Dysfunction.},
journal = {Analytical chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.analchem.5c02455},
pmid = {41042700},
issn = {1520-6882},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Emerging evidence strongly suggests that protein glycosylation is strongly related to this disease. However, the extent and functional consequences of site-specific N-glycosylation alterations in AD remain to be further explored. Here, we employed a dendrimer boronic acid (DBA)-based enrichment strategy combined with multiplexed proteomics to systematically analyze protein N-glycosylation in post-mortem human brain tissues. We identified 3,105 N-glycosylation sites on 1,299 glycoproteins from nine AD cases and nine healthy controls, and performed a systematic and site-specific investigation of glycosylation alterations in AD. Glycoproteins involved in cholesterol efflux were upregulated, whereas those associated with chemical synaptic transmission and ion transport were significantly downregulated in AD compared to control brain samples. We observed widespread dysregulation of N-glycosylation across multiple protein domains, particularly in the ConA-like lectins/glucanases and Zn-dependent exopeptidases domains. Notably, we identified 161 N-glycosylation sites located within aggregation-prone regions (APRs), and reduced glycosylation at APRs on plaque-associated glycoproteins may be associated with protein aggregation and plaque formation. Additionally, downregulated N-glycosylation sites were enriched in synaptic membrane proteins, such as Ca[2+] ion channels, GABA-gated chloride channels, and glutamate receptors, implicating glycosylation loss in synaptic dysfunction. Our findings suggest that the loss of N-glycosylation may contribute to the pathogenesis of AD through impairing synaptic transmission and promoting protein aggregation. This study provides novel insights into glycosylation-dependent mechanisms of neurodegeneration, highlighting N-glycosylation as a potential therapeutic target for AD treatment.},
}

@article {pmid41042497,
year = {2025},
author = {Schreiber, CP and Kovacik, A and Bishop, J and Helman, J},
title = {Amyloid-related Imaging Abnormalities (ARIA) in the Context of Alzheimer's Disease and Amyloid-targeting Therapies: An Introduction for Advanced Practice Providers.},
journal = {Drugs & aging},
volume = {},
number = {},
pages = {},
pmid = {41042497},
issn = {1179-1969},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the accumulation of amyloid-beta (Aβ) and neurofibrillary tangles of hyperphosphorylated tau in the brain. Amyloid-targeting therapies (ATTs) are the first available disease-modifying treatments shown to slow cognitive and functional decline for patients with mild cognitive impairment owing to AD and early symptomatic AD. Currently two ATTs are commercially available, donanemab (Kisunla™) and lecanemab (Leqembi[®]). The main potential side effect and safety concern of ATT treatment is amyloid-related imaging abnormalities (ARIA). ARIA can be categorized into two types that can co-occur: ARIA-E (edema/sulcal effusion) and ARIA-H (hemorrhage/superficial siderosis). Although both are often asymptomatic and ARIA-E typically resolves radiographically over time, both forms can be radiologically and/or clinically serious. Treating clinicians should be equipped with a comprehensive understanding of ARIA. This review aims to provide advanced practice providers, who are pivotal to patient care in AD, with critical insights into ARIA to safely identify risk factors, understand treatment guidelines, and gain familiarity with appropriate management strategies. It emphasizes the importance of understanding APOE genotype and vascular factors in ARIA risk and recognizing the clinical and radiographic manifestations of ARIA. Practical recommendations are provided for monitoring and managing ARIA, including dose management strategies and education on symptom awareness. By fostering a comprehensive understanding of ARIA and its monitoring and management, this review aims to support the safe and effective implementation of ATTs, contributing to optimized patient care for those treated with ATTs.},
}

@article {pmid41042431,
year = {2025},
author = {Shah, N and Natesan, G and Gupta, R},
title = {Uncovering Necroptosis in Alzheimer's Disease: A Systematic Review of Evidence Across Experimental Models.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {83},
pmid = {41042431},
issn = {1573-6830},
mesh = {*Necroptosis/physiology ; *Alzheimer Disease/pathology/metabolism ; Humans ; Animals ; Disease Models, Animal ; Signal Transduction ; },
abstract = {Alzheimer's disease (AD), one of the most challenging neurodegenerative disorders, with high prevalence worldwide, is characterized by progressive cognitive decline and accumulation of amyloid-β plaques and neurofibrillary tau tangles. Despite significant research, the limited efficacy of current treatments underscores the critical need to identify novel pathogenic mechanisms and therapeutic targets. Necroptosis, a regulated and highly inflammatory form of programmed cell death, has emerged as one of the key contributors to AD pathogenesis. This systematic review comprises 25 high-quality in vivo, in vitro, and autopsy studies, published between 2015 and 2025, extracted from PubMed, Scopus, and Science Direct databases. The keywords include "necroptosis", "RIPK1", "RIPK3", "MLKL", "pMLKL", "necroptosis inhibitors", "Alzheimer's disease", and "neurodegeneration". The review summarizes the multiple molecular mechanisms, including TNF-α/TNFR1 signaling, TRIF-mediated RIPK3 activation, and RHIM-dependent MLKL phosphorylation, associated with necroptosis in the pathogenesis of AD. All the studies converge on necroptosis as a central pathogenic pathway linking key molecular and cellular abnormalities observed in AD. The accumulated evidence strongly supports prioritizing the development of brain-penetrant necroptosis inhibitors and clinical validation of associated biomarkers. These insights signal a significant shift in AD therapeutics, moving from symptomatic treatment to mechanistically targeted interventions that can alter disease progression.},
}

*Necroptosis/physiology
*Alzheimer Disease/pathology/metabolism
Humans
Animals
Disease Models, Animal
Signal Transduction

@article {pmid41041548,
year = {2025},
author = {Trigiani, L and Chernavsky, N and Kim, R and Hong, N and Hawkins, R and Le, E and Bahninameh, Z and Yamaguchi, K and Bernard, J and Huang, A and Rivera, D and Allan-Rahill, N and Lamont, M and Marongiu, R and Iadecola, C and Nishimura, N and Schaffer, C},
title = {Memory deficits in hypertensive ApoE4 mice reversed by P2Y12 inhibition via different mechanisms in males and perimenopausal females.},
journal = {Research square},
volume = {},
number = {},
pages = {},
doi = {10.21203/rs.3.rs-7643285/v1},
pmid = {41041548},
issn = {2693-5015},
abstract = {Apolipoprotein E4 (ApoE4) genotype, hypertension, and biological sex are critical risk factors for Alzheimer's disease and related dementias. Yet, their combined impact on early cerebrovascular dysfunction, brain inflammation, and memory impairment remains poorly understood. We developed a translational mouse model incorporating human ApoE4, hypertension via angiotensin II infusion, and induced accelerated ovarian failure (AOF) to mimic perimenopause in females to investigate these interactions. Hypertensive ApoE4 mice of both sexes exhibited impaired spatial working memory, decreased cerebral blood flow, increased neuroinflammation, and decreased blood brain barrier integrity, recapitulating key early clinical features observed in human populations with these risk factors. Brain blood flow reduction was associated with an increased incidence of capillary stalling, with notable sex differences in the extent and cellular composition of stalls: in males, stalling was strongly elevated and mostly due to red blood cell arrest, while stalling was modestly elevated in peri-AOF females with most stalls including leukocytes. Treatment with prasugrel, a P2Y12 receptor inhibitor, improved memory performance in both sexes but was correlated with different physiological effects - restored cerebral blood flow in males and reduced microglia motility and inflammation in peri-AOF females. Platelet depletion mimicked prasugrel's blood flow and cognitive benefits in males, while microglia depletion selectively rescued memory in females. Our work emphasizes the necessity of including translationally relevant female mouse models in neurodegenerative disease studies, and our findings highlight the importance of risk profile-specific interventions and demonstrate that early vascular dysfunction may be a key, sex-dependent driver of cognitive decline.},
}

@article {pmid41040848,
year = {2025},
author = {Kumar, A and Pichet Binette, A and Bali, D and Janelidze, S and Stomrud, E and Palmqvist, S and Vogel, JW and Hansson, O and Mattsson-Carlgren, N},
title = {Cell-weighted polygenic risk scores are associated with β-amyloid and tau biomarkers in Alzheimer's disease.},
journal = {Brain communications},
volume = {7},
number = {5},
pages = {fcaf353},
pmid = {41040848},
issn = {2632-1297},
abstract = {The molecular pathways influencing the build-up of β-amyloid and tau pathology in Alzheimer's disease are unclear. To investigate how the involvement of different cell types influences β-amyloid and tau, we utilized single-cell RNA-seq data to derive cell-weighted polygenic risk scores. We included participants from the BioFINDER-1 study, including cognitively unimpaired (N = 734) individuals and patients with mild cognitive impairment (N = 235), Alzheimer's diseasedementia (N = 97) or non-Alzheimer's disease neurodegenerative diseases (N = 227). We developed seven polygenic risk scores, including six cell-weighted (for astrocytes, excitatory neurons, inhibitory neurons, microglia, oligodendrocyte precursor cells and oligodendrocytes) and one full polygenic risk score without cell specificity. For each of the polygenic risk score models, we calculated seven scores (polygenic risk score 1-7) based on different P-value thresholds (ranging from P-value < 0.05 to P-value < 5e-08) of variants from an independent large Alzheimer's disease genome-wide association study. We tested associations between the polygenic risk scores with β-amyloid [using cerebrospinal fluid (CSF) β-amyloid1-42/β-amyloid1-40], tau (using CSF pTau217) and cognitive measures (Mini-Mental State Examination score and Preclinical Alzheimer Cognitive Composite) using regression models adjusting for age, sex and the top genotype principal components. We also replicated the polygenic risk score association with β-amyloid (CSF β-amyloid1-42/β-amyloid1-40) and tau (CSF pTau217) in an independent cohort (BioFINDER-2), including cognitively unimpaired (N = 773) individuals and patients with mild cognitive impairment (N = 358), Alzheimer's disease dementia (N = 286) or non-Alzheimer's disease neurodegenerative diseases (N = 319). We observed differential cellular effects on β-amyloid, pTau217 and cognitive measures. There are substantial effects of neuronal-specific polygenic risk scores on β-amyloid, pTau217 and cognitive measures. The microglial-polygenic risk scores showed more significant effects on pTau217 than on β-amyloid. β-Amyloid positivity partly mediated the associations between polygenic risk scores and pTau217, with the lowest mediation effect observed for the microglial-polygenic risk scores (on average 33%). Cell-weighted gene expression has differential effects on pathological β-amyloid and tau metabolism, as well as cognitive decline. Cell-weighted gene expression related to microglia is preferentially relevant for the metabolism of soluble phosphorylated tau through partly β-amyloid-independent mechanisms. Cell-weighted gene expression related to neurons shows the strongest associations with cognition. These findings inform further studies that address specific cell types for various aspects of Alzheimer's disease, including the development of novel treatment strategies.},
}

@article {pmid41040192,
year = {2025},
author = {Scheidemantel, LP and de Paiva Lopes, K and Gaiteri, C and Menon, V and De Jager, PL and Schneider, JA and Buchman, AS and Wang, Y and Tasaki, S and Raittz, RT and Bennett, DA and Vialle, RA},
title = {Integration of aged brain multi-omics reveals cross-system mechanisms underlying Alzheimer's disease heterogeneity.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.1101/2025.09.23.678110},
pmid = {41040192},
issn = {2692-8205},
abstract = {The molecular correlates of Alzheimer's disease (AD) are increasingly being defined by omics. Yet, the findings from different data types or cohorts are often difficult to reconcile. Collecting multiple omics from the same individuals allows a comprehensive view of disease-related molecular mechanisms, while addressing conflicting findings derived from single omics. Such same-sample multi-omics can reveal, for instance, when changes observed in the transcriptome share distinct but coordinated signals in epigenetics and proteomics, relationships otherwise unclear. Here, we apply a data-driven multi-omic framework to integrate epigenomic, transcriptomic, proteomic, metabolomic, and cell-type-specific population data from up to 1,358 aged human brain samples from the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). We demonstrate the existence of sprawling cross-omics cross-system biological factors that also relate to AD phenotypes. The strongest AD-associated factor (factor 8) involved elevated immune activity at the epigenetic level, decreased expression of heat shock genes in the transcriptome, and disrupted energy metabolism and cytoskeletal dynamics in the proteome. We also showed immune-related factors (factors 2 and 3) with discordant enrichments, reflecting reactive-like glial subpopulations and protective contributions from surveillance microglia. Both were negatively associated with AD pathology, suggesting potential immune resilience mechanisms. Finally, unsupervised clustering of participants revealed eleven molecular subtypes of the aging brain, including three clusters strongly associated with AD but displaying distinct molecular signatures and phenotypic characteristics. Our findings provide a comprehensive map of molecular mechanisms underlying AD heterogeneity, highlighting the complex role of neuroinflammatory processes, and yielding potential novel biomarkers and therapeutic targets for precision medicine approaches to AD treatment.},
}

@article {pmid41039514,
year = {2025},
author = {El-Nagah, SMA and Abdel-Halim, M and Heikal, OA and AbdelKader, RM},
title = {Neuroprotective role of rice bran extract and its constituents in a neuroinflammatory mouse model.},
journal = {BMC complementary medicine and therapies},
volume = {25},
number = {1},
pages = {351},
pmid = {41039514},
issn = {2662-7671},
mesh = {Animals ; Mice ; *Neuroprotective Agents/pharmacology ; *Oryza/chemistry ; *Plant Extracts/pharmacology/chemistry ; Disease Models, Animal ; PPAR gamma/metabolism ; Male ; *Neuroinflammatory Diseases/drug therapy ; Brain/drug effects/metabolism ; Amyloid beta-Peptides/metabolism ; Mice, Inbred C57BL ; Alzheimer Disease/drug therapy ; },
abstract = {BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor known to play a critical role in regulating neuroinflammation and neurodegenerative processes, including Alzheimer's disease. Prior studies from our group demonstrated that rice bran extract (RBE) enhances cognitive function and increases PPARγ DNA-binding activity in the brain, effects that were abolished by PPARγ antagonism. These findings suggest that bioactive constituents within RBE may modulate PPARγ signaling. The current study aimed to provide additional evidence for the involvement of PPARγ activation in the neuroprotective effects of RBE and to identify key RBE-derived components that may contribute to these effects.

METHODS: A neuroinflammatory mouse model was treated orally for 21 consecutive days with RBE. The brain CD36 and amyloid-beta (Aβ) protein levels were measured. HPLC and GC were used to assess the levels of RBE components. To measure alterations in fatty acid content after treatment with RBE, brain levels of DHA, EPA and AA were assessed using UHPLC/MS-MS.

RESULTS: RBE treatment increased the brain levels of CD36, the direct PPARγ target, and decreased Aβ levels. A strong correlation was detected between the Aβ and CD36 protein levels. As RBE was found to be rich in linolenic acid (ALA), linoleic acid (LA) and oleic acid, their metabolites concentrations in mice brain were measured, and results indicated higher concentration of EPA and DHA after RBE treatment.

CONCLUSIONS: RBE exerts neuroprotective effects potentially through activation of the PPARγ pathway, as evidenced by CD36 upregulation and Aβ reduction. The enrichment of RBE in polyunsaturated fatty acids (PUFAs), along with the observed increase in their brain-penetrant metabolites (EPA and DHA), suggests these lipids may contribute to the cognitive benefits of RBE.},
}

Animals
Mice
*Neuroprotective Agents/pharmacology
*Oryza/chemistry
*Plant Extracts/pharmacology/chemistry
Disease Models, Animal
PPAR gamma/metabolism
Male
*Neuroinflammatory Diseases/drug therapy
Brain/drug effects/metabolism
Amyloid beta-Peptides/metabolism
Mice, Inbred C57BL
Alzheimer Disease/drug therapy

@article {pmid41038644,
year = {2025},
author = {Rohatgi, S and Zhu, S and Calle Cadavid, E and Ford, JN and Kozak, BM and Ganem Chagui, O and Vejdani-Jahromi, M and Griffin, HR and Farzaneh, H and Huang, RY and Seah, JC and Omid-Fard, N and Gomez-Isla, T and Dickson, JR and Ramírez Gómez, L and Romero, JM},
title = {Are Deep White Matter Hyperintensities Associated with Amyloid-Related Imaging Abnormalities in Patients with Alzheimer Disease Treated with Lecanemab?.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A8822},
pmid = {41038644},
issn = {1936-959X},
abstract = {BACKGROUND AND PURPOSE: Amyloid-related imaging abnormalities (ARIA) are common complications of antiamyloid immunotherapy for Alzheimer disease (AD). Identifying imaging biomarkers that predict ARIA risk may help guide treatment decisions. This study investigates the relationship between deep white matter hyperintensities (DWMH), perivascular spaces (PVS), and ARIA incidence in patients with AD treated with lecanemab.

MATERIALS AND METHODS: This retrospective cohort study included 27 ARIA-positive patients identified between November 2023 and November 2024, and 27 age- and sex-matched ARIA-negative controls. Baseline MRI was assessed for DWMH burden (Fazekas score) and PVS grades in the basal ganglia and centrum semiovale. Simple logistic regression was performed to evaluate associations between imaging markers and ARIA risk.

RESULTS: ARIA-positive patients had significantly higher Fazekas scores compared with ARIA-negative patients (1.37 versus 1.0; P = .0262), indicating a greater DWMH burden. PVS grades in the basal ganglia were numerically higher in ARIA-positive patients (1.81 versus 1.56, P = .0733) but did not reach statistical significance. Simple logistic regression identified the Fazekas score as a significant predictor of ARIA (OR: 2.812; 95% CI, 1.076-8.438; P = .0343). The area under the receiver operating characteristic curve for the model was 0.640 (95% CI, 0.492-0.788; P = .078).

CONCLUSIONS: Higher DWMH burden, as quantified by the Fazekas score, is significantly associated with ARIA risk in patients with AD treated with lecanemab. These findings suggest that DWMH may serve as a potential imaging biomarker for ARIA risk stratification. Larger studies incorporating additional vascular biomarkers, including cerebral amyloid angiopathy markers, are warranted to refine risk prediction models.},
}

@article {pmid41038490,
year = {2025},
author = {Naghib, SM and Khorasani, MA and Sharifianjazi, F and Tavamaishvili, K},
title = {Bifunctional chitosan-based nanocarriers as promising therapeutic approach for brain disease therapy: A critical review focusing on multiple sclerosis over emerging strategies, technologies and applications.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148003},
doi = {10.1016/j.ijbiomac.2025.148003},
pmid = {41038490},
issn = {1879-0003},
abstract = {Chitosan (CS) has appeared as a promising candidate in brain disease (BD) (such as Alzheimer's, Parkinson's, and Multiple sclerosis (MS)) therapy due to its anti-inflammatory, antioxidative, and neuroprotective properties. CS's capacity to interact with the blood-brain barrier (BBB) enhances the central nervous system (CNS) drug permeability, offering new avenues for effective treatment strategies aimed at overcoming the limitations of conventional therapies. Furthermore, CS's role in regenerative medicine extends beyond drug delivery, as it fosters neural repair by providing a supportive microenvironment for oligodendrocyte proliferation and neuronal regeneration. Studies have shown that CS-based scaffolds, when combined with neurotrophic factors and stem cells, can enhance remyelination and neuroprotection in BD models. The immunomodulatory effects of CS further contribute to reducing neuroinflammation by shifting immune responses toward an anti-inflammatory phenotype, thereby mitigating the progression of BD-associated damage. This review provides a comprehensive analysis of the latest advancements in CS-based BD therapies, exploring its multifunctional applications in drug delivery, immune modulation, and tissue engineering. The discussion also addresses the current challenges in clinical translation, including variability in CS formulations, regulatory considerations, and potential safety concerns. Future research directions should focus on optimizing CS derivatives, improving its bioavailability, and integrating it with emerging therapeutic approaches such as gene therapy and biomimetic nanocarriers.},
}

@article {pmid41038475,
year = {2025},
author = {Zhou, J and Guo, X and Yu, W and Bu, H and Du, Y and Li, S and Kuang, H and Wu, L},
title = {Pharmacological action, mechanism and structure-activity relationship of traditional Chinese medicine polysaccharide in the treatment of Alzheimer's disease: A review.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {148017},
doi = {10.1016/j.ijbiomac.2025.148017},
pmid = {41038475},
issn = {1879-0003},
abstract = {Alzheimer's disease (AD) is a significant neurodegenerative disorder characterized by a progressive decline in cognitive functions. The pathogenesis of AD remains largely elusive, resulting in Western medications that often exhibit limited efficacy and frequent side effects. In contrast, traditional Chinese medicine (TCM) has been utilized for managing AD, recognized for its favorable safety profile and multi-target therapeutic potential. Polysaccharides, which are essential bioactive components found in TCM extracts, have attracted considerable interest due to their safety and ability to target multiple biological pathways. This article examines the pharmacological effects and mechanisms of TCM polysaccharides in the treatment of AD, focusing on research conducted over the past decade. Additionally, it explores the structure-activity relationships of these polysaccharides, providing a foundation for further investigation into polysaccharide-based interventions for AD and suggesting potential avenues for future studies aimed at structural enhancements.},
}

@article {pmid41036749,
year = {2025},
author = {Bartolomeu, PF and Fortes, IS and Zimmer, AR and Lopes, MS and de Andrade, SF},
title = {8-Hydroxyquinoline Derivatives as Drug Candidates for the Treatment of Alzheimer's Disease.},
journal = {Current medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0109298673409645250823055140},
pmid = {41036749},
issn = {1875-533X},
abstract = {Alzheimer's disease (AD) is the most prevalent form of dementia among older adults worldwide. Amidst several hypotheses to explain the pathobiology of the disease are biochemical indicators such as β-amyloid (Aβ) plaques; neurofibrillary tangles, caused by hyperphosphorylated tau protein; oxidative stress; metal dyshomeostasis; low levels of acetylcholine, and neuroinflammation. Considering the multifactorial nature of AD, there has been an increase in research for novel multitarget compounds, mainly utilizing molecular hybridization for drug design. In this review, we focus on the 8-hydroxyquinoline moiety, a privileged metal-binding agent with Aβ antiaggregating properties, and its derivatives, aiming to have an effect on multiple molecular targets. Furthermore, the most prominent structure-activity relationships found on the analyzed compounds, along with the most promising strategies explored by researchers, are discussed. That way, we hope to provide a comprehensive perspective on the development of anti- Alzheimer agents based on the 8-hydroxyquinoline moiety in the last decade.},
}

@article {pmid41035985,
year = {2025},
author = {Ghaliby, FAKA and Alhasan, L},
title = {Histopathological study of the neuroprotective effects of Gum Arabic and Fenchol on neuronal cells in an Alzheimer's disease rat model.},
journal = {Open veterinary journal},
volume = {15},
number = {8},
pages = {3871-3877},
pmid = {41035985},
issn = {2218-6050},
mesh = {Animals ; *Alzheimer Disease/drug therapy/pathology/chemically induced ; *Neuroprotective Agents/pharmacology/therapeutic use ; Male ; Rats ; *Gum Arabic/pharmacology/therapeutic use ; Disease Models, Animal ; *Neurons/drug effects ; Interleukin-6/blood ; Brain/drug effects/pathology ; Rats, Sprague-Dawley ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder influenced by environmental and genetic factors. It is primarily characterized by beta-amyloid plaque deposition, neurofibrillary tangles, and impaired neuronal signaling. Given the lack of a definitive cure, research has increasingly focused on identifying natural compounds with neuroprotective and therapeutic potential.

AIM: This study evaluates the effects of natural compounds (Fenchol and Gum Arabic) on immune modulation and neuroinflammatory markers, specifically interleukin-6 (IL-6), in a rat model of AD. By examining the effects of these natural products on the immune response and brain tissue pathology, this research aims to provide new insights into their potential therapeutic benefits for slowing AD progression.

METHODS: In this study, 36 adult male rats were randomly assigned to five groups: (1) a negative control group received standard feed and water, (2) a positive control group treated with aluminum chloride (17 mg/kg/day orally), (3) a Gum Arabic-treated group (2 ml, 10 g/100 ml orally) post-induction, (4) a Fenchol-treated group (2 ml, 5 mg/80 ml orally), and (5) a memantine-treated group (2 ml, 1.57 g/25 ml orally). After 1 month, histopathological assessments were performed to evaluate neuronal integrity, granule cell density, and beta-amyloid accumulation in the hippocampus. Additionally, serum IL-6 concentrations were measured via ELISA to assess systemic neuroinflammatory responses. Data were statistically analyzed using analysis of variance followed by least significant difference (LSD) post hoc tests.

RESULTS: Histopathological analysis revealed significant neurodegeneration in the positive control group, characterized by cytoplasmic vacuolation, reduced granule cell density, and elevated beta-amyloid levels. The Gum Arabic-treated group exhibited a partial neuroprotective effect, with a notable reduction in neurodegeneration, increased granule cell density, and a 50% decrease in amyloid plaques. The Fenchol-treated group demonstrated improved neuronal integrity and a marked reduction in beta-amyloid aggregates. The memantine-treated group exhibited the most substantial neuroprotective effect, significantly preserving granule cells and minimizing beta-amyloid deposition. Biochemical analysis revealed that IL-6 levels were markedly elevated in the positive control group (85.00 ± 3.00 ng/l) compared to the negative control (60.00 ± 2.00 ng/l). All treatment groups showed significant reductions in IL-6 levels. Memantine and combined treatments restored IL-6 levels close to normal. Fenchol and Gum Arabic alone reduced IL-6 levels, though to a lesser extent, indicating partial inflammatory effects.

CONCLUSION: The findings suggested that Gum Arabic and Fenchol possess neuroprotective properties, suggesting their potential as therapeutic agents for AD, with efficacy comparable to that of memantine. Their ability to downregulate IL-6 further highlights their potential in mitigating neuroinflammation associated with Alzheimer's pathology. Further investigations are warranted to elucidate their underlying mechanisms and evaluate their potential clinical applications.},
}

Animals
*Alzheimer Disease/drug therapy/pathology/chemically induced
*Neuroprotective Agents/pharmacology/therapeutic use
Male
Rats
*Gum Arabic/pharmacology/therapeutic use
Disease Models, Animal
*Neurons/drug effects
Interleukin-6/blood
Brain/drug effects/pathology
Rats, Sprague-Dawley

@article {pmid41035827,
year = {2025},
author = {Cai, M and Cai, K and Wei, Z and Zhou, J and Shu, J and Wang, W and Sun, W and Hu, J},
title = {Exercise-mediated cerebrovascular repair in Alzheimer's disease: from pathophysiology to therapeutic precision.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1632365},
pmid = {41035827},
issn = {1663-4365},
abstract = {Cerebrovascular dysfunctions, encompassing changes in cerebrovascular microstructure, blood-brain barrier (BBB) integrity, cerebrovascular reactivity, and cerebral blood flow (CBF), accelerate the pathological progression of Alzheimer's disease (AD). Exercise emerges as a promising non-pharmacological intervention that enhances cerebrovascular repair for the treatment of AD. This review summarizes the pathological vascular changes in AD pathology, such as pericyte loss, endothelial dysfunction, and capillary fibrosis, which exacerbate hypoperfusion, hypoxia, and amyloidogenesis. We further discuss the contributing vascular factors and underlying signaling mechanisms to explore potential targets for AD diagnosis and therapy. Finally, we present evidence concerning the impact of exercise on cerebral vascular signaling and the cells involved in vascular plasticity. We also address the impact of various exercise patterns on cerebrovascular health. This work aims to uncover the potential and intervention effects of exercise on cerebrovascular non-malignant alterations and will provide exercise strategies for treating AD.},
}

@article {pmid41035821,
year = {2025},
author = {Noto, NM and Speth, RC and Robison, LS},
title = {Cerebral amyloid angiopathy: a narrative review.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1632252},
pmid = {41035821},
issn = {1663-4365},
abstract = {Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder characterized by the accumulation of amyloid-beta (Aβ) in the walls of cerebral vessels. It is commonly associated with cognitive decline, cerebral hemorrhage, and other neurological pathologies. Despite its prevalence and impact, there are currently no approved treatments for CAA. CAA frequently co-occurs with Alzheimer's disease (AD), but affected patients are often excluded from anti-amyloid therapies due to increased risks of cerebral edema and hemorrhage, underscoring the urgent need for alternative and safe approaches for treating individuals with CAA. Over the years, various animal models have been developed to investigate the pathophysiology of CAA and evaluate potential treatments. Recent studies have demonstrated that certain repurposed drugs, originally approved for other conditions, show promise for treating CAA. Additionally, it has been shown that positive lifestyle changes may benefit vascular health, reduce amyloid burden and neuroinflammation, and improve cognitive resilience in individuals with CAA. In this review, we summarize the current knowledge on CAA, its relationship with AD, insights from preclinical and clinical studies, and emerging evidence supporting the potential of drug repurposing and lifestyle modification in managing CAA.},
}

@article {pmid41035200,
year = {2025},
author = {Gaffour, A and Bakker, M and Bera, K and Přecechtělová, JP},
title = {Reduced Binding of Tau(210-240) to BIN1: Phosphate Charges Prefer n-Src/Distal Loops over RT-Src Loops.},
journal = {Biophysical journal},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bpj.2025.09.037},
pmid = {41035200},
issn = {1542-0086},
abstract = {Within the disordered tangles of Tau is a proline-rich region (PRR) which is selectively targeted by the SH3 domain of BIN1, a known genetic factor for Alzheimer's disease, and may hold the key to understanding the disorder and treatment strategies. Hyperphosphorylation of Tau is known to disrupt complex formation, providing researchers with an excellent preventative or remediative targets. This work compiles an extensive (>60 μs) collection of all-atomistic molecular dynamics (MD) simulations of the Tau(210-240) fragment, representing the majority of the P2 subdomain of the PRR, benchmarking various forcefields, phosphorylations, and modifications against experimental NMR chemical shifts and spin-spin coupling for comparison. Additionally, several simulations of the binding complex analyzed for their binding energies by MMGBSA calculations and computational alanine scanning to pinpoint the exact residues involved, and the disruptions caused by the phosphate group. We noted that the additional charges decrease salt-bridges formed by positive residues in Tau, particularly on R221, and negative residues in BIN1 by up to 32%, and a strong preference in Tau, particularly in the latter half, for contact towards the distal and n-Src loops instead of residues in the RT-Src loop.},
}

@article {pmid41034564,
year = {2025},
author = {Makarov, N and Bordukova, M and Quengdaeng, P and Garger, D and Rodriguez-Esteban, R and Schmich, F and Menden, MP},
title = {Large language models forecast patient health trajectories enabling digital twins.},
journal = {NPJ digital medicine},
volume = {8},
number = {1},
pages = {588},
pmid = {41034564},
issn = {2398-6352},
support = {950293 - COMBAT-RES//European Union's Horizon 2020 Research and Innovation Programme/ ; 950293 - COMBAT-RES//European Union's Horizon 2020 Research and Innovation Programme/ ; },
abstract = {Generative artificial intelligence is revolutionizing digital twin development, enabling virtual patient representations that predict health trajectories, with large language models (LLMs) showcasing untapped clinical forecasting potential. We developed the Digital Twin-Generative Pretrained Transformer (DT-GPT), extending LLM-based forecasting solutions to clinical trajectory prediction. DT-GPT leverages electronic health records without requiring data imputation or normalization and overcomes real-world data challenges such as missingness, noise, and limited sample sizes. Benchmarking on non-small cell lung cancer, intensive care unit, and Alzheimer's disease datasets, DT-GPT outperformed state-of-the-art machine learning models, reducing the scaled mean absolute error by 3.4%, 1.3% and 1.8%, respectively. It maintained distributions and cross-correlations of clinical variables, and demonstrated explainability through a human-interpretable interface. Additionally, DT-GPT's ability to perform zero-shot forecasting highlights potential advantages of LLMs as clinical forecasting platforms, proposing a path towards digital twin applications in clinical trials, treatment selection, and adverse event mitigation.},
}

@article {pmid41034513,
year = {2025},
author = {Zhuo, Y and Lu, Y and Zhu, Y and Wen, N and Zou, G and Lu, H and Pei, X and Zhang, Y and Zhang, Q and Wang, X and Zhang, W and Zhang, Q and Wang, Z and Xie, S and Li, CQ and Tan, W and Qiu, L},
title = {Targeted clearance of extracellular Tau using aptamer-armed monocytes alleviates neuroinflammation in mice with Alzheimer's disease.},
journal = {Nature biomedical engineering},
volume = {},
number = {},
pages = {},
pmid = {41034513},
issn = {2157-846X},
support = {21991080//National Natural Science Foundation of China (National Science Foundation of China)/ ; 92253304//National Natural Science Foundation of China (National Science Foundation of China)/ ; },
abstract = {Extracellular Tau determines the progression of Alzheimer's disease, yet therapeutic strategies targeting it are hindered by poor brain delivery and limited clearance. Here we developed a Tau-clearing cell therapy based on monocytes functionalized with a high-affinity Tau-specific aptamer. The aptamer was covalently conjugated to the surface of monocytes (derived from bone marrow leucocytes and cultured under monocyte-inducing conditions) via bioorthogonal chemistry without affecting their viability or function. Upon intravenous administration in mice expressing mutant and disease-relevant human Tau, the engineered monocytes actively crossed the blood-brain barrier and accumulated in Tau-rich brain regions such as the hippocampus and striatum. They efficiently phagocytosed extracellular Tau, leading to a significant reduction in Tau burden. As a result, glial activation was suppressed, neuroinflammation was alleviated, and neuronal and mitochondrial integrity was preserved. Long-term treatment improved memory and spatial learning, without inducing toxicity or behavioural side effects. These results demonstrate that aptamer-guided monocytes can achieve targeted delivery, effective clearance and sustained neuroprotection, offering a promising strategy for therapeutic intervention in Alzheimer's disease.},
}

@article {pmid41032155,
year = {2025},
author = {Gao, X and Yang, K and Yuan, X and Song, M and Wang, T and Shen, C},
title = {Research progress of exosomes used in the Alzheimer's disease treatment.},
journal = {Discover nano},
volume = {20},
number = {1},
pages = {173},
pmid = {41032155},
issn = {2731-9229},
support = {82402735//National Natural Science Foundation of China/ ; 2023NSFSC1481//Natural Science Foundation of Sichuan Province/ ; 2023HXBH122//Postdoctoral Research Foundation of West China Hospital of Sichuan University/ ; },
abstract = {Alzheimer's disease (AD) is a common form of dementia characterized by memory loss, cognitive and linguistic abilities declining and self-care capabilities diminishment. With the aging population globally, AD poses a significant threat to public health. Current treatments for AD aim to alleviate symptoms and slow down disease progression, but due to the limited understanding of underlying disease mechanisms, AD is still impossible to be cured yet. In recent years, there has been an exponential growth in exosome-related research because of their excellent biocompatibility ability, loading capacity and cellular internalization, making exosome to be one of the hotspots and a promising strategy in AD therapy research. This comprehensive review systematically explores the potential roles of various exosome-based nanotherapeutic strategy in AD treatment, with a particular focus on their specific biological mechanisms of action. Firstly, we elaborated on the pathological mechanisms of AD formation as well as the mechanisms related to the formation, secretion and function of exosome. Additionally, we highlighted the research progress in the development of exosome-based nanotherapeutic strategies for AD treatment and their corresponding biological mechanisms. Furthermore, we delved into the challenges and opportunities these strategies facing in clinical application. Looking forward to future research directions and trends, our review aims to provide a more comprehensive understanding and guidance with the application of exosome in AD treatment. Exosome-based nanotherapeutic strategies, as a new therapeutic approach, have opened up new possibilities for the treatment of AD and brought new light to patients.},
}

@article {pmid41032080,
year = {2025},
author = {Khatun, P and Li, X and Xiaoxi, Z and Zhai, J and Ullah, A and Bo, Y and Lyu, Q},
title = {Effect of Omega-3 Polyunsaturated Fatty Acid Supplements on Cognitive Performance in Patients with Mild Cognitive Impairment or Alzheimer's Disease: A Systematic Review and Meta-Analysis.},
journal = {Nutrition reviews},
volume = {},
number = {},
pages = {},
doi = {10.1093/nutrit/nuaf167},
pmid = {41032080},
issn = {1753-4887},
support = {YJ20220181//2022 International Postdoctoral Exchange Fellowship Program/ ; 232102310069//Henan Medical Science and Technology Research Program/ ; //Preferential support for scientific research of overseas persons in Henan Province/ ; },
abstract = {CONTEXT: A positive effect of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on brain activity has been observed within subjects who have Alzheimer's disease (AD) or mild cognitive impairment (MCI). However, inconsistent findings have been reported regarding the efficacy or ineffectiveness of an n-3 PUFA dietary intervention for cognitive improvement.

OBJECTIVE: To address this problem, our thorough investigation and statistical analysis sought to assess the impact of n-3 PUFA dietary intake on cognitive function among persons diagnosed with AD or MCI.

DATA SOURCES: The databases consulted included PubMed, PubMed Central Library, and the Cochrane Library.

DATA EXTRACTION: Nine articles reporting on the findings of randomized controlled trials that looked at the link between n-3 PUFA intake and cognitive performance-related outcomes were included in the comprehensive evaluation, with the meta-analysis utilizing 7 of these. Key details such as author, publication year, study area, research type, pathology (MCI or AD), were incorporated into the data extraction procedure.

DATA ANALYSIS: Evaluation of the included studies used Cochrane risk-of-bias instruments, a random-effects model, standardized mean differences (SMDs) and 95% CIs.

RESULTS: Our findings have provided evidence of the effectiveness of an n-3 PUFA treatment in improving Full-Scale IQ (FSIQ) (SMD -0.82; 95% CI: -1.57, -0.08; P = .000), information processing (SMD -2.90; 95% CI: -5.25, -0.56; P = .000), and digit span/working memory/attention aspects of cognitive functioning (SMD -1.89; 95% CI: -3.27, -0.51; P = .000). No evidence was found for the effectiveness of an n-3 PUFA treatment in improving image completion (SMD -0.07; 95% CI: -0.50, 0.35; P = .000), picture layout (SMD -0.08; 95% CI: -0.32, 0.16; P = .075), block design SMD -0.15; 95% CI: -0.37, 0.03; P = .123), or arithmetic aspects of cognitive functioning (SMD -0.33; 95% CI: -0.61, 0.04; P = .007).

CONCLUSION: In summary, n-3 PUFAs have been found to significantly affect some domains of cognitive function, such as FSIQ, information processing, and digit span/working memory/attention in subjects with MCI. However, no significant effect was observed for some domains, such as picture completion, picture arrangement, or block design.},
}

@article {pmid41031197,
year = {2025},
author = {Wang, Q and Wang, DL and Zhang, XC and Jiang, XY and Jiang, HN and Yang, XY and Zhang, T and Lv, YY and Li, Q},
title = {Efficacy and safety of traditional Chinese medicine and Western medicine in Alzheimer's disease: a systematic review and meta-analysis.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1607945},
pmid = {41031197},
issn = {1664-2295},
abstract = {OBJECTIVE: This study aimed to compare the efficacy and safety of traditional Chinese medicine (TCM) compounds with single Western medicines in treating Alzheimer's disease (AD) through a systematic review and meta-analysis.

METHODS: In this study, we searched for randomized controlled trials on the treatment of AD with TCM compounds published before March 2025 in Chinese and English databases (PubMed, Embase, Cochrane, China National Knowledge Infrastructure, VIP, and Wanfang) and conducted a meta-analysis using Stata15.0 software.

RESULTS: A total of 23 studies were included, involving 2,035 participants (1,173 in the experimental group and 862 in the control group). Traditional Chinese herbal compounds showed good clinical efficacy and maintenance effects in the treatment of AD. The effective rate of TCM compounds in treating AD was higher than that of Western medicine (relative risk ratio = 1.19, 95% CI: 1.04-1.37, p = 0.009). In terms of the Alzheimer's Disease Assessment Scale-Cognitive and Hierarchic Dementia Scale-Revised scores, TCM compounds were superior to Western medicine (standardized mean difference = -0.22, 95% CI: -0.40--0.05). There were no significant differences between the two groups in the Mini-Mental State Examination or Activities of Daily Living scores. Additionally, there were no significant differences in adverse reactions between the TCM compounds and Western medicine groups.

CONCLUSION: The present research indicates that TCM compounds could be a promising therapeutic option for AD, demonstrating encouraging results in terms of efficacy and safety, particularly regarding certain cognitive functions.},
}

@article {pmid41030887,
year = {2025},
author = {Pan, Q and Lu, J and Xiao, Z and Zhang, H and Liu, G and Li, Y},
title = {Construction of a Rat Model of Hemilateral Parkinson's Disease Induced by Human Wild-Type α-Synuclein Overexpression.},
journal = {Neuropsychiatric disease and treatment},
volume = {21},
number = {},
pages = {2183-2194},
pmid = {41030887},
issn = {1176-6328},
abstract = {OBJECTIVE: Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer's disease. The precise etiology and pathogenesis of PD remain unclear. Human wild-type α-synuclein has been implicated in PD pathogenesis. The objective of this study is to examine the role of α-synuclein in PD by establishing a rat model of substantia nigra degeneration and Motor behavioral changes through the induced overexpression of human α-synuclein.

METHODS: Rats were randomly assigned to either the Negative control group or the adeno-associated virus serotype 9 (AAV9) treatment group. Animals in the AAV9 group received 2.5 μL of AAV9 expressing human wild-type α-synuclein, while those in the Negative control group received an equal volume of AAV9 expressing green fluorescent protein via stereotactic unilateral injection into the substantia nigra pars compacta. Behavioral assessments were conducted at 1-, 3-, and 8-weeks following virus administration. Tyrosine hydroxylase and human α-synuclein expression in the substantia nigra pars compacta were analyzed. Additionally, dopamine, dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum were quantified.

RESULTS: After 3 weeks of virus induction, neurodegeneration of the right substantia nigra was observed, with a reduction in the number of tyrosine hydroxylase-immunopositive neurons in the AAV9 group. By 8 weeks, substantia nigra neurodegeneration had further progressed, and animals in the AAV9 group exhibited apomorphine-induced asymmetrical rotation and altered forelimb use.

CONCLUSION: Overexpression of human wild-type α-synuclein led to substantia nigra degeneration and Motor behavioral changes in rats, providing a viable model for exploring the pathogenesis of Parkinson's disease. Limitations include the 8-week observation window and the absence of neuroinflammation markers.},
}

@article {pmid41030378,
year = {2025},
author = {Gazes, Y and Suzuki, H and Morris, LA and Lee, S and Jin, Z and Huey, ED and Chen, BB and Le Heron, C and Heibronner, SR and Vanegas-Arroyave, N},
title = {A transdiagnostic, multi-modal approach to understanding apathy: Methodological and analytical framework.},
journal = {Neuroimage. Reports},
volume = {5},
number = {4},
pages = {100289},
pmid = {41030378},
issn = {2666-9560},
abstract = {Apathy is characterized by loss of motivation and manifests as a reduction of goal-directed behavior. Apathy is highly prevalent across neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), and is an important contributor to the disability and reduce quality of life in these conditions. The treatment of apathy remains challenging due to a lack of specific therapies, largely attributed to an incomplete understanding of its cognitive and neuroanatomical underpinnings, crucial for developing targeted interventions. Apathy can be mechanistically studied through effort-based decision-making (EBDM) paradigms, where individuals choose between low- and high-effort tasks for varying reward magnitudes. Anatomically, apathy has been associated with alterations in brain regions previously implicated in EBDM. Using a novel transdiagnostic study design in individuals with AD and PD, we aim to: (1) evaluate the independent effects of reward and effort sensitivity as a mechanistic link between apathy and neurodegeneration of basal ganglia-frontal networks and, (2) in a subset of PD patients receiving deep brain stimulation (DBS) surgery, determine whether electrical manipulation of subthalamic nucleus and/or DBS connectivity, directly alter reward and effort information processing and, consequently, goal-directed behavior. Understanding how neurodegeneration-alone or in combination with neuromodulatory interventions-drives apathy, is essential for guiding clinical decision-making and therapeutic development. Given its prevalence across neurodegenerative disorders, apathy provides a unique framework for investigating shared and disease-specific neuroanatomical, functional, and behavioral mechanisms. In this protocol paper, we describe the rationale and methodology of our proposed multimodal approach, to investigate apathy in a transdiagnostic cohort of individuals with AD and PD.},
}

@article {pmid41029918,
year = {2025},
author = {Agarwal, M and Singhal, M and Basist, P and Tamta, N and Kumar, S and Saha, S},
title = {Evaluation of Hordenine's Therapeutic Potential in Alzheimer's Disease-Induced Cognitive and Oxidative Impairments.},
journal = {Recent advances in food, nutrition & agriculture},
volume = {},
number = {},
pages = {},
doi = {10.2174/012772574X389943250908070348},
pmid = {41029918},
issn = {2772-5758},
abstract = {INTRODUCTION: This research aimed to investigate the potential of Hordenine (HR) against Alzheimer's Disease (AD) induced by Streptozotocin (STZ) in Wistar rats by evaluating its impact on cognitive function, oxidative stress, inflammatory cytokines, and neuroprotective biomarkers in comparison to donepezil.

METHODS: The study involved five groups of Wistar rats: a control group, a group with STZinduced AD, and three treatment groups receiving varying doses of HR (50 mg/kg and 75 mg/kg) and donepezil (5 mg/kg). Over 28 days, the animals underwent various behavioural tests to assess cognitive function, along with biochemical analyses to measure A+cetylcholinesterase (AChE) activity, oxidative stress markers, inflammatory cytokines (IL-1β, TNF-α), and nuclear factor kappa B (NF-κB) levels, and histological examination. Additionally, molecular docking studies were performed to assess the interaction of HR with AChE.

RESULTS: STZ administration caused significant cognitive decline, oxidative stress, and elevated inflammatory markers. HR supplementation, particularly at 75 mg/kg, significantly improved cognition, reduced oxidative stress, and decreased pro-inflammatory cytokines (IL-1β, TNF-α), as well as NF-κB levels, while increasing Brain-Derived Neurotrophic Factor (BDNF) expression. Molecular docking studies revealed strong binding of HR to AChE, suggesting potential inhibitory effects.

DISCUSSION: Hordenine demonstrated promising neuroprotective effects against STZ-induced neurotoxicity by improving cognition and reducing oxidative stress and inflammation, suggesting HR's potential as an adjunct therapy for Alzheimer's disease, offering a protective mechanism that may complement existing treatments like donepezil.

CONCLUSION: The research shows that the medicinal plant HR exhibits neuroprotective potential against AD induced by STZ. Further research involving clinical trials is warranted to fully establish the efficacy and safety of HR in the treatment of AD.},
}

@article {pmid41029885,
year = {2025},
author = {Zhou, J and Zhong, Y and Jin, C and Dong, L and Zhou, R and Wang, Y and Fan, Z and Zheng, X and Xing, X and Wang, J and Tian, M and Zhang, H},
title = {A novel electric field approach for improving cognitive function through ameliorating cell-specific pathology in P301S tauopathy mice.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {210},
pmid = {41029885},
issn = {1758-9193},
support = {82394433//National Natural Science Foundation of China/ ; 82030049//National Natural Science Foundation of China/ ; 2022YFE0118000//National Key Research and Development Program of China/ ; 226-2024-00059//Fundamental Research Funds for the Central Universities/ ; },
mesh = {Animals ; *Tauopathies/pathology/therapy/genetics ; Mice ; Mice, Transgenic ; Disease Models, Animal ; Microglia/pathology/metabolism ; *Cognition/physiology ; Brain/pathology/metabolism ; Neurons/pathology/metabolism ; tau Proteins/genetics/metabolism ; *Cognitive Dysfunction/therapy/pathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress/physiology ; *Electric Stimulation Therapy/methods ; },
abstract = {Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer's disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.},
}

Animals
*Tauopathies/pathology/therapy/genetics
Mice
Mice, Transgenic
Disease Models, Animal
Microglia/pathology/metabolism
*Cognition/physiology
Brain/pathology/metabolism
Neurons/pathology/metabolism
tau Proteins/genetics/metabolism
*Cognitive Dysfunction/therapy/pathology
Male
Mice, Inbred C57BL
Oxidative Stress/physiology
*Electric Stimulation Therapy/methods

@article {pmid41028047,
year = {2025},
author = {Khan, MI and Jeong, ES and Tasreen, G and Khan, MZ and Shin, JH and Kim, JD},
title = {The therapeutic potential of beta-carotene against neuroinflammation and amyloid beta in SH-SY5Y cells.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {33803},
pmid = {41028047},
issn = {2045-2322},
support = {NRF-2018R1D1A1B07047021//National Research Foundation of Korea/ ; },
mesh = {Humans ; *beta Carotene/pharmacology ; *Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Apoptosis/drug effects ; *Neuroprotective Agents/pharmacology ; Antioxidants/pharmacology ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Alzheimer Disease/drug therapy/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; },
abstract = {Neurodegenerative diseases, particularly Alzheimer's disease (AD), represent a significant public health challenge due to their increasing prevalence and the lack of effective treatments. In this study, we explored the neuroprotective effects of beta-carotene, a naturally occurring carotenoid, by investigating its ability to inhibit or reduce apoptosis and inflammation while enhancing antioxidant potential in SH-SY5Y neuroblastoma cells. Beta-carotene was extracted from Chlorella vulgaris using high-performance liquid chromatography (HPLC). We utilized SH-SY5Y cells, a widely employed in vitro model for studying neurodegenerative processes, to evaluate these therapeutic effects. A combination of colorimetric assays, enzyme-linked immunosorbent assays (ELISA), and quantitative real-time PCR (qRT-PCR) was used to assess the impact of beta-carotene on enzyme activity, cytokine production, and gene expression. The caspase assay results demonstrated that beta-carotene effectively reduced the activity of pro-apoptotic caspases and downregulated the expression of pro-apoptotic genes such as Bax, Bak and caspases, thereby inhibiting apoptosis in SH-SY5Y cells. Additionally, beta-carotene exhibited potent antioxidant properties by upregulating NRF2 and superoxide dismutase (SOD), along with enhancing ABTS and DPPH radical scavenging activities.showed antiinflamatory effects reduce the concentrations of proinflamatory cytokines TNFα, IL-1 β and IFN-γ, and supress the inflamtion patway by supressing the expression of Akt, PIK3, STAT1 and NF-kB, Akt etc. Importantly, beta-carotene treatment led to the suppression of β-secretase (BACE1), γ-secretase and acetylcholinesterase (AChE) activities, and the downregulation of genes involved in amyloid-beta production, including BACE1, and PECN1 eventualy resulted in dcerase concentration o Aβ peptides. These findings suggest that β-carotene could be a promising therapeutic candidate for the prevention and treatment of neurodegenerative diseases, particularly Alzheimer's disease, however further investigations are recomended in animal models and clinical trials before incorporating beta-cerotene into pharmaceutical formulations for AD treatment.},
}

Humans
*beta Carotene/pharmacology
*Amyloid beta-Peptides/metabolism
Cell Line, Tumor
Apoptosis/drug effects
*Neuroprotective Agents/pharmacology
Antioxidants/pharmacology
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Alzheimer Disease/drug therapy/metabolism
Amyloid Precursor Protein Secretases/metabolism

@article {pmid41027951,
year = {2025},
author = {Sriram, S and Nivethitha, V and Arun Kaarthic, TP and Archita, S and Murugan, T},
title = {Advanced MRI based Alzheimer's diagnosis through ensemble learning techniques.},
journal = {Scientific reports},
volume = {15},
number = {1},
pages = {33840},
pmid = {41027951},
issn = {2045-2322},
mesh = {*Alzheimer Disease/diagnostic imaging/diagnosis ; Humans ; *Magnetic Resonance Imaging/methods ; Deep Learning ; Neural Networks, Computer ; *Brain/diagnostic imaging ; *Machine Learning ; Aged ; Male ; Female ; Ensemble Learning ; },
abstract = {Alzheimer's Disease is a condition that affects the brain and causes changes in behavior and memory loss while making it hard to carry out tasks properly. It's vital to spot the illness early, for effective treatment. MRI technology has advanced in detecting Alzheimer's by using machine learning and deep learning models. These models use neural networks to analyze brain MRI results automatically and identify key indicators of Alzheimer's disease. In this study, we used MRI data to train a CNN for diagnosing and categorizing the four stages of Alzheimer's disease with deep learning techniques, offering significant advantages in identifying patterns in medical imaging for this neurodegenerative condition compared to using a CNN exclusively trained for this purpose. They evaluated ResNet50, InceptionResNetv2 as well as a CNN specifically trained for their study and found that combining the models led to highly accurate results. The accuracy rates for the trained CNN model stood at 90.76%, InceptionResNetv2 at 86.84%, and ResNet50 at 90.27%. In this trial run of the experiment conducted by combining all three models collaboratively resulted in an accuracy rate of 94.27% compared to the accuracy rates of each model working individually.},
}

*Alzheimer Disease/diagnostic imaging/diagnosis
Humans
*Magnetic Resonance Imaging/methods
Deep Learning
Neural Networks, Computer
*Brain/diagnostic imaging
*Machine Learning
Aged
Male
Female
Ensemble Learning

@article {pmid41027737,
year = {2025},
author = {Dimitrov, D and Raja, S and Noor, H and Takahashi, T},
title = {Common Mechanism Underlying Synaptic Dysfunction Caused by Preformed Fibril-Induced Accumulation of α-Synuclein or Tau in a Culture Propagation Model.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.0394-25.2025},
pmid = {41027737},
issn = {1529-2401},
abstract = {In sporadic neurodegenerative diseases, the endogenous proteins α-synuclein in Parkinson's disease and tau in Alzheimer's disease undergo pathogenic prion-like propagation over many years, accumulating in both soluble and insoluble forms in neurons including synapses, where they impair synaptic transmission and potentially cause various neuronal symptoms. To investigate the functional outcome of such synaptic accumulation, we induced accumulation of endogenous proteins in murine and human synapses by incubating mouse (of either sex) neuronal cultures with pathogenic preformed fibrils (pffs). Two weeks after treatment with human α-synuclein or tau pff, the respective endogenous proteins accumulated in neurons including presynaptic terminals, where we also observed tubulin accumulation, suggesting microtubule over-assembly. These were not associated with mRNA upregulation and were prevented by pharmacological stimulation of autophagy. Both pffs caused accumulation of p62 in cell bodies, suggesting compromised protein degradation. pHluorin imaging in synapses indicated a marked prolongation of vesicular endocytic time, which was rescued by pharmacological depolymerization of microtubules or by the over-expression of full-length dynamin 1. Since dynamin is a high-affinity binding partner of microtubules as well as an endocytic key molecule, over-assembled microtubules can sequester dynamin, thereby inhibiting endocytosis. We conclude that pff-induced accumulation of α-synuclein or tau in presynaptic terminals can disrupt vesicle endocytosis through a common mechanism. Since endocytosis-dependent vesicle recycling is critical for maintaining neurotransmitter release, its disruption can affect the neurocircuitry operations involved, thereby causing diverse symptoms associated with neurodegenerative diseases. Thus, our data suggest a common molecular mechanism underlying synaptic dysfunctions associated with Parkinson's and Alzheimer's diseases.Significance statement The accumulation of the pathogenic proteins α-synuclein and tau drives prion-like trans-neuronal propagation and underlies distinct neurodegenerative diseases, such as Parkinson's and Alzheimer's disease. Using a synaptic culture model of protein propagation, we identified a shared mechanism of synaptic dysfunction caused by these otherwise distinct proteins. In our models, propagated α-synuclein or tau disrupt protein degradation pathways, leading to their accumulation. These accumulated proteins promote excessive microtubule assembly and sequester the key endocytic protein dynamin, eventually impairing synaptic vesicle endocytosis. This cascade results in synaptic dysfunction that could compromise neurocircuit operations critical for brain functions. Our clarification of these mechanistic steps will improve our understanding of the synaptic pathophysiology underlying diverse symptoms of distinct neurodegenerative diseases.},
}

@article {pmid41025909,
year = {2025},
author = {Sajimon, M and Wheeler, CJ and Foley, AR and Chan, K and Griffin, MN and Dinakarapandian, DM and Holberton, A and Joy, J and Paravastu, AK and Wood, LB and Raskatov, JA},
title = {Asparagine Deamidation Attenuates Toxicity, Aggregation, and Microglial Responses of Alzheimer's Amyloid-β.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00544},
pmid = {41025909},
issn = {1948-7193},
abstract = {Alzheimer's disease (AD) is a growing global challenge that imposes a tremendous burden on society and economies. Though recently approved anti-amyloid β (Aβ) immunotherapies show effectiveness in clearing amyloid and slowing cognitive decline, the removal of cerebral Aβ can also cause serious adverse events (SAEs). Therefore, decreasing the detrimental effects of Aβ in the brain without promoting SAEs is an unmet need in AD treatment. Here, we show that deamidation of Asparagine 27(N27) in Aβ1-42 can significantly reduce Aβ's neurotoxicity and decrease selective microglial pro-inflammatory cytokine production. We also show that deamidation of N27 produces a pronounced decrease in Aβ's aggregation propensity and decreases soluble oligomer formation, suggesting a potential mechanism for its mitigation of Aβ's detrimental cellular effects. Modulation of these Aβ properties by N27 deamidation represents a proof of concept for a potential strategy to alter the detrimental effects of Aβ that may not require its removal from the brain. Our findings on reducing Aβ's toxic properties by N27 deamidation may provide a basis for future therapeutic interventions.},
}

@article {pmid41024939,
year = {2024},
author = {Saleh, AY and Valentina, R and Susanto, TD and Saputra, DAY},
title = {Beyond stroke therapy, neuroaid (a chinese herbal) has an effect on cognition and neurogenesis, a bibliometric study.},
journal = {F1000Research},
volume = {13},
number = {},
pages = {799},
doi = {10.12688/f1000research.152581.2},
pmid = {41024939},
issn = {2046-1402},
mesh = {Humans ; *Drugs, Chinese Herbal/therapeutic use/pharmacology ; *Cognition/drug effects ; *Stroke/drug therapy ; Bibliometrics ; *Neurogenesis/drug effects ; Animals ; },
abstract = {INTRODUCTION: NeuroAiD, also known as MLC601 or MLC901, is a Chinese herbal combination used worldwide for stroke treatment. It contains herbal components and five hewan components. MLC601 contains herbal components and hewan components, while MLC901 has a similar herbal composition. NeuroAiD is used to support neurologic recovery after stroke and to aid cognitive function in Alzheimer's disease. Studies show that NeuroAiD has potential in treating Alzheimer's disease and is beneficial in both local and global stroke models and in the Kortikal culture. However, there is limited bibliometric research on NeuroAiD, which is a method of collecting data from published articles to analyze developments and trends in the field of research. This research contributes significantly to the literature and helps develop more effective stroke treatment strategies.

METHODS: In this work, a literature review methodology is employed to gather data from the Scopus database using the keywords neuroaid. Data were analyzed using Biblioshiny and VOSviewer software to produce visualizations and bibliometric maps. We conducted quantitative and qualitative analysis.

RESULTS: The research trend found are documents by year, most relevant sources, factorial map of the most cited documents, factorial map of The documents with the highest contributes, documents by author, documents by country or territory, documents by subject area, documents by affiliation, network visualization, overlay visualization of scopus database using vosviewer, density visualization, thematic map, thematic evolution, topic dendogram, and world cloud.

CONCLUSIONS: The study investigates the potential of Neuroaid, a neuroprotective drug, for stroke prevention and cognitive function enhancement. It uses terms like "cognition" and "neurogenesis" to highlight its potential. While the study's focus may be limited, it provides valuable insights into research direction and potential areas of neuroaid for stroke treatment.},
}

Humans
*Drugs, Chinese Herbal/therapeutic use/pharmacology
*Cognition/drug effects
*Stroke/drug therapy
Bibliometrics
*Neurogenesis/drug effects
Animals

@article {pmid41024926,
year = {2025},
author = {Bitar, I and Alabdalrazzak, M and Zamzam, M and Desai, Y and Abushaban, K},
title = {Clinically Silent Amyloid-Related Imaging Abnormality With Edema Following Lecanemab Therapy: A Case Report.},
journal = {Cureus},
volume = {17},
number = {8},
pages = {e91230},
pmid = {41024926},
issn = {2168-8184},
abstract = {Amyloid-related imaging abnormalities with edema (ARIA-E) are a known complication of anti-amyloid monoclonal antibody therapies such as lecanemab. ARIA-E represents vasogenic cerebral edema resulting from treatment-related disruption of vascular amyloid and appears on MRI as cortical or gyriform T2 fluid-attenuated inversion recovery (FLAIR) hyperintensities. Clinically, ARIA-E ranges from asymptomatic radiologic findings to symptomatic events such as headache, confusion, or seizures, making routine surveillance important during therapy. We present the case of a 60-year-old woman with biomarker-confirmed AD who developed radiographically evident ARIA-E following six biweekly infusions of lecanemab. Surveillance MRI revealed new cortically based and gyriform T2 FLAIR hyperintensities in the posterior occipital and bilateral temporal lobes, consistent with parenchymal and sulcal edema. Notably, the patient remained neurologically asymptomatic throughout the episode. Lecanemab therapy was discontinued, and she was managed conservatively with close outpatient follow-up. This case highlights the importance of routine imaging during anti-amyloid therapy and demonstrates that conservative management may be appropriate in select asymptomatic cases of ARIA-E.},
}

@article {pmid41023855,
year = {2025},
author = {Zou, M and Xu, SS and Zhu, SG and Yuan, CX and Huang, JF and Zhu, JH and Zhang, X and Wang, JY},
title = {Elevated D-dimer levels after lecanemab infusions: a case report.},
journal = {BMC geriatrics},
volume = {25},
number = {1},
pages = {742},
pmid = {41023855},
issn = {1471-2318},
support = {2023RC215//Zhejiang Provincial Medical Technology Program/ ; },
mesh = {Humans ; *Fibrin Fibrinogen Degradation Products/metabolism ; Aged, 80 and over ; Male ; *Alzheimer Disease/drug therapy/blood ; Infusions, Intravenous ; Biomarkers/blood ; },
abstract = {BACKGROUND: Lecanemab is a disease-modifying immunotherapy for Alzheimer's disease (AD) and has been increasingly prescribed to the patients in the world. It has a definite therapeutic effect in slowing cognitive decline in AD patients, but its adverse drug reactions should not be ignored.

CASE PRESENTATION: We reported an 82-year-old Chinese AD patient who developed recurrent D-dimer elevation after lecanemab infusions. His D-dimer levels were positively correlated with activated partial thromboplastin time, C-reactive protein, and neutrophil percentage, but negatively correlated with platelet count.

CONCLUSIONS: Elevated D-dimer levels may be associated with the enhanced phagocytic response to vascular amyloid β upon lecanemab treatment. Our report expands knowledge on lecanemab's adverse drug reactions, suggesting that D-dimer levels and potential thromboembolic events should be monitored during treatment.

CLINICAL TRIAL NUMBER: not applicable.},
}

Humans
*Fibrin Fibrinogen Degradation Products/metabolism
Aged, 80 and over
Male
*Alzheimer Disease/drug therapy/blood
Infusions, Intravenous
Biomarkers/blood

@article {pmid41023476,
year = {2025},
author = {Bhatt, K and Jayanthi, N and Kumar, M},
title = {FHESA: fourier decomposition and hilbert transform based EEG signal analysis for Alzheimer's disease detection.},
journal = {Physical and engineering sciences in medicine},
volume = {},
number = {},
pages = {},
pmid = {41023476},
issn = {2662-4737},
abstract = {Alzheimer's Disease (AD) is a chronic neurological disorder that impairs the cognitive and behavioral abilities of older people. Early detection and treatment are crucial for minimizing the progression of the disease. Electroencephalogram (EEG) makes it possible to investigate the brain activities linked to various forms of disabilities experienced by individuals with AD. Nevertheless, the EEG signals are non-linear and non-stationary in nature making it difficult to retrieve the concealed information from the EEG signals. Therefore, a Fourier Decomposition Method (FDM) and Hilbert Transform (HT) based EEG signals analysis (FHESA) method is developed in this paper for the automated detection of AD. The FHESA method aims to efficiently analyze the EEG data to identify the important brain regions vulnerable to AD, and to assess the impact of various EEG channels for the timely and early detection of AD. The proposed FHESA method is divided into three primary stages. The first stage deals with the decomposition of the EEG signals into a finite number of Fourier Intrinsic Band Functions (FIBFs). In the second stage, HT is applied to all FIBFs to obtain instantaneous amplitude, frequency, and phase, that are then used to construct feature vectors. In the last stage, various Machine Learning (ML) algorithms are used to classify these feature vectors for efficient AD detection. Two distinct data sets are employed to assess the effectiveness of the proposed FHESA method. The outcome demonstrates that with dataset-I and dataset-II, the proposed methodology can detect AD with 98% and 99% accuracy, respectively. The performance of the proposed FHESA method is compared to other state-of-the-art methods used for AD detection. The promising results show that the proposed FHESA method can assist neurological experts in identifying and utilizing EEG signals for AD detection.},
}

@article {pmid41023471,
year = {2025},
author = {Wang, Y and Yang, J and Jiang, X and Yuan, R and Cheng, R and Lu, N and Gao, A and Liu, S},
title = {Potential new drug sources for the treatment of Parkinson's disease: flavonoid O-glycosides.},
journal = {Molecular biology reports},
volume = {52},
number = {1},
pages = {966},
pmid = {41023471},
issn = {1573-4978},
support = {82274125//National Natural Science Foundation of China/ ; },
mesh = {*Parkinson Disease/drug therapy ; *Flavonoids/therapeutic use/pharmacology/chemistry ; Humans ; *Glycosides/therapeutic use/pharmacology/chemistry ; Animals ; Biological Products/therapeutic use/pharmacology ; },
abstract = {Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. With the increase in the global aging population, the global prevalence of PD has soared, and the burden of global medical resources is increasingly heavy. Although modern medicine has progressed in treating PD, existing drugs still have drawbacks regarding Mechanism and efficacy, intensifying the urgency of developing new drugs. Researchers have favored natural treatments for their safety in recent years and have increasingly become an essential source for developing new drugs. Flavonoid O-glycoside compounds are one of the main active ingredients of natural products and have shown satisfactory efficacy in treating PD, thus becoming potential drugs for treating neurodegenerative diseases. In this study, we systematically evaluated the Mechanism of several specific flavonoid O-glycoside compounds in the treatment of PD, conducted a relatively in-depth summary and discussion of their biological activities, and compared them with other flavonoid O-glycoside compounds. This provides a theoretical basis for further future mechanism research on flavonoid O-glycoside compounds. And lay the foundation and set an example for the development and application of natural products. This review indicates that flavonoid O-glycoside compounds are up-and-coming new therapeutic drugs for Parkinson's disease (PD) and can be used in PD prevention and treatment strategies.},
}

*Parkinson Disease/drug therapy
*Flavonoids/therapeutic use/pharmacology/chemistry
Humans
*Glycosides/therapeutic use/pharmacology/chemistry
Animals
Biological Products/therapeutic use/pharmacology

@article {pmid41021789,
year = {2025},
author = {Huang, M and Su, X and Bian, L and Xu, L and Pang, H and Song, Z and Sun, L and Zhang, H and Ma, Y},
title = {Preliminary efficacy analysis of middle meningeal artery embolization using Glubran 2 for chronic subdural hematoma.},
journal = {Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences},
volume = {},
number = {},
pages = {15910199251380388},
doi = {10.1177/15910199251380388},
pmid = {41021789},
issn = {2385-2011},
abstract = {ObjectiveTo preliminarily conclude the safety and efficacy of middle meningeal artery embolization (MMAE) with Glubran 2 in treating chronic subdural hematoma (CSDH).MethodsThis retrospective analysis was performed on 40 consecutive CSDH patients who received MMAE with Glubran 2 between 2021 and 2023. The patients were followed up for 3 years post-operationally. Surgical procedures included burr hole drainage (BHD) and MMAE, both of which were performed under local anesthesia. MMAE with Glubran 2 was performed through transfemoral access. Postoperative recurrence was defined as an increase in hematoma volume based on computed tomography (CT) and/or magnetic resonance imaging (MRI) accompanied by clinical symptoms, which require further treatment within 3 years postoperatively.ResultsIn this study, 40 CSDH patients (34 male and six female) with a mean age of 68.2 ± 13.2 years were included. Of these, 38 patients underwent MMAE-assisted BHD. Two patients received MMAE alone. A single-branch embolization was performed on 20 hematomas in 18 patients, and a double-branch on 27 hematomas in 22 patients. At the three-year follow-up, 33 patients were successfully contacted, and 24 patients showed significant improvement or were asymptomatic after treatment. Three patients passed away owing to non-CSDH-related reasons. One patient developed decompensated liver cirrhosis, one experienced Alzheimer's disease, and four patients experiencing deteriorated functions were unclear but non-CSDH related as demonstrated by absorbed hematomas on head CT or MRI during return visits. The median follow-up time was 35 (IQR 27-40) months, and the median mRS score was 0 (IQR 0-0).ConclusionMMAE-assisted BHD with Glubran 2 is feasible, safe, and effective in treating CSDH, with no associated complications.},
}

@article {pmid41020462,
year = {2025},
author = {Lee, YC and Tai, YC},
title = {Seronegative but Cerebrospinal Fluid-positive NMDA Receptor Encephalitis in an Alzheimer's Dementia Patient with Good Treatment Outcome: A Case Report.},
journal = {Acta neurologica Taiwanica},
volume = {34},
number = {3},
pages = {161-164},
doi = {10.4103/ANT.ANT_113_0041},
pmid = {41020462},
issn = {1028-768X},
mesh = {Humans ; Female ; Aged ; *Alzheimer Disease/complications ; *Anti-N-Methyl-D-Aspartate Receptor Encephalitis/cerebrospinal fluid/complications/therapy ; Immunoglobulins, Intravenous/therapeutic use ; Treatment Outcome ; Electroencephalography ; Autoantibodies/cerebrospinal fluid ; },
abstract = {We present a rare case of elderly-onset anti-N-methyl-D-aspartate (NMDA) receptor encephalitis combined with underlying Alzheimer dementia, characterized by seronegativity but cerebrospinal fluid (CSF) antibody positivity, which showed a significant improvement following intravenous immunoglobulin (IVIG) treatment. The case highlights serial electroencephalogram (EEG) changes. We focus the discussion on factors contributing to favorable recovery. A 78-year-old woman with Alzheimer's dementia and hypertension experienced rapid onset of further cognitive decline over 1 week, presenting with disorientation, irrelevant speech, and disorganized behaviors. Myoclonus of both upper limbs and focal seizures 10 days later which lead her into intensive care unit (ICU) admission. Test results revealed positive anti-NMDA antibodies in CSF but negative in serum. Serial electroencephalograms (EEG) exhibited extreme delta brush activity transitioning to excess beta activity. Initial treatment with a 5-day course of steroid pulse therapy showed limited efficacy. Subsequently, 5 days of IVIG therapy provided marked improvement in consciousness and cognitive function and also normalized the EEG. This patient presented with severe neurological dysfunction, the need for ICU management, and presence of extreme delta brush EEG pattern. Generally, the prognosis was unfavorable. However, advanced age onset and anti-NMDA antibody positivity in CSF with seronegativity in serum may imply better prognosis. Thus, testing anti-NMDA receptor antibody in both serum and CSF is mandatory and under this complicated situation, timely immunotherapy may be the influencing factors of good prognosis.},
}

Humans
Female
Aged
*Alzheimer Disease/complications
*Anti-N-Methyl-D-Aspartate Receptor Encephalitis/cerebrospinal fluid/complications/therapy
Immunoglobulins, Intravenous/therapeutic use
Treatment Outcome
Electroencephalography
Autoantibodies/cerebrospinal fluid

@article {pmid41020412,
year = {2025},
author = {Villeneuve, S and Poirier, J and Breitner, JCS and Tremblay-Mercier, J and Remz, J and Raoult, JM and Yakoub, Y and Gallego-Rudolf, J and Qiu, T and Fajardo Valdez, A and Mohammediyan, B and Javanray, M and Metz, A and Sanami, S and Ourry, V and Wearn, A and Pastor-Bernier, A and Edde, M and Gonneaud, J and Strikwerda-Brown, C and Tardif, CL and Gauthier, CJ and Descoteaux, M and Dadar, M and Vachon-Presseau, É and Baril, AA and Ducharme, S and Montembeault, M and Geddes, MR and Soucy, JP and Rajah, N and Laforce, R and Bocti, C and Davatzikos, C and Bellec, L and Rosa-Neto, P and Baillet, S and Evans, AC and Collins, DL and Chakravarty, MM and Blennow, K and Zetterberg, H and Spreng, RN and Pichet Binette, A and , },
title = {The PREVENT-AD cohort: Accelerating Alzheimer's disease research and treatment in Canada and beyond.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {10},
pages = {e70653},
doi = {10.1002/alz.70653},
pmid = {41020412},
issn = {1552-5279},
support = {//Fondation Brain Canada/ ; //Fonds de recherche du Québec - Santé/ ; PJT-438655/CAPMC/CIHR/Canada ; PJT-367122/CAPMC/CIHR/Canada ; PJT-410106/CAPMC/CIHR/Canada ; PJT-463677/CAPMC/CIHR/Canada ; PJT-153287/CAPMC/CIHR/Canada ; PJT-178210/CAPMC/CIHR/Canada ; PJT-451830/CAPMC/CIHR/Canada ; PJT-165921/CAPMC/CIHR/Canada ; NIG-17-08//Alzheimer Society of Canada/ ; R01AG068563/AG/NIA NIH HHS/United States ; 3R01AG068563-04S1/AG/NIA NIH HHS/United States ; AARG-22-927100/ALZ/Alzheimer's Association/United States ; SG-23-1038904QC/ALZ/Alzheimer's Association/United States ; //Fondation Jean-Louis Lévesque/ ; //Canada Foundation for Innovation/ ; //Canada First Research Excellence Fund/ ; //Fondation de la Famille Lemaire/ ; 2017-00915//Vetenskapsrådet/ ; 2022-00732//Vetenskapsrådet/ ; JPND2019-466-236//EU Joint Programme Neurodegenerative Disease Research/ ; },
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy ; Canada ; Aged ; Female ; Magnetic Resonance Imaging ; Male ; Disease Progression ; Longitudinal Studies ; Biomarkers/blood/cerebrospinal fluid ; Positron-Emission Tomography ; Cohort Studies ; Amyloid beta-Peptides ; Neuroimaging ; },
abstract = {The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is an investigator-driven study that was created in 2011 and enrolled cognitively normal older adults with a family history of sporadic AD. Participants are deeply phenotyped and have now been followed annually for more than 12 years (median follow-up 8.0 years, SD 3.1). Multimodal magnetic resonance imaging (MRI), genetic, neurosensory, clinical, cerebrospinal fluid, and cognitive data collected until 2017 on 348 participants who agreed to open sharing with the neuroscience community were already available. We now share a new release including 6 years of additional follow-up cognitive data, and additional MRI follow-ups, clinical progression, new longitudinal behavioral and lifestyle measures (questionnaires, actigraphy), longitudinal AD plasma biomarkers, amyloid-beta and tau positron emission tomography (PET), magnetoencephalography, as well as neuroimaging analytic measures from all MRI modalities. We describe the PREVENT-AD study, the data shared with the global research community, as well as the model we created to sustain longitudinal follow-ups while also allowing new innovative data collection. HIGHLIGHTS: The PResymptomatic EValuation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) is a single-site longitudinal study that started in 2011 with annual follow-up data collection on individuals at risk of Alzheimer's disease who were all cognitively normal at enrolment. All 387 participants were enrolled between 2011 and 2017 and 306 (79%) of these participants were still in the study as of December 2023. While the PREVENT-AD dataset was not originally planned to be shared with the global research community, 348 participants retrospectively consented for their data to be shared with researchers worldwide. The first release of data was in 2019. We now share a second release that includes 6 years of additional follow-up visits, information on clinical progression and novel cognitive, behavioral, genetic, plasma and neuroimaging (amyloid and tau positron emission tomography [PET], magnetoencephalography [MEG], and new magnetic resonance imaging [MRI] sequences) data. It also includes analytic outputs for neuroimaging modalities.},
}

Humans
*Alzheimer Disease/diagnostic imaging/therapy
Canada
Aged
Female
Magnetic Resonance Imaging
Male
Disease Progression
Longitudinal Studies
Biomarkers/blood/cerebrospinal fluid
Positron-Emission Tomography
Cohort Studies
Amyloid beta-Peptides
Neuroimaging

@article {pmid41019419,
year = {2025},
author = {Punsawad, C and Kaewman, P and Techarang, T and Sketriene, D and Lalert, L},
title = {Low-Dose Paracetamol Treatment Protects Neuronal Oxidative Stress and Neuroinflammation in D-Galactose-Induced Accelerated Aging Model.},
journal = {Scientifica},
volume = {2025},
number = {},
pages = {5559483},
pmid = {41019419},
issn = {2090-908X},
abstract = {Aging increases the risk of neurodegenerative diseases such as Parkinson's and Alzheimer's (PD and AD) which are potentially linked to increased oxidative stress and inflammation. Paracetamol (APAP) is known for its antioxidant and anti-inflammatory properties; however, its potential neuroprotective effects against age-related oxidative stress and neuroinflammation remain inadequately investigated. Therefore, we aimed to examine whether low-dose APAP could mitigate oxidative stress and neuroinflammation in a D-galactose (D-gal)-induced aging model. In our study, fifty adult male ICR mice were divided into five groups (n = 10). Except for the normal control group, all mice received D-gal subcutaneous injections (200 mg/kg) and were fed vehicle, 15 or 50 mg/kg APAP, or 100 mg/kg vitamin E daily for six weeks. After treatment, liver function was assessed by serum liver enzyme analysis. The liver and brain pathologies were examined using hematoxylin and eosin staining. Brain oxidative stress was evaluated through malondialdehyde (MDA) measurement. Additionally, immunohistochemistry was used to determine levels of inflammatory cytokines (TNF-α, IL-1β, TGF-β, and IL-10) and the oxidative stress marker, NADPH Oxidase 4 (NOX4). The study found no significant changes in serum liver enzymes or liver morphology among the experimental groups. However, the D-gal group exhibited increased neuronal cell loss, along with elevated levels of MDA and NOX4 in the frontal cortex and hippocampus. Moreover, D-gal mice showed elevated levels of TNF-α, IL-1β, and TGF-β, accompanied by decreased IL-10 levels. Notably, treatment with low-dose APAP and vitamin E mitigated neuronal cell loss, decreased MDA levels, and attenuated NOX4 expression induced by D-gal injection. Furthermore, low-dose APAP, particularly at 50 mg/kg, and vitamin E reversed the alterations in TNF-α, IL-1β, and IL-10 induced by D-gal, while TGF-β was unaffected. We suggest that low-dose APAP exerts antioxidant and anti-inflammatory activities to protect against neurodegeneration in a mouse model of brain aging induced by chronic D-gal injection.},
}

@article {pmid41019272,
year = {2025},
author = {Fernandes, JVA and Ramos, JVO and Vilar, LADS and Holanda, MMA},
title = {Brexpiprazole for agitation in alzheimer's disease: A systematic review and meta-analysis of randomized controlled trials.},
journal = {Indian journal of psychiatry},
volume = {67},
number = {9},
pages = {852-861},
pmid = {41019272},
issn = {0019-5545},
abstract = {BACKGROUND: Agitation in Alzheimer's disease (AD) severely affects patients and caregivers. Brexpiprazole, a serotonin-dopamine modulator, is the potential treatment; however, recent trials and variations in dosing have raised questions about its optimal efficacy and safety.

AIM: To evaluate the efficacy and safety of brexpiprazole in the treatment of agitation associated with AD, with a focus on dose-specific outcomes.

METHODS: A systematic search was conducted in PubMed, Embase, and the Cochrane Library for Randomized Controlled Trials (RCT) comparing brexpiprazole with placebo in AD-related agitation. Primary efficacy outcomes included changes in the Cohen-Mansfield Agitation Inventory (CMAI) and Clinical Global Impression-Severity (CGI-S) scores. Safety outcomes encompassed treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and mortality. Meta-analyses were performed using a random-effects model, with mean differences (MD) and odds ratios (OR) reported with 95% confidence intervals (CI).

RESULTS: Four RCTs with 1,710 participants were included. Brexpiprazole 2 mg significantly reduced CMAI scores (MD: -5.618; 95% CI: -7.884, -3.351; P < 0.001) and CGI-S scores (MD: -0.513; 95% CI: -0.890, -0.135; P = 0.008) compared to placebo. Lower doses (0.5-1 mg) demonstrated limited efficacy. TEAEs were more frequent with brexpiprazole 2 mg (OR: 1.554; 95% CI: 1.045, 2.312; P = 0.030), while SAEs (OR: 1.389; P = 0.384) and mortality (OR: 2.189; P = 0.301) did not significantly differ from placebo.

CONCLUSION: Brexpiprazole 2 mg is effective in reducing agitation symptoms in AD with an acceptable safety profile.},
}

@article {pmid41018231,
year = {2025},
author = {Tziveleka, LA and Cascione, M and Pellegrino, P and Bianco, A and Leporatti, S and De Matteis, V},
title = {Immunomodulatory natural polysaccharide-based nanoparticles for the treatment of neurodegenerative diseases.},
journal = {Ibrain},
volume = {11},
number = {3},
pages = {277-296},
pmid = {41018231},
issn = {2769-2795},
abstract = {Polysaccharide-based nanoparticles offer significant potential for the treatment of neurodegenerative diseases and the modulation of inflammatory responses in the central nervous system. These biopolymers, when derived from natural sources, possess inherent immunomodulatory properties, which can be leveraged to regulate immune activity, positioning them as promising candidates for both prophylactic and therapeutic strategies. Furthermore, when integrated with other materials, polysaccharides form nanocomposites with enhanced structural, physicochemical, and biological properties, making them highly versatile platforms for drug delivery in the central nervous system. This review provides a comprehensive analysis of polysaccharide-based nanoparticles, focusing on their application in the treatment of three major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, and multiple sclerosis. Emphasis is placed on optimizing these nanomaterials for targeted drug delivery and immune modulation, underscoring their potential to improve therapeutic outcomes in neurodegenerative disorders. The review also examines the structural, chemical, and biological characteristics of key polysaccharides, and explores their innovative roles in combating neuroinflammation and neurodegeneration.},
}

@article {pmid41017736,
year = {2025},
author = {Laouini, SE and Bouafia, A and Azzi, M and Laib, I and Fellah, M and Abdullah, MMS and Al-Lohedan, HA and Abdullah, JAA},
title = {Synthesis and Characterization of Amoxicillin-Functionalized Ag/AgCl Nanoparticles: A Promising Multifunctional Platform for Next-Generation Nanomedicine.},
journal = {Journal of biomedical materials research. Part B, Applied biomaterials},
volume = {113},
number = {10},
pages = {e35661},
doi = {10.1002/jbm.b.35661},
pmid = {41017736},
issn = {1552-4981},
support = {ORF-2025-54//Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, Ongoing Research Funding program/ ; },
mesh = {*Amoxicillin/chemistry/pharmacology ; *Silver/chemistry/pharmacology ; *Silver Compounds/chemistry/pharmacology ; *Anti-Bacterial Agents/pharmacology/chemistry ; *Metal Nanoparticles/chemistry ; Escherichia coli/growth & development ; Animals ; *Nanomedicine ; Antioxidants/chemistry/pharmacology ; *Biofilms/drug effects/growth & development ; Cholinesterase Inhibitors/chemistry/pharmacology ; },
abstract = {This study synthesized and characterized amoxicillin-functionalized Ag/AgCl nanoparticles (Amoxicillin@Ag/AgCl NPs) for biomedical applications. The nanoparticles were prepared via a coprecipitation method and functionalized with amoxicillin to enhance therapeutic potential. Characterization techniques (X-ray diffraction [XRD], Fourier-transform infrared (FTIR), scanning electron microscopy [SEM], and UV-Vis) confirmed successful functionalization and improved physicochemical properties. The crystallite size increased from 17.29 ± 3.44 to 20.47 ± 4.17 nm, while the bandgap widened from 2.33 to 2.40 eV, indicating enhanced electronic interactions. Antioxidant activity was significantly improved, with 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging reaching 97.87% and β-carotene bleaching inhibition at 95.47% (175 μg/mL). The antibiofilm efficacy was notable, with inhibition rates of 90.24% for E. coli (250 μg/mL), 81.47% for S. typhimurium (175 μg/mL), and 87.68% for B. subtilis (250 μg/mL). In enzymatic inhibition studies, Amoxicillin@Ag/AgCl NPs showed neuroprotective potential, inhibiting acetylcholinesterase (AChE) (93.74% at 160 μg/mL) and butyrylcholinesterase (BChE) (97.41% at 80 μg/mL), highlighting their potential in Alzheimer's treatment. Additionally, they exhibited anti-inflammatory effects, inhibiting lipoxygenase (LOX) by 90.47% (120 μg/mL). To the best of our knowledge, this is the first report on the synthesis of Amoxicillin@Ag/AgCl NPs that simultaneously demonstrate strong antioxidant, antibiofilm, neuroprotective, and anti-inflammatory properties, underscoring their novelty as next-generation nanomedicines.},
}

*Amoxicillin/chemistry/pharmacology
*Silver/chemistry/pharmacology
*Silver Compounds/chemistry/pharmacology
*Anti-Bacterial Agents/pharmacology/chemistry
*Metal Nanoparticles/chemistry
Escherichia coli/growth & development
Animals
*Nanomedicine
Antioxidants/chemistry/pharmacology
*Biofilms/drug effects/growth & development
Cholinesterase Inhibitors/chemistry/pharmacology

@article {pmid41017725,
year = {2025},
author = {Zhang, J and He, S and Xiao, Q and Jiang, W and Wang, B and Lu, J and Gu, H and Liao, Y and Wang, Z and Xu, Y and Wang, D and Tang, X and Qi, L},
title = {Engineered mesenchymal stem cell-derived extracellular vesicles overexpressing miR-146a alleviate neuroinflammation in Alzheimer's disease.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00404},
pmid = {41017725},
issn = {1673-5374},
abstract = {Alzheimer's disease is an inflammatory neurodegenerative disease for which no effective clinical treatment currently exists. We have previously reported that mesenchymal stem cell.derived extracellular vesicles delay retinal degeneration by exerting anti-inflammatory effects though the miR-146a.nuclear receptor subfamily 4 group A member 3 axis; however, it remains unclear how NR4A3 drives inflammation. Herein, we engineered mesenchymal stem cell. derived extracellular vesicles overexpressing miR-146a to explore their possible neuroprotective effects and the underlying mechanisms in both cell and animal models of Alzheimer's disease. In HT22 cells co-cultured with lipopolysaccharide-induced RAW264.7/BV2 cells, extracellular vesicles overexpressing miR- 146a significantly reduced the number of apoptotic cells and inhibited proinflammatory cytokine expression, nuclear factor (NF)-κB activation, and caspase-3/ apoptosis regulator BAX signaling. These effects of extracellular vesicles overexpressing miR-146a were replicated in 5×FAD mice. In addition, extracellular vesicles overexpressing miR-146a inhibited the activation of microglia and astrocytes, reduced amyloid-β and phosphorylated tau expression, lowered the number of apoptotic cells in the hippocampus, and improved the cognitive function of these Alzheimer's disease model mice. Mechanistically, miR-146a negatively regulated the expression of nuclear receptor subfamily 4 group A member 3 and suppressed the expression of proinflammatory cytokines and nuclear factor-κB signaling. Furthermore, NR4A3 overexpression promoted nuclear factor-κB and proinflammatory cytokine expression as well as nuclear factor-κB signaling. The upregulation of NR4A3 and the inflammatory response was reversed by miR-146a overexpression. Finally, NR4A3 was identified as a transcriptional activator of nuclear factor-κB using chromatin immunoprecipitation polymerase chain reaction. Collectively, these findings indicate that extracellular vesicles overexpressing miR-146a may alleviate the progression of Alzheimer's disease by exerting anti-inflammatory effects via the NR4A3. nuclear factor-κB axis. They are thus a potential therapeutic candidate for the clinical treatment of neurodegenerative diseases.},
}

@article {pmid41017722,
year = {2025},
author = {Xu, X and Li, J and Wang, F and Xue, K and He, J and Meng, X and Shen, Y},
title = {Genetic and pathway complexity in Alzheimer's disease: Insights from multi-omic data about the immune response and mitochondrial function.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00184},
pmid = {41017722},
issn = {1673-5374},
abstract = {Despite recent developments, the genetics and biology of Alzheimer's disease remain insufficiently characterized. As an important first step toward developing effective treatment strategies to slow or prevent Alzheimer's disease onset, the identification of relevant genetic markers is crucial. In the present study, we analyzed transcriptomic and multi-omic datasets across multiple cohorts (the Alzheimer's Disease Neuroimaging Initiative, Religious Orders Study and Rush Memory and Aging Project, Mount Sinai Brain Bank, and Mayo Clinic Alzheimer's Disease Genetics Studies) using gene set enrichment analysis, machine learning algorithms, and polygenic risk scoring to identify gene sets relevant to Alzheimer's disease risk and pathological features. For prioritized gene sets, we performed epigenome-wide association studies to assess DNA methylation patterns, and used multi-omic mediation analysis to characterize the causal gene regulatory networks. Overall, we identified several key gene sets relevant to Alzheimer's disease pathology-particularly, those related to immune system function and mitochondrial dysfunction. Upregulated pathways, including neutrophil degranulation and tumor necrosis factor-α signaling pathways, correlated strongly with aspects of neuroinflammation in Alzheimer's disease. By contrast, downregulated oxidative phosphorylation pathways further suggested mitochondrial dysfunction. Gene sets that contained mitochondrially located genes (e.g., SGK1 and LRRK1) were identified as significantly contributing to neurodegeneration. Moreover, genes such as CXCL1, TGFB2, and DUSP1 were consistently implicated in all datasets, thus emphasizing their involvement in immune modulation and mitochondrial function. The multimodal investigation outlined in the current study represents useful steps toward comprehending the genetic architecture of Alzheimer's disease, including an expanded understanding of the spatial interactions of genes associated with disease susceptibility. Mitochondrial dysfunction and immune modulation were pathological pathways that converged on Alzheimer's disease and future treatment novel options. Using the frameworks provided in the current comprehensive study, we present opportunities to explore targeted treatment strategies that may alter immune systems and mitochondrial function to optimize treatment outcomes for individuals at increased risk of or living with Alzheimer's disease.},
}

@article {pmid41017717,
year = {2025},
author = {Yuan, H and Shi, J and Gu, C and Yuan, J and Huang, C and Li, X and Zhou, K and Qi, J},
title = {Akkermansia muciniphila: A next-generation gut probiotic supporting neurorepair and functional recovery.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00701},
pmid = {41017717},
issn = {1673-5374},
abstract = {The brain-gut axis is a bidirectional signal transduction system between the gastrointestinal tract and the central nervous system that integrates neural, endocrine, and immune functions. In recent years, the role of the intestinal flora in regulating neural function and affecting the progression of different neurological diseases has received increasing attention. Akkermansia muciniphila is a mucindegrading bacterium of the intestinal flora present in the intestinal mucus layer that can regulate host immunity, the intestinal barrier and neuroimmune homeostasis. In recent years, a growing body of literature has suggested that Akkermansia muciniphila may play beneficial roles in nerve injury and regeneration by regulating brain-gut axis signalling. This review comprehensively summarizes the latest research results on the role of Akkermansia muciniphila in neurological diseases such as spinal cord injury, multiple sclerosis, Parkinson's disease, and Alzheimer's disease. The mechanisms by which Akkermansia muciniphila regulates inflammatory cytokines, neurotransmitters, and shortchain fatty acids are also highlighted. Various Akkermansia muciniphila-based interventions, such as those involving outer membrane proteins, extracellular vesicles, and pasteurized Akkermansia muciniphila, are discussed, and their therapeutic potential in restoring intestinal homeostasis, alleviating neuroinflammation, and supporting neuronal repair is explored. Although promising results from animal models have been reported, significant challenges remain in translating these findings into clinical practice and therapeutic applications. The differences in Akkermansia muciniphila colonization efficiency, host responses, and intervention strategies in different disease states limit the results of these studies. In addition, Akkermansia muciniphila may exhibit different mechanisms of action in acute and chronic neurodegenerative diseases, and thus more targeted mechanistic studies are needed. Despite these limitations, Akkermansia muciniphila represents a novel and potent pathway for the modulation of the brain-gut axis to support neural repair and functional recovery. By enhancing intestinal barrier integrity and regulating neuroimmunity, Akkermansia muciniphila has broad prospects as a microbial candidate for the treatment of central nervous system diseases. Future research should focus on optimizing the administration method and clinical trials to verify its efficacy, ultimately providing new treatment options in the field of neural regeneration and microbial therapy.},
}

@article {pmid41017705,
year = {2025},
author = {Wang, H and Wei, Y and Wang, J and Liu, J and Ou, S and Wang, J},
title = {Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00354},
pmid = {41017705},
issn = {1673-5374},
abstract = {The voltage-gated sodium channel Nav1.6, encoded by the sodium voltage-gated channel alpha subunit 8 gene, is a crucial regulator of neuronal excitability, with widespread expression throughout the central and peripheral nervous systems. Recent breakthroughs in structural biology, particularly the elucidation of the cryo-EM architecture of Nav1.6 at a resolution of 0.31 nm, have provided unprecedented insights into its molecular organization and functional modulation. As a key mediator of action potential initiation and propagation, Nav1.6 possesses unique biophysical properties, including persistent and resurgent sodium currents that critically influence neuronal firing patterns. This comprehensive review synthesizes current knowledge on the physiological functions and pathological roles of Nav1.6 in multiple neurological conditions. Key findings include the following: (1) Epilepsy studies reveal more than 250 sodium voltage-gated channel alpha subunit 8 mutations with distinct genotype-phenotype correlations, where gain-of-function variants lead to severe epileptic encephalopathies, while loss-of-function variants are associated with generalized epilepsy, highlighting the potential of Nav1.6-selective blockers such as XEN901 and GS967. (2) In Alzheimer's disease, Nav1.6 mediates amyloid-β oligomer-induced neuronal hyperexcitability through amyloid precursor protein-dependent membrane trafficking and regulates beta-secretase 1 expression via nuclear factor of activated T cells 1 signaling, suggesting novel disease-modifying strategies. (3) Parkinson's disease research has demonstrated that Nav1.6 upregulation in reactive astrocytes in the globus pallidus contributes to motor deficits through calcium-mediated abnormalities in neuronal synchronization. (4) Amyotrophic lateral sclerosis involves Nav1.6-dependent cortical hyperexcitability preceding motor neuron degeneration, with riluzole showing partial efficacy through sodium current modulation. (5) Multiple sclerosis pathophysiology features Nav1.6 redistribution in demyelinated axons, which drives calcium-dependent axonal injury via reverse Na+/Ca2+ exchange. (6) Chronic pain mechanisms involve Nav1.6 overexpression in dorsal root ganglia neurons, regulated by the p38 mitogen-activated protein kinase and tumor necrosis factor-α signaling pathways. (7) Traumatic brain injury models show that exercise-induced cognitive improvement is correlated with the normalization of Nav1.6-mediated excitability. Therapeutic development has progressed from nonselective sodium channel blockers to precision approaches, including state-dependent pore blockers designed using structural insights; allosteric modulators targeting specific conformations; gene therapy strategies using clustered regularly interspaced short palindromic repeats and antisense oligonucleotides; and miRNA-based regulation of channel expression. Current challenges include achieving sufficient subtype selectivity, optimizing blood-brain barrier penetration, and developing clinically relevant biomarkers for patient stratification. Future directions emphasize the integration of advanced technologies-such as singlecell multiomics to map neuronal subtype-specific expression patterns, patient-derived organoids for personalized drug testing, and machine learning-assisted drug design-to accelerate translation. Large-scale collaborative efforts will be essential to validate therapeutic candidates and establish genotype-guided treatment protocols for Nav1.6-related disorders.},
}

@article {pmid41017698,
year = {2025},
author = {Li, Y and Zhang, Y and Wang, Y and Ye, K and Liu, L and Tian, M and Han, X and Chen, X and Zheng, T and Li, F and Gao, X and Xia, Q and Wang, D},
title = {N6-methyladenosine modification regulates cell death in cognitive impairment.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-25-00813},
pmid = {41017698},
issn = {1673-5374},
abstract = {Neurodegenerative diseases are characterized by a decline in brain structure and function. Their pathology involves multiple cell death pathways, including ferroptosis, cuproptosis, and pyroptosis. These pathways are intricately linked to genes associated with metabolism, antioxidant defense, lipid metabolism, chronic inflammation, and nerve regeneration processes. Key regulators of atypical cell death pathways show aberrant N6-methyladenosine modification levels under pathological conditions. As the most abundant and dynamic RNA modification in brain tissue, N6-methyladenosine plays crucial functional roles. Notably, there exists an intricate interplay between N6-methyladenosine modifications and these cell death pathways, both of which are robustly associated with the pathogenesis of neurodegenerative diseases. However, the molecular mechanisms underlying this association remain unclear. This paper reviews the correlation between N6-methyladenosine and various cell death patterns in neurodegenerative diseases, with emphasis on the molecular mechanisms underlying the interaction between N6-methyladenosine epigenetic regulation and ferroptosis, cuproptosis, and pyroptosis in cognitive impairment. N6- methyladenosine-modified ferroptosis plays an important role in neurodegenerative diseases. There is also a close association between N6-methyladenosine modification and key molecules related to cuproptosis, which may promote the deposition of copper in the brain. Chronic inflammation, a hallmark of neurodegenerative diseases, is related to pyroptosis and N6-methyladenosine modification. It is widely thought that ferroptosis, cuproptosis, and pyroptosis are interconnected processes that may share a common pathway affecting the pathogenesis of neurodegenerative diseases, and are related to key molecules involved in N6-methyladenosine epigenetic modification. This suggests a great potential for future neurodegenerative diseases treatment strategies regulated by N6-methyladenosine modification. N6-methyladenosine modification plays a dual role in nerve injury and regeneration by dynamically regulating processes such as ferroptosis, cuproptosis, and pyroptosis and their key molecules. It maintains the "death-regeneration" balance in oxidative stress and inflammation while selectively promoting axon regeneration through the modulation of methylases. This mechanism indicates a considerable therapeutic target for neurological disorders.},
}

@article {pmid41017390,
year = {2025},
author = {Chen, JD and Chen, SY and Liao, CC and Fang, CY and Yen, GC},
title = {Enhancing cognitive memory function using Phyllanthus emblica polysaccharides via modulating autophagy and reshaping the gut microbiota.},
journal = {Food & function},
volume = {},
number = {},
pages = {},
doi = {10.1039/d5fo03048j},
pmid = {41017390},
issn = {2042-650X},
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by neuroinflammation, oxidative stress, amyloid-beta (Aβ) plaque buildup, Tau hyperphosphorylation, and gut microbiota imbalance. Natural polysaccharides have been shown to mitigate cognitive decline by regulating the microbiota-gut-brain axis and autophagy, inhibiting neuroinflammation, enhancing Aβ efflux, and facilitating the clearance of Tau protein. Phyllanthus emblica polysaccharides (PEP) exhibit anti-inflammatory, antioxidant, and gut microbiota-modulating properties in colitis and obese mice. However, the potential of PEP in AD prevention remains unclear, prompting the need to investigate the underlying mechanisms of PEP in AD prevention. Physicochemical analysis characterized PEP (MW: 1.182 × 10[3] kDa) as a non-crystalline, heat-stable α-acidic pyran heteropolysaccharide composed of galactose and arabinose monosaccharides. In vivo results showed that PEP administration significantly alleviated cognitive decline by reducing neuroinflammatory cytokines (TNF-α, IL-6, and IL-1β) and MDA levels while increasing anti-inflammatory factors (IL-4 and IL-10) and antioxidants (SOD, catalase, and GPx) in AlCl3-treated rats. Mechanistically, PEP upregulated autophagy-related proteins (Atg5, Beclin1, and LC3B) and LRP1 expression while downregulating AD-related proteins (BACE1, APP, Aβ, and phospho-Tau[Ser404]). Additionally, PEP treatment elevated short-chain fatty acids (SCFAs) and SCFA-producing bacteria, particularly the Christensenellaceae_R-7_group. In summary, PEP demonstrated preventive effects by exerting antioxidant, anti-inflammatory, autophagy-inducing, AD-related protein-suppressing, and microbiota-modulating properties, alleviating cognitive impairment in rats subjected to AlCl3 treatment.},
}

@article {pmid41017285,
year = {2025},
author = {Guo, S and Wei, F and Sun, H and Jin, H and Cheng, W and Fu, C and Wang, H and Yin, Y},
title = {Astrocyte-Specific Nrf2 Expression Transforms Neurotoxic Reactive Astrocytes to Neuroprotective Phenotype in 3xTg-AD Mice.},
journal = {Glia},
volume = {},
number = {},
pages = {},
doi = {10.1002/glia.70087},
pmid = {41017285},
issn = {1098-1136},
support = {82472014//National Natural Science Foundation of China/ ; 81974270//National Natural Science Foundation of China/ ; 24ZR1450000//Natural Science Foundation of Shanghai Municipality/ ; 23ZR1441200//Natural Science Foundation of Shanghai Municipality/ ; },
abstract = {Astrocyte reactivity is a common feature of Alzheimer's disease (AD), with reactive astrocytes traditionally subdivided into neurotoxic or neuroprotective phenotypes. It's crucial to transform neurotoxic reactive astrocytes to neuroprotective phenotypes for the treatment of AD, particularly during the progression of the disease. In this study, we evaluated the role of nuclear factor E2-related factor 2 (Nrf2) in facilitating the phenotype transformation of reactive astrocytes in vivo and in vitro by overexpressing Nrf2 in hippocampal astrocytes of 3xTg-AD mice using adeno-associated virus (AAV) vectors, as well as treating neurotoxic reactive astrocytes with dimethyl fumarate (a Nrf2 activator). We also evaluated the therapeutic effect of astrocyte-specific Nrf2 in 3xTg-AD mice with coexpression of Aβ and tau pathologies. Our findings indicate that Nrf2 could facilitate the conversion of neurotoxic reactive astrocytes to neuroprotective phenotypes in vivo and in vitro. AAV-mediated astrocyte-specific Nrf2 expression improved cognitive function, reduced Aβ and tau pathologies, rescued the loss of neurons and synapses, and ameliorated neuroinflammation in 3xTg-AD mice. These findings highlighted the role of Nrf2 in modulating reactive astrocyte phenotypes and suggested the potential for utilizing AAV to target astrocyte-specific Nrf2 as a promising therapeutic strategy for AD.},
}

@article {pmid41016794,
year = {2025},
author = {Huang, Y and Wei, F and Cheng, X and Shi, Y and Liu, Z and Ye, L},
title = {Neurotropin alleviates Alzheimer's disease pathology by inhibiting FUS-mediated Calhm2 transcription, blocking the Calhm2/EFhd2 interaction, to improve mitochondrial dysfunction-associated microglia polarization.},
journal = {Bioscience trends},
volume = {},
number = {},
pages = {},
doi = {10.5582/bst.2025.01220},
pmid = {41016794},
issn = {1881-7823},
abstract = {Neurotropin, a non-protein extract widely used for the treatment of neuropathic pain, has recently been reported to protect against ischemic brain injury, enhance remyelination in demyelinating diseases, and ameliorate neuroinflammation and memory deficits. However, its role in microglial polarization and mitochondrial dysfunction in Alzheimer's disease (AD) remains poorly understood. In this study, we investigated the therapeutic potential of Neurotropin in the 5xFAD mouse model of AD. Neurotropin administration alleviated cognitive decline, reduced amyloid-β (Aβ) deposition, suppressed neuroinflammation, and preserved neuronal density. Mechanistically, Neurotropin improved mitochondrial morphology, restored ATP production, increased mitochondrial DNA copy number, and reduced oxidative stress while promoting a shift in microglial polarization from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype. Transcriptomic and molecular analyses revealed that calcium homeostasis modulator family member 2 (Calhm2) was markedly upregulated in 5xFAD mice, colocalized with microglia, and transcriptionally regulated by fused in sarcoma (FUS), while Calhm2 interacted with EF-hand domain containing protein D2 (EFhd2). Neurotropin suppressed FUS-mediated Calhm2 transcription and attenuated Calhm2-EFhd2 interaction. Importantly, overexpression of Calhm2 in both microglial cells and 5xFAD mice abolished the beneficial effects of Neurotropin, leading to exacerbated mitochondrial dysfunction, oxidative stress, and inflammatory cytokine release. Together, these findings identify Calhm2 as a critical mediator of Neurotropin's neuroprotective effects and demonstrate that Neurotropin alleviates AD pathology by suppressing FUS-dependent Calhm2 transcription and blocking the Calhm2/EFhd2 interaction. This study provides new insights into the mechanism of Neurotropin action and highlights its therapeutic potential for AD.},
}

@article {pmid41016150,
year = {2025},
author = {Bautista-Aguilera, ÓM and Manik, A and Diez-Iriepa, D and Szałaj, N and Zaręba, P and Więckowska, A and Żmudzki, P and Honkisz-Orzechowska, E and Knez, D and Gobec, S and Sałat, K and Martínez-Alonso, B and Guarnizo-Herrero, V and Durán, GT and Torrado-Salmerón, C and Bellver-Sanchis, A and Nsiona-Defise, I and Ribalta-Vilella, M and Pallàs, M and López-Muñoz, F and Griñán-Ferré, C and Marco-Contelles, J and Iriepa, I},
title = {N-Methyl-N-((1-methyl-5-(3-(piperidin-1-yl)propoxy)-1H-benzo[d]imidazol-2-yl)methyl)prop-2-yn-1-amine (MBA-159), a new multitarget small molecule for the therapy of Alzheimer's disease.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {192},
number = {},
pages = {118603},
doi = {10.1016/j.biopha.2025.118603},
pmid = {41016150},
issn = {1950-6007},
abstract = {As part of a project aimed at the pharmacological optimization of Contilisant, herein we describe molecular modelling studies that led to the identification of MBA-159 as a new polyfunctionalized, multitarget-directed ligand and a promising drug candidate for the treatment of Alzheimer's disease. We synthesized MBA-159 and conducted comprehensive in vitro and in vivo evaluations. In in vivo studies MBA-159 demonstrated favourable pharmacokinetics, anti-amnesic properties and significantly improved non-spatial memory (contextual and recognition memory) in a mouse model of scopolamine-induced amnesia. Additionally, MBA-159 showed a tendency to increase synaptic plasticity biomarkers and reduce neuroinflammatory trends (assessed by qPCR), as well as cognitive enhancement in a senescence-accelerated prone mouse 8 model.},
}

@article {pmid41015981,
year = {2025},
author = {Abushakra, S and Power, A and Watson, D and Porsteinsson, A and Sabbagh, M and MacSweeney, E and Cohen, S and Boada Rovira, M and Doraiswamy, PM and Liang, E and Flint, S and Kesslak, JP and McLaine, R and Albayrak, A and Schaefer, J and Yu, J and Tolar, L and Dickson, S and Hey, JA and Tolar, M},
title = {Clinical Efficacy, Safety and Imaging Effects of Oral Valiltramiprosate in APOEε4/ε4 Homozygotes with Early Alzheimer's Disease: Results of the Phase III, Randomized, Double-Blind, Placebo-Controlled, 78-Week APOLLOE4 Trial.},
journal = {Drugs},
volume = {},
number = {},
pages = {},
pmid = {41015981},
issn = {1179-1950},
support = {R01-AG065253/AG/NIA NIH HHS/United States ; },
abstract = {BACKGROUND: The apolipoprotein E ε4 (APOE ε4) allele is the strongest genetic risk factor for Alzheimer's disease (AD), with homozygotes accumulating a high burden of cerebral beta-amyloid (Aβ) pathology. Valiltramiprosate/ALZ-801 is a small-molecule potent inhibitor of Aβ-oligomer formation. The efficacy, safety/tolerability, and brain volume effects of oral valiltramiprosate were evaluated in this phase III, randomized, double-blind, placebo-controlled, multi-center, 78-week trial in homozygotes with early symptomatic AD.

METHODS: The study enrolled eligible APOE4/4 subjects aged 50-80 years with Early AD (Mini-Mental State Examination [MMSE] 22-30), which included mild cognitive impairment (MCI) and mild dementia, Clinical Dementia Rating-Global Score (CDR-G) of 0.5 or 1, who were randomized 1:1 to valiltramiprosate (265 mg twice/day) or placebo. The primary outcome was AD Assessment Scale-Cognitive Subscale (ADAS-Cog13); the key secondary outcomes were CDR-Sum of Boxes (CDR-SB) and Amsterdam-Instrumental Activities of Daily Living (IADL), and a secondary outcome was Disability Assessment for Dementia (DAD). The main imaging outcome was hippocampal volume on MRI; diffusion tensor imaging (MRI-DTI) assessed microstructural tissue integrity. Amyloid-related imaging abnormalities (ARIA) were monitored with MRIs every 26 weeks.

RESULTS: A total of 325 participants enrolled and received study drug. At 78 weeks, the overall efficacy population did not show significant effects on ADAS-Cog13 or other clinical outcomes compared with placebo (ADAS-Cog13: 11% slowing; p = 0.607, N = 320), but showed significant slowing of hippocampal atrophy (18%, p = 0.017, N = 290). Prespecified analyses by disease severity (stratification variable) showed no significant clinical effects in mild AD (MMSE ≤26, N = 195). The prespecified MCI group (MMSE >26, N = 125) showed nominally significant positive effects on ADAS-Cog13 (52%, nominal p = 0.041) and DAD (96%, nominal p = 0.016), positive trend on CDR-SB (102%, nominal p = 0.053), with significant hippocampal atrophy slowing (26%, p = 0.004), and positive grey/white matter effects on MRI-DTI. In the MCI group, positive ADAS-Cog13 drug effects showed significant subject-level correlations with positive effects on imaging outcomes. The most common adverse events were nausea, vomiting, and decreased appetite (more than double placebo rate), with no increased risk of brain edema or microhemorrhages.

CONCLUSIONS: The APOE4/4 Early AD population did not show significant clinical efficacy at 78 weeks but showed significant brain atrophy slowing. Prespecified analyses at the MCI stage showed nominally significant slowing of clinical decline with significant hippocampal atrophy slowing. Oral valiltramiprosate may provide a favorable benefit-risk profile and simple treatment paradigm for homozygotes with MCI. These results will inform the design of future MCI trials.

TRIAL REGISTRATION: Clinicaltrials.gov: NCT04770220; EudraCT Number: 2020-005755-20.},
}

@article {pmid41015797,
year = {2025},
author = {Shuang, NI and Xiaofei, L and Xiaoyan, G and Zuxi, GU and Panqing, WU and Chao, C and Shengnan, LI and Xianwei, G and Lianwei, XU},
title = {Mechanism of Tiaogeng decoction in a cognitive dysfunction mouse model.},
journal = {Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan},
volume = {45},
number = {5},
pages = {987-997},
pmid = {41015797},
issn = {2589-451X},
support = {81874482//Natural Science Foundation-funded Project: Mechanism of Tiaogeng Decoction improving Cognitive Function via Regulating Nuclear Factor-erythroid 2-related Factor 2/c-Jun N-terminal kinase/Aβ Oxidative Stress Network in Hippocampus Neurons/ ; },
mesh = {Animals ; *Drugs, Chinese Herbal/administration & dosage ; Mice ; *Cognitive Dysfunction/drug therapy/genetics/metabolism/psychology ; Female ; Disease Models, Animal ; Hippocampus/drug effects/metabolism ; Oxidative Stress/drug effects ; Mice, Inbred C57BL ; Mice, Transgenic ; Humans ; Amyloid beta-Peptides/metabolism/genetics ; Apoptosis/drug effects ; NF-E2-Related Factor 2/metabolism/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism/genetics ; },
abstract = {OBJECTIVE: To explore the mechanism of action of Tiaogeng decoction (, TG) in alleviating oxidative stress damage in the hippocampus of a mouse model of cognitive impairment.

METHODS: Amyloid precursor protein/presenilin-1 (APP/PS1) transgenic female mice were randomly divided into model, estradiol valerate, low-, medium-, and high-dose TG groups, female C57 mice were used as the control group (n = 12/group). After 12 weeks of treatment, the behavior of mice was tested with the Morris water maze, and brain tissue samples were collected, and changes in hippocampal neurons were observed using electron microscopy. The deposition of beta-amyloid protein (Aβ) amyloid plaques in the hippocampus was determined by light microscopy. Aβ1-42 protein levels were detected through immunofluorescence. Oxidative stress indicators in the hippocampus were detected by enzyme linked immunosorbent assay. The expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2), c-Jun N-terminal kinase (JNK), phospho-JNK (p-JNK), B-cell lymphoma-2 (Bcl-2), caspase-9, and cleaved caspase-9 were detected by Western blot. Hippocampal cell apoptosis was detected using the terminal deoxynucleotidyl transferase-mediated nick end Labeling.

RESULTS: TG improved the cognitive function of APP/PS1 mice, as judged by improvements in several indices from the Morris water maze test. TG increased Nrf2, superoxide dismutase, and heme oxygenase-1 protein expression and reduced malondialdelyde and reactive oxygen species expression. TG also inhibited the expression of JNK proteins, upregulated the expression of Bcl-2, and downregulated the expression of caspase-9, reducing cell apoptosis. TG decreased the percentage of the hippocampal cornu ammonis 1 area positive for Aβ1-42, reducing mitochondrial damage caused by oxidative stress and Aβ protein deposition.

CONCLUSIONS: TG may improve memory ability while reducing oxidative stress and apoptosis. It also reduces Aβ protein deposition in the hippocampus, protecting the central nervous system and improving memory function. TG may reduce the risk of AD.},
}

Animals
*Drugs, Chinese Herbal/administration & dosage
Mice
*Cognitive Dysfunction/drug therapy/genetics/metabolism/psychology
Female
Disease Models, Animal
Hippocampus/drug effects/metabolism
Oxidative Stress/drug effects
Mice, Inbred C57BL
Mice, Transgenic
Humans
Amyloid beta-Peptides/metabolism/genetics
Apoptosis/drug effects
NF-E2-Related Factor 2/metabolism/genetics
Proto-Oncogene Proteins c-bcl-2/metabolism/genetics