@article {pmid40559320,
year = {2025},
author = {Gharaibeh, S and Alsabbah, A and Alloubani, A and Gharaibeh, A},
title = {Reciprocal Interactions Between Periodontal Disease and Alzheimer's Disease: Implications for Mutual Triggering, Exacerbation, and Treatment Interventions-A Comprehensive Review of the Literature.},
journal = {Neurology international},
volume = {17},
number = {6},
pages = {},
doi = {10.3390/neurolint17060081},
pmid = {40559320},
issn = {2035-8385},
abstract = {Periodontal health is connected to many systemic diseases, such as cardiovascular, diabetes mellitus, and neurodegenerative diseases. The oral-brain axis has gained increasing interest in the pathogenesis of diseases. Emerging studies have highlighted the potential role of periodontal disease in the development and progression of Alzheimer's disease. However, Alzheimer's disease also affects periodontal disease and oral health. In this review, we address the correlation between the two diseases and the mechanisms by which one contributes to the other. Exploring the correlation between Alzheimer's disease and periodontal disease will assist in better understanding the pathophysiology of diseases and pave the way for the development of therapeutic and preventive strategies.},
}

@article {pmid40559212,
year = {2025},
author = {Lee, AW and Hirani, R and Ogulnick, J and Tiwari, RK and Etienne, M},
title = {Emerging Therapies for Neurological Disorders: A Clinical Review of MANAGED (Music, Art, Nature-Based, Animal-Assisted, Game, Essential Oil, Dance) Care.},
journal = {NeuroSci},
volume = {6},
number = {2},
pages = {},
doi = {10.3390/neurosci6020051},
pmid = {40559212},
issn = {2673-4087},
abstract = {In the face of the limitations in pharmacological and surgical interventions for neurological conditions such as Parkinson's and Alzheimer's disease, patients are increasingly turning to non-pharmacological and alternative therapies to manage their symptoms and improve their quality of life. This shift underscores the urgent need for accessible, effective, and affordable treatments. This literature review examines a range of alternative and personalized therapies, including game therapy, animal-assisted therapy, dance therapy, art therapy, music therapy, aroma therapy, and shinrin-yoku therapy. These modalities have demonstrated promising results in mitigating symptoms and enhancing well-being among individuals grappling with neurological disorders. Moreover, these therapies offer a holistic approach that complements traditional medical interventions, underscoring the importance of integrating diverse treatment modalities. Despite their historical roots in non-clinical settings, their potential in modern clinical practice remains untapped. The findings suggest the necessity for further research, particularly large cohort studies, to validate the efficacy of these personalized therapies and advocate for their widespread adoption. In an era marked by escalating healthcare costs, the exploration of alternative therapies presents a compelling avenue for enhancing patient care while simultaneously addressing economic challenges within the healthcare system.},
}

@article {pmid40559126,
year = {2025},
author = {Li, Z and Zhang, Y and Su, R and Yang, J and Chen, F and Chen, L and Yao, C and Li, S and Cui, P and Meng, X and Huang, G},
title = {Notoginsenoside R1, a Novel Natural PPARγ Agonist, Attenuates Cognitive Deficits in a Mouse Model of Diabetic Alzheimer's Disease Through Enhancing GLUT4-Dependent Neuronal Glucose Uptake.},
journal = {Phytotherapy research : PTR},
volume = {},
number = {},
pages = {},
doi = {10.1002/ptr.70006},
pmid = {40559126},
issn = {1099-1573},
support = {82474108//National Natural Science Foundation of China/ ; 82371423//National Natural Science Foundation of China/ ; 2023A1515220241//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515030035//Natural Science Foundation of Guangdong Province/ ; 2022A1515012323//Natural Science Foundation of Guangdong Province/ ; 2021A151510836//Natural Science Foundation of Guangdong Province/ ; //Shenzhen Science and Technology Program/ ; JCYJ20220530151006013//Basic research projects of Shenzhen Science and Technology Program/ ; JCYJ20180507184656626//Basic research projects of Shenzhen Science and Technology Program/ ; ZDSYS20140509173142601//Shenzhen Key Laboratory of Neurosurgery/ ; RCBS20210609104629074//Shenzhen Development and Reform Commissions Stroke Screening and Prevention Public Service Platform improving program/ ; //Guangdong Innovation Platform of Translational Research for Cerebrovascular Diseases/ ; },
abstract = {Our previous studies demonstrated the potential of notoginsenoside R1 (NGR1), a primary bioactive compound from Panax notoginseng, in alleviating diabetic encephalopathy in db/db mice and mitigating amyloid-β (Aβ)-induced neuronal damage. This study aimed to investigate the positive effects of NGR1 against cognitive deficits in a diabetic Alzheimer's disease (AD) mouse model (APP/PS1xdb/db mice). APP/PS1xdb/db mice were intragastrically administrated with NGR1 (40 mg/kg/day) or co-administrated with NGR1 and a selective PPARγ inhibitor GW9662 for 16 weeks. We identified NGR1 as a novel PPARγ agonist through molecular docking, surface plasmon resonance, and dual-luciferase reporter assay. NGR1 treatment significantly promoted the membrane translocation of GLUT4 and enhanced 2-deoxyglucose uptake in primary mouse hippocampal neurons. Furthermore, NGR1 treatment notably mitigated cognitive deficits in APP/PS1xdb/db mice. This treatment correlated with reduced blood glucose levels, lowered blood HbA1c, and decreased serum insulin levels, coupled with enhanced glucose tolerance and insulin sensitivity. Additionally, NGR1 treatment ameliorated Aβ burden, suppressed microglia-induced neuroinflammation, and notably increased cerebral glucose uptake, as demonstrated by [18]F-FDG PET scans. NGR1 treatment could upregulate PPARγ and GLUT4 expression and increase phosphorylation of Akt at Ser473 while decreasing phosphorylation of IRS-1 at Ser616 in the hippocampus of APP/PS1xdb/db mice. Crucially, the protective effects of NGR1 were abolished by co-administration with GW9662. NGR1 demonstrated efficacy in enhancing neuronal glucose uptake through the activation of the PPARγ/Akt/GLUT4 signaling pathways in APP/PS1xdb/db mice, positioning it as a promising candidate for diabetic AD treatment.},
}

@article {pmid40558561,
year = {2025},
author = {Jarne-Ferrer, J and Pallàs, M and Griñán-Ferré, C and Bellver-Sanchis, A},
title = {Investigating the Synergistic Neuroprotective Effects of Plant-Derived Antioxidants and the Psychedelic N,N-Dimethyltryptamine in Alzheimer's Disease Therapy.},
journal = {Cells},
volume = {14},
number = {12},
pages = {},
doi = {10.3390/cells14120934},
pmid = {40558561},
issn = {2073-4409},
mesh = {*Alzheimer Disease/drug therapy/pathology ; Animals ; *Antioxidants/pharmacology/therapeutic use ; *Neuroprotective Agents/pharmacology/therapeutic use ; Caenorhabditis elegans/drug effects ; Oxidative Stress/drug effects ; Drug Synergism ; Amyloid beta-Peptides/metabolism ; Humans ; Disease Models, Animal ; Animals, Genetically Modified ; },
abstract = {Alzheimer's disease (AD) is a chronic and complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and irreversible impairment of brain functions. The etiology of AD is multifactorial, involving a complex interplay of genetic, environmental, and physiological factors, including the aggregation of amyloid-β (Aβ) and oxidative stress (OS). The role of OS in AD pathogenesis is of particular significance, given that an imbalance between oxidants and antioxidants promotes cellular damage, exacerbates Aβ deposition, and leads to cognitive deterioration. Despite extensive research, current therapeutic strategies have largely failed, likely due to the use of single-target drugs unable to halt the multifactorial progression of the disease. In this study, we investigated the synergistic therapeutic effect of plant-derived bioactive compounds Withanone, Apigenin, Bacoside A, Baicalin, and Thymoquinone in combination with N,N-Dimethyltryptamine (NN-DMT), a psychedelic molecule. We used a transgenic Caenorhabditis elegans model to assess the behavioral and molecular outcomes following compound exposure. Motility assays, thioflavin S staining, and survival assays under oxidative stress were employed to evaluate the treatment efficacy. The results of the behavioral and molecular analyses indicated that the combination therapy exhibited a higher efficacy than the monotherapies, leading to a significant reduction in age-related motility defects in the AD model. Furthermore, the combination treatment substantially reduced Aβ plaque burden, enhanced survival following OS insult, and demonstrated a synergistic effect in mitigating AD-related hallmarks. Taken together, these findings support the potential of combining NN-DMT with specific bioactive compounds as a promising multi-target therapeutic approach for AD.},
}

*Alzheimer Disease/drug therapy/pathology
Animals
*Antioxidants/pharmacology/therapeutic use
*Neuroprotective Agents/pharmacology/therapeutic use
Caenorhabditis elegans/drug effects
Oxidative Stress/drug effects
Drug Synergism
Amyloid beta-Peptides/metabolism
Humans
Disease Models, Animal
Animals, Genetically Modified

@article {pmid40558456,
year = {2025},
author = {Arpaia, P and Cacciapuoti, M and Cataldo, A and Criscuolo, S and De Benedetto, E and Masciullo, A and Pesola, M and Schiavoni, R},
title = {Assessing the Role of EEG Biosignal Preprocessing to Enhance Multiscale Fuzzy Entropy in Alzheimer's Disease Detection.},
journal = {Biosensors},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/bios15060374},
pmid = {40558456},
issn = {2079-6374},
support = {B89J23002490005//Italian Ministry of Enterpise and Made in Italy/ ; B69J23001290005//Italian Ministry of Enterpise and Made in Italy/ ; PNRR DM 351/2022 - M4C1//Italian Ministry of University and Research/ ; },
mesh = {*Alzheimer Disease/diagnosis ; *Electroencephalography/methods ; Humans ; Entropy ; Fuzzy Logic ; Support Vector Machine ; *Signal Processing, Computer-Assisted ; Algorithms ; },
abstract = {Quantitative electroencephalography (QEEG) has emerged as a promising tool for detecting Alzheimer's disease (AD). Among QEEG measures, Multiscale Fuzzy Entropy (MFE) shows great potential in identifying AD-related changes in EEG complexity. However, MFE is intrinsically linked to signal amplitude, which can vary substantially among EEG systems, and this hinders the adoption of this metric for AD detection. To overcome this issue, this study investigates different preprocessing strategies to make the calculation of MFE less dependent on the specific amplitude characteristics of the EEG signals at hand. This contributes to generalizing and making more robust the adoption of MFE for AD detection. To demonstrate the robustness of the proposed preprocessing methods, binary classification tasks with Support Vector Machines (SVMs), Random Forest (RF), and K-Nearest Neighbor (KNN) classifiers are used. Performance metrics, such as classification accuracy and Matthews Correlation Coefficient (MCC), are employed to assess the results. The methodology is validated on two public EEG datasets. Results show that amplitude transformation, particularly normalization, significantly enhances AD detection, achieving mean classification accuracy values exceeding 80% with an uncertainty of 10% across all classifiers. These results highlight the importance of preprocessing in improving the accuracy and the reliability of EEG-based AD diagnostic tools, offering potential advancements in patient management and treatment planning.},
}

*Alzheimer Disease/diagnosis
*Electroencephalography/methods
Humans
Entropy
Fuzzy Logic
Support Vector Machine
*Signal Processing, Computer-Assisted
Algorithms

@article {pmid40558228,
year = {2025},
author = {Niculescu, V and Dimitriu, AL and Nistor-Cseppento, DC and Tirla, S and Gherle, A and Uivaraseanu, B and Burnei, C},
title = {Multicenter Study of Comorbidities in Patients with Periprosthetic Fractures After Total Hip Arthroplasty and Their Association with Immediate Postoperative Complications.},
journal = {Clinics and practice},
volume = {15},
number = {6},
pages = {},
doi = {10.3390/clinpract15060110},
pmid = {40558228},
issn = {2039-7275},
abstract = {Background/Objectives: Periprosthetic fractures (PFs) can occur in both the upper and lower limbs, commonly resulting from falls at the same level. The frequency of PFs following total hip arthroplasty (THA) ranges from 0.045% to 4.1%, and this incidence is influenced by several factors, including age, gender, the type of prosthesis used, and existing comorbidities. Previous studies on this subject have been small in scale and did not adequately address the associated comorbidities, which pose a challenge for the aging population. This study aims to comparatively assess the incidence of THA-related PFs, immediate postoperative complications, and comorbidities in patients with PFs from three emergency hospitals. Methods: A retrospective observational study was conducted from 1 January to 31 December 2024, in which 54 patients with PFs hospitalized in three emergency hospitals (Bucharest, Oradea, and Ploiești) were evaluated, divided into Group B (n = 29), Group O (n = 14), and Group P (n = 11). Results: Of all patients with PFs, 81.48% had minor complications-grade 1, 9.26% had grade 2 complications (complications requiring medical treatment or other minor interventions), and 3.70% had complications requiring surgery or invasive procedures. Clavien-Dindo grade 5 (patient death) had an incidence of 3.70%. Cardiac pathology was the most common pathology; hypertension predominated in Group O (42.85%). Alzheimer's disease was associated in 7 patients (12.96%). Without associated pathology, about 13% of patients were identified. Diabetes mellitus also occurred frequently in 31.50%. Data analysis indicates a very weak positive correlation between the Dindo Index and the Charlson Comorbidity Index (r = 0.046), which is not statistically significant (p = 0.628). The effect size, measured by Fisher's z, is also reported as 0.046. Conclusions: No significant differences were found among the evaluated centers regarding therapeutic approaches, postoperative complications, and associated comorbidities. Furthermore, there is insufficient evidence to suggest a significant association between the Charlson Comorbidity Index and the Clavien-Dindo Index.},
}

@article {pmid40558015,
year = {2025},
author = {Tanaka, T and Suzuki, H and Taruta, H and Saga, A and Li, G and Fujisawa, S and Kaneko, MK and Kato, Y},
title = {Development of a Novel Anti-human EphA1 Monoclonal Antibody, Ea1Mab-30, for Multiple Applications.},
journal = {Monoclonal antibodies in immunodiagnosis and immunotherapy},
volume = {44},
number = {3},
pages = {41-52},
doi = {10.1089/mab.2025.0006},
pmid = {40558015},
issn = {2167-9436},
mesh = {Humans ; Animals ; *Receptor, EphA1/immunology/genetics ; CHO Cells ; Cricetulus ; *Antibodies, Monoclonal/immunology/biosynthesis ; Mice ; Caco-2 Cells ; Cricetinae ; Antibody Specificity/immunology ; Cell Line, Tumor ; },
abstract = {Erythropoietin-producing hepatocellular receptor A1 (EphA1) is one of the Eph receptor family members, the largest group of receptor tyrosine kinases. EphA1 is expressed in various tissues and regulates cellular homeostasis by interacting with its membrane-bound ephrin ligands and other receptors. EphA1 critically correlates with the pathogenesis in several disorders, including Alzheimer's disease and cancers. Therefore, establishing sensitive monoclonal antibodies (mAbs) for EphA1 has been desired for basic research, diagnosis, and treatment. In this study, a novel specific and sensitive anti-human EphA1 mAb, clone Ea1Mab-30 (mouse IgG1, kappa), was established by the Cell-Based Immunization and Screening (CBIS) method. Ea1Mab-30 demonstrated reactivity with an EphA1-overexpressed Chinese hamster ovary-K1 cell line (CHO/EphA1), an endogenously EphA1-expressing bladder carcinoma cell line (5637), and a colorectal adenocarcinoma cell line (Caco-2) in flow cytometry. Crossreactivities of Ea1Mab-30 with other Eph receptors were not observed. Furthermore, the values of apparent binding affinity for CHO/EphA1 and 5637 were determined to be 8.9 × 10[-9] M and 1.7 × 10[-9] M, respectively. Furthermore, Ea1Mab-30 detected EphA1 protein in CHO/EphA1 and 5637 lysates using Western blot analysis. Ea1Mab-30 also clearly stained EphA1 of formalin-fixed paraffin-embedded CHO/EphA1 using immunohistochemistry. Ea1Mab-30, established by CBIS method, could help analyze the EphA1-contributed cellular functions and have potential applications in pathological diagnosis and treatment with specificity and high affinity for EphA1-expressing cells.},
}

Humans
Animals
*Receptor, EphA1/immunology/genetics
CHO Cells
Cricetulus
*Antibodies, Monoclonal/immunology/biosynthesis
Mice
Caco-2 Cells
Cricetinae
Antibody Specificity/immunology
Cell Line, Tumor

@article {pmid40556661,
year = {2025},
author = {Ahammad, RU and Spencer, B and Quach, B and Salehi, S and Rissman, RA},
title = {A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70117},
pmid = {40556661},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders characterized by abnormal protein aggregation, with amyloid beta (Aβ) and α-synuclein (α-syn) as key pathological markers. Increasing evidence highlights a pathological interplay between Aβ and α-syn, exacerbating neurodegeneration in both AD and PD. In this study, we evaluated the effects of reducing amyloid precursor protein (APP) processing on α-syn pathology using a splice-switching oligonucleotide (SSO) targeting APP exon 15 in Thy1-α-syn transgenic (α-syn-tg) mice.

METHODS: α-syn-tg mice received systemic APP SSO treatment. Immunohistochemistry and immunoblotting assessed α-syn, phosphorylated α-syn (P-Syn), and APP C-terminal fragments (CTFs) in the cortex, hippocampus, and thalamus. Neuronal integrity in different brain regions were examined, and behavioral assessments evaluated cognitive and motor functions.

RESULTS: APP SSO treatment significantly reduced α-syn and P-Syn in the cortex, hippocampus, and thalamus while also reversing neuronal loss in the hippocampal CA3 region. Interestingly, α-syn-tg mice exhibited elevated levels of alternative APP CTFs, which were reduced by APP SSO treatment, implicating APP processing dysregulation in α-syn pathology. Although behavioral assessments revealed no significant impairments or improvements in female α-syn-tg mice.

DISCUSSION: Our findings demonstrate that targeting APP reduces α-syn pathology and rescues neuronal loss, supporting the therapeutic potential of APP modulation in synucleinopathies. While no behavioral changes were observed in transgenic mice, further research exploring different models and conditions may provide additional insights into the full range of therapeutic benefits. Future studies should optimize delivery methods and explore combination therapies to enhance outcomes in neurodegenerative diseases with overlapping proteinopathies.

HIGHLIGHTS: APP-targeting SSO reduces α-syn and P-Syn in α-syn-tg mice.APP SSO lowers APP CTFs, linking APP processing to α-syn pathology.Neuronal loss in the hippocampal CA3 region is restored following APP SSO treatment.Behavioral assessments show no significant changes in female α-syn-tg mice.Findings support APP modulation as a potential strategy for synucleinopathies.},
}

@article {pmid40556653,
year = {2025},
author = {Lan, Y and Ding, J and Yu, T and Cheng, C},
title = {Research progress of platelets in neurodegenerative diseases.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1544605},
pmid = {40556653},
issn = {1663-4365},
abstract = {Neurodegenerative disease (NDD) is a disease state characterized by the loss of neuronal cells in the brain and spinal cord, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). They have become a major challenge for the world's health system in the twenty-first century, with an increasing incidence year by year, complex and diverse causes, and a lack of effective therapeutic. The brain and spinal cord are composed of neurons, and activated platelets are highly similar to neurons. The occurrence and development of these diseases are often accompanied by platelet activation, suggesting that platelets play an important role in the pathological process of NDDs. This article reviews the research progress of platelets in common NDDs, and elaborates on the mechanisms of platelets' involvement in NDDs and the use as a therapeutic option for NDDs to providing new ideas for the diagnosis and treatment of NDDs.},
}

@article {pmid40556526,
year = {2025},
author = {Yener, K and Hayat, A},
title = {Evaluation of the effects of tideglusib and calcium sulfate on the healing of experimental bone defects in rabbits.},
journal = {Polish journal of veterinary sciences},
volume = {28},
number = {2},
pages = {213-223},
doi = {10.24425/pjvs.2025.154940},
pmid = {40556526},
issn = {2300-2557},
mesh = {Animals ; Rabbits ; *Calcium Sulfate/pharmacology/therapeutic use/administration & dosage ; Bone Regeneration/drug effects ; Bone Transplantation/veterinary ; Wound Healing/drug effects ; Male ; },
abstract = {This study aimed to evaluate the effects of tideglusib and bone graft mixture on bone healing. Tideglusib is a drug used in the treatment of various neurological disorders such as Alzheimer's disease. In a relevant study, the positive effect of tideglusib on the Wnt pathway, one of the pathways involved in bone regeneration and dentin tissue regeneration, was demonstrated. Dentin and bone tissues have structurally similar healing mechanisms. Therefore, tideglusib may have a similar effect on the bone tissue. The main goal of bone grafting is to provide bone regeneration and functional healing through remodeling. Bone graft materials are divided into four types based on their source: autogenous, allogenous, xenogenous, and alloplastic. Because these graft materials have various advantages and disadvantages, research continues to focus on alternative materials and applications. Sixteen New Zealand rabbits were included in this study. A unicortical 3.5 mm diameter defect was created in the tibia of rabbits under general anesthesia. The groups in the study were as follows: Group 1, left proximal tibia defect area was controlled (defect area was left empty); Group 2, left distal tibia defect area was treated with tideglusib + calcium sulfate; Group 3, right proximal tibia defect area was treated with calcium sulfate only; Group 4, right distal tibia defect area was treated with tideglusib only. Mediolateral (M/L) radiographs of the tibia were taken on the 30th and 60th postoperative days. On the 30th day, the first eight rabbits were sacrificed, and on the 60th day, the remaining eight were sacrificed for histopathological examination. New bone formation in the obtained samples was evaluated by radiological and histopathological analyses. The study concluded that the combination of tideglusib and calcium sulfate significantly enhanced bone healing compared with the other groups (p<0.005). This suggests that tideglusib, either alone or in combination with bone graft materials, could serve as a promising alternative for the repair of bone defects.},
}

Animals
Rabbits
*Calcium Sulfate/pharmacology/therapeutic use/administration & dosage
Bone Regeneration/drug effects
Bone Transplantation/veterinary
Wound Healing/drug effects
Male

@article {pmid40556306,
year = {2025},
author = {McVea, A and DiFilippo, A and McLachlan, M and Betcher, B and Zammit, M and Betthauser, TJ and Converse, A and Murali, D and Stone, C and Hartley, S and Johnson, S and Tudorascu, DL and Laymon, CM and Cohen, AD and Minhas, D and Luo, W and Mathis, C and Lao, PJ and Ances, B and Zaman, S and Mapstone, M and Head, E and Handen, BL and Christian, BT and , },
title = {PET-measured amyloid beta accumulates at an accelerated rate in Down syndrome compared to neurotypical populations.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70357},
doi = {10.1002/alz.70357},
pmid = {40556306},
issn = {1552-5279},
support = {//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; /AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Down Syndrome/diagnostic imaging/metabolism ; *Amyloid beta-Peptides/metabolism ; Male ; Female ; *Positron-Emission Tomography ; *Alzheimer Disease/diagnostic imaging/metabolism ; Middle Aged ; *Brain/diagnostic imaging/metabolism ; Adult ; Aged ; Aniline Compounds ; Thiazoles ; },
abstract = {INTRODUCTION: Individuals with Down syndrome (DS) have a high prevalence of Alzheimer's disease (AD) and reveal an earlier age of amyloid beta (Aβ) onset compared to sporadic AD. Differences in amyloid accumulation rates between DS and sporadic AD populations have not been established.

METHODS: Participants with ≥ 3 [C-11]PiB scans (spanning > 6 years) and transitioning to Aβ+ were included, resulting in 20 DS and 23 neurotypical (NT) participants. Amyloid accumulation was compared using global standardized uptake value ratio (SUVR) for Aβ deposition, with individual growth rates (r) estimated using the logistic growth model (S U V R (t) = S U V R B L + K 1 + e - r (t - t 50) $SUVR\ (t) = SUV{{R}_
{BL}}
+ \frac{K}{
{1 + {{e}^
{ - r({t - {{t}_
{50}}
})
}}
}}
$).

RESULTS: The average growth rate in the DS cohort was 0.28 (0.08)/year versus 0.20 (0.08)/year for NT (p = . 002 $p = .002$), an increase of 40%.

DISCUSSION: Using individual longitudinal analyses, accelerated amyloid accumulation in DS is observed, This has important considerations for informing treatment trial design and monitoring beta-amyloid changes in future AD studies involving individuals with DS.

HIGHLIGHTS: Aβ accumulation rate was estimated using a logistic growth model. There was no overlap in the age of amyloid positivity between DS and NT cohorts. Participants with DS accumulate amyloid 40% faster than those with sporadic AD.},
}

Humans
*Down Syndrome/diagnostic imaging/metabolism
*Amyloid beta-Peptides/metabolism
Male
Female
*Positron-Emission Tomography
*Alzheimer Disease/diagnostic imaging/metabolism
Middle Aged
*Brain/diagnostic imaging/metabolism
Adult
Aged
Aniline Compounds
Thiazoles

@article {pmid40555646,
year = {2025},
author = {Wang, Q and Sun, X and Wu, X and Liu, J and Chang, C and Liu, Y and Xu, T and Liu, Q},
title = {An Ultrasensitive Wearable Nanosensor for Minimally Invasive Self-Screening of Alzheimer's Disease.},
journal = {Nano letters},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.nanolett.5c02255},
pmid = {40555646},
issn = {1530-6992},
abstract = {The rising global prevalence of Alzheimer's disease (AD) has emerged as a critical public health challenge, placing strain on families, communities, and healthcare systems. Despite advances in diagnostic methods, current techniques for early AD detection remain limited, often being invasive, costly, and impractical for regular use. Here, we report a fully integrated wearable nanosensor offering an easily accessible and user-friendly strategy for AD screening. This biosensing platform incorporates a microneedle-based interstitial fluid (ISF) sampling device and an ultrasensitive graphene field-effect transistor (GFET) chip, enabling rapid and precise detection of AD biomarkers. Furthermore, this nanosensor was successfully validated in transgenic murine models, demonstrating reliable differentiation between AD and non-AD mouse groups with high specificity. Overall, this study offers a promising alternative tool to the existing invasive and expensive techniques for the AD preliminary screening, paving the way for drug discovery, early diagnosis, and personalized treatment of AD.},
}

@article {pmid40555521,
year = {2025},
author = {Lokesh, M and Bandaru, LJM and Rajanna, A and Dhayal, VS and Challa, S},
title = {Microglial Dysfunction Mediated by Pb and Amyloid Beta Peptides as a Possible Mechanism of Neurotoxicity.},
journal = {Journal of applied toxicology : JAT},
volume = {},
number = {},
pages = {},
doi = {10.1002/jat.4839},
pmid = {40555521},
issn = {1099-1263},
support = {58/57/2012-BMS//Indian Council of Medical Research/ ; },
abstract = {This study delves into the inflammatory and degenerative impacts of lead (Pb) toxicity and amyloid beta peptides (Aβ-peptide 1-40 and Aβ-peptide 25-35) on brain cells, particularly by fostering M1 polarization in microglial cells and subsequent neuronal cell death, crucial in conditions like Alzheimer's disease. Microglia were exposed to IC50 concentrations of Pb, and Aβ-peptide 1-40 and Aβ-peptide 25-35 exhibited notable increases in intracellular ROS levels (32.95%) upon exposure to combinatorial treatments. Moreover, there was a significant decline in total antioxidant capacity to 69.57%, suggesting oxidative damage and compromised cellular defenses against stress, coupled with heightened glutamate levels (921.3 μM). Treatment with Pb alongside Aβ-peptide 1-40 and Aβ-peptide 25-35 also led to elevated intracellular calcium levels (33.83%) and increased production of pro-inflammatory cytokines IL-6 (5.54 pg/mL), TNF-α (5.8 pg/mL), and IFN-γ (13.52 pg/mL) and reduced levels of anti-inflammatory cytokines IL-10 (5.61 pg/mL) and IL-4 (14.46 pg/mL) in microglial cells compared with the control group. Furthermore, upregulation of NF-κB/p65 pathway-associated markers was observed, and when co-cultured with neuronal cells for 24 h, polarized microglia induced neuronal cell death (57.9%). These findings provide insights into the complex molecular mechanisms involved in lead-induced neurotoxicity and neurodegenerative disorders.},
}

@article {pmid40555519,
year = {2025},
author = {Gerasimov, E and Rakovskaya, A and Pchitskaya, E and Vlasova, O and Dahl, R and Bezprozvanny, I},
title = {A positive allosteric modulator of the SERCA pump rescues hippocampal neuronal circuits dysfunction and cognitive defects in a mouse model of Alzheimer's disease.},
journal = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1523/JNEUROSCI.2337-24.2025},
pmid = {40555519},
issn = {1529-2401},
abstract = {Alzheimer's disease (AD) is a common neurodegenerative disorder that affects normal neuronal functioning, alters neuronal circuits activity and memory formation and storage. Disrupted neuronal calcium (Ca[2+]) signaling is one of the drivers of AD pathogenesis. Previously we suggested that positive allosteric modulators (PAMs) of the sarco/endoplasmic reticulum Ca[2+] ATPase (SERCA) pump may help to stabilize cytosolic Ca[2+] levels and exert neuroprotective effects in AD neurons. In the current manuscript we demonstrate synaptoprotective properties of several SERCA PAMs using an in vitro model of amyloid toxicity. Based on in vitro experiments, we selected the SERCA PAM NDC-9009 for in vivo evaluation in male and female 5xFAD transgenic mice model of Alzheimer's disease. Using the miniscope imaging technique, we observed hyperactivity and abnormal connectivity of hippocampal neuronal ensembles 5xFAD mice. We further discovered that the function of the hippocampal neuronal circuits in 5xFAD mice was normalized by NDC-9009 intraperitoneal administration. NDC-9009 intraperitoneal administration also rescued memory defects in 5xFAD mice as quantified by the fear conditioning behavioral test and significantly reduced accumulation of amyloid plaques in hippocampal region of these mice. The obtained results support the potential utility of NDC-9009 and other SERCA PAMs as lead molecules for development of disease-modifying treatments for AD and potentially other neurodegenerative disorders.Significance statement Alzheimer's disease (AD) is a significant medical and social burden, yet no treatment currently exists. One of the hallmarks of AD is disrupted Ca[2+] signaling, which contributes to neuronal dysfunction and degeneration. In the current study, we demonstrate the potential of the SERCA pump positive allosteric modulators (PAMs) as promising disease-modifying agents. Through an in vitro screening, we identified NDC-9009 as the most effective SERCA PAM, promoting robust cytosolic calcium clearance and exhibiting neuroprotective properties. Furthermore, using miniature fluorescence in vivo imaging, a significant restoration of hippocampal neuronal ensembles activity and cognitive function after chronic administration of NDC-9009 in the transgenic AD mouse model was demonstrated.},
}

@article {pmid40555242,
year = {2025},
author = {Maloney, EK and Bleakley, A and White, AJ},
title = {Alzheimer's and Dementia Research Coverage in News Media Outlets Consumed by Population Groups that Are Underrepresented on Alzheimer's and Dementia-Focused Research Registries.},
journal = {Research on aging},
volume = {},
number = {},
pages = {1640275251346851},
doi = {10.1177/01640275251346851},
pmid = {40555242},
issn = {1552-7573},
abstract = {A lack of diversity in Alzheimer's (AD) and dementia research is an important barrier to identifying strategies for prevention and treatment. Research suggests media coverage of AD/dementia research will familiarize people with the issue and motivate them to place more importance in the issue in general. This study explores how news media may inform groups that are under-represented in AD/dementia through coverage of the issue. A national survey identified the media outlets that were most often consumed and used for health information within target populations. Transcripts from these media outlets were content analyzed to examine AD/dementia coverage. The timeframe included the months before and after the US FDA's approval of the drug Aduhelm and the controversy surrounding it. Results highlight differences in under-represented groups' media consumption patterns and coverage of AD/dementia and indicates a failure to inform about an event that may have widespread effect on Medicare and AD/dementia research.},
}

@article {pmid40555059,
year = {2025},
author = {Faysal, M and Zehravi, M and Amin, MA and Rab, SO and Jahnavi, P and Arjun, UVNV and Gupta, JK and Billah, AAM and Vodeti, R and Prasad, PD and Aseri, SSS and Siddiqui, FA and Bin Emran, T},
title = {Clinical insights into the mechanisms of infectious microbes and microbiota in chronic neurologic and psychiatric diseases.},
journal = {Pathology, research and practice},
volume = {272},
number = {},
pages = {156090},
doi = {10.1016/j.prp.2025.156090},
pmid = {40555059},
issn = {1618-0631},
abstract = {Chronic neurologic and psychiatric diseases such as schizophrenia, depression, Parkinson's, and Alzheimer's are increasingly linked to infectious microorganisms and gut microbiota. This review explores how pathogenic microorganisms and microbial communities impact neuropsychiatric, neurodegenerative, and neuroinflammatory processes, highlighting the gut-brain axis' crucial communication network in influencing behavior and brain function. Infectious agents like bacteria, viruses, and fungi cause disease by causing neurotoxic reactions, disrupting the blood-brain barrier, and activating neuroinflammatory cascades. Gut dysbiosis impacts immunological homeostasis and neural transmission by altering the synthesis of metabolites from microorganisms, such as short-chain fatty acids and neurotransmitter precursors. Neurodegeneration and psychiatric diseases are influenced by molecular mechanisms such as toll-like receptor signaling, microglial activation, and mitochondrial dysfunction. This review highlights the potential of microbiota-targeted treatments such as probiotics, prebiotics, and microbiome transplantation as novel treatments for chronic diseases. Understanding the intricate interactions between infectious microorganisms, microbiota, and the central nervous system enables the formation of precision medicine strategies to challenge the rising incidence of neurologic and psychiatric diseases. Future research should explore causal relationships and identify specific microbial biomarkers to enhance early diagnosis, prevention, and personalized treatment plans.},
}

@article {pmid40554441,
year = {2025},
author = {Tu, H and Zhou, S and Lin, J},
title = {Combined Effects of Donepezil and Memantine on Behavioral and Psychological Symptoms, Cognitive Function, and Daily Living Abilities in Patients With Alzheimer's Disease.},
journal = {British journal of hospital medicine (London, England : 2005)},
volume = {86},
number = {6},
pages = {1-15},
doi = {10.12968/hmed.2024.1037},
pmid = {40554441},
issn = {1750-8460},
mesh = {Humans ; *Donepezil/administration & dosage/therapeutic use/adverse effects ; *Alzheimer Disease/drug therapy/psychology ; Male ; Female ; *Memantine/administration & dosage/therapeutic use/adverse effects ; Aged ; *Activities of Daily Living ; Retrospective Studies ; *Cognition/drug effects ; Quality of Life ; Drug Therapy, Combination ; Aged, 80 and over ; Nootropic Agents/administration & dosage ; Dose-Response Relationship, Drug ; Cholinesterase Inhibitors/administration & dosage ; },
abstract = {Aims/Background Combined with memantine, donepezil has a beneficial impact on the treatment of moderate to severe Alzheimer's disease (AD), but it can potentially increase the risk of adverse events. The aim of this study is to compare the effects of low-dose and high-dose donepezil combined with memantine on the behavioral and psychological symptoms, cognitive function, and daily living abilities of patients with moderate to severe AD, and to explore their safety. Methods This retrospective study includes 106 AD patients who received treatment in the Third People's Hospital of Fuyang from January 2022 to January 2024. The patients were grouped according to treatment regimen: patients receiving low-dose donepezil (5 mg/day) combined with memantine were included in the low-dose group (n = 45), and those receiving high-dose donepezil (10 mg/day) combined with memantine were included in the high-dose group (n = 61). The assessment results of behavioral and psychological symptoms, cognitive function, daily living ability, quality of life, sleep quality, as well as the occurrence of adverse reactions during treatment were obtained from electronic medical records for the two groups of patients before and after 24 weeks of treatment, and were compared using appropriate statistical tests. Results After 24 weeks of treatment, the scores of neuropsychiatric inventory (NPI) and behavioral pathology in Alzheimer's disease rating scale (BEHAVE-AD) were similar between the two groups (p > 0.05). The scores of Mini-Mental State Examination (MMSE) and Alzheimer's disease assessment scale-cognitive section (ADAS-Cog) were similar between the two groups (p > 0.05). The scores of activities of daily living (ADL) were comparable between the two groups (p > 0.05), and the low-dose group had significantly higher quality of life-Alzheimer's disease (QOL-AD) scores compared to the high-dose group (p < 0.05). The Pittsburgh sleep quality index (PSQI) scores of patients in the high-dose group were significantly higher than those before treatment and those in the low-dose group (p < 0.05). There was no statistically significant difference in PSQI scores between the low-dose group before and after treatment (p > 0.05). During the treatment period, the total incidence of adverse reactions in the low-dose group was significantly lower than that in the high-dose group (11.11% vs. 27.87%, p < 0.05). Conclusion Both 5 mg/day or 10 mg/day donepezil in combination with memantine holds the potential to improve behavioral and psychological symptoms, cognitive function and daily living abilities in patients with moderate-to-severe AD. In addition, high doses of donepezil may lead to decreased sleep quality in patients, increased risk of adverse reactions, and less improvement in quality of life than low doses.},
}

Humans
*Donepezil/administration & dosage/therapeutic use/adverse effects
*Alzheimer Disease/drug therapy/psychology
Male
Female
*Memantine/administration & dosage/therapeutic use/adverse effects
Aged
*Activities of Daily Living
Retrospective Studies
*Cognition/drug effects
Quality of Life
Drug Therapy, Combination
Aged, 80 and over
Nootropic Agents/administration & dosage
Dose-Response Relationship, Drug
Cholinesterase Inhibitors/administration & dosage

@article {pmid40554071,
year = {2025},
author = {Wang, F and Zhou, Q and Chen, Z and Xie, L and Zheng, N and Chen, Z and Sun, Q and Du, J and Lin, J and Li, B and Li, L},
title = {Cyclovirobuxine inhibits ferroptosis to mitigate Alzheimer disease in glutamate-induced SH-SY5Y cell: the role of the liquid-liquid phase separation of FTH1.},
journal = {Molecular pharmacology},
volume = {107},
number = {7},
pages = {100046},
doi = {10.1016/j.molpha.2025.100046},
pmid = {40554071},
issn = {1521-0111},
abstract = {Ferroptosis represents a distinct form of cell death that differentiates it from conventional apoptosis. Numerous studies have demonstrated that ferroptosis holds significant potential for elucidating neuronal damage in Alzheimer disease (AD). In addition, liquid-liquid phase separation has emerged as a significant biological process in recent years. It plays a crucial role in the regulation of various proteins in vivo and is closely associated with ferroptosis. Meanwhile, nuclear factor erythroid 2-related factor 2 (Nrf2) serves as a crucial signaling pathway in ferroptosis and plays a significant role in regulating many key components of the ferroptosis pathway. In addition, an increasing volume of research is being conducted on natural medicines aimed at enhancing the treatment of AD. Cyclovirobuxine (Cyc) is an alkaloid compound extracted from the traditional Chinese medicinal plant, boxwood. It has demonstrated therapeutic potential in the treatment of neurodegenerative diseases. Therefore, in this study, we established an AD cell model using glutamate-induced SH-SY5Y. In glutamate-induced SH-SY5Y cells, Cyc treatment significantly improved mitochondrial function and effectively inhibited lipid peroxidation and restored the downregulation of FTH1 levels induced. Furthermore, Cyc treatment activated the Nrf2 signaling pathway, significantly elevated the nuclear levels of Nrf2, and inhibited both iron deposition and lipid peroxidation. Cyc treatment conferred resistance to ferroptosis in erastin-stimulated SH-SY5Y cells, wherein the Nrf2 signaling pathway and FTH1 protein play crucial roles. The collective findings presented here underscore the protective mechanism of action of Cyc in AD and emphasize its potential as a therapeutic agent for AD treatment. SIGNIFICANCE STATEMENT: It reveals at the cellular level the mechanism by which cyclovirobuxine improves Alzheimer disease through the inhibition of ferroptosis, providing a novel approach and strategy for the treatment of patients with Alzheimer disease.},
}

@article {pmid40554062,
year = {2025},
author = {Ma, R and Wang, S and Cui, YL and Zhang, H and Chen, X and Xie, J and Li, Y},
title = {Therapeutic role of caveolin family in stem cell fate and development for management of chronic degenerative diseases: A scientometric study to an in-depth review.},
journal = {Journal of advanced research},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jare.2025.06.034},
pmid = {40554062},
issn = {2090-1224},
abstract = {BACKGROUND: Caveolins (CAV), a family of integral membrane proteins, are involved in regulating stem cell fate, which are critical for tissue repair and regeneration. Drawing from scientometric studies and comprehensive research, this review investigates the mechanisms by which CAV regulates stem cell fate can improve the efficiency and accuracy of stem cell therapy in treating chronic degenerative diseases (CDD). For instance, CAV1 inhibits neuronal differentiation of neural stem/progenitor cells (NSCs/NPCs) by downregulating VEGF, p44/42MAPK phosphorylation and NeuroD1 signaling pathway following ischemic stroke, while CAV3 interacts with MG53 to enhance the therapeutic effects of bone marrow mesenchymal stem cells (BMSCs) in diabetic wound healing by activating the eNOS/NO signaling pathway.

AIM OF REVIEW: Our review aims to elaborate the impact of CAV on diverse stem cell populations and regulatory mechanisms, as well as point out novel insights brought by CAV and stem cell therapy in the management of CDD, such as stroke, Alzheimer's disease (AD), Parkinson's disease (PD), diabetes, pulmonary arterial hypertension (PAH), breast cancer and liver cancer.

Based on scientometrics studies, this review synthesizes current analyses of the CAV family's role in determining the fate of various stem cell populations, thereby providing new perspectives for the prevention and treatment of CDD.},
}

@article {pmid40553197,
year = {2025},
author = {Unal, O and Akgun-Unal, N and Baltaci, AK},
title = {Unveiling mysteries of aging: the potential of melatonin in preventing neurodegenerative diseases in older adults.},
journal = {Biogerontology},
volume = {26},
number = {4},
pages = {125},
pmid = {40553197},
issn = {1573-6768},
mesh = {Humans ; *Melatonin/therapeutic use ; *Neurodegenerative Diseases/prevention & control/metabolism ; *Aging/drug effects/metabolism ; Aged ; Antioxidants/therapeutic use ; Animals ; Oxidative Stress/drug effects ; *Neuroprotective Agents/therapeutic use ; },
abstract = {Neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, result in a substantial health problem for the elderly, marked by ongoing neuronal degeneration and a deterioration in mental faculties. These disorders are frequently linked to oxidative stress, problems with mitochondria, and persistent inflammation in the brain, which worsen neuronal damage. The neurohormone melatonin, primarily secreted by the pineal gland, has gained recognition as a promising therapeutic agent due to its antioxidant, anti-inflammatory, and neuroprotective effects. Melatonin's functions extend beyond its regulation of circadian rhythms, as research has demonstrated its ability to remove free radicals, improve mitochondrial performance, and adjust immune system responses, ultimately reducing the progression of neurodegenerative disease. Research findings from preclinical and clinical trials imply that taking melatonin supplements could lead to improved cognitive abilities, slower disease progression, and an overall better quality of life for elderly individuals suffering from neurodegenerative conditions. The mechanisms through which melatonin acts, the best dosage, and its long-term effectiveness are still being researched. This review underscores the potential benefits of melatonin as a supplementary treatment for neurodegenerative disorders in older adults, stressing the necessity for additional studies to confirm its efficacy and standardize its use in treatment plans.},
}

Humans
*Melatonin/therapeutic use
*Neurodegenerative Diseases/prevention & control/metabolism
*Aging/drug effects/metabolism
Aged
Antioxidants/therapeutic use
Animals
Oxidative Stress/drug effects
*Neuroprotective Agents/therapeutic use

@article {pmid40552995,
year = {2025},
author = {Shepherd, TM},
title = {Imaging the Treatment of Alzheimer Disease: 2030 Could Look Very Different.},
journal = {Radiology},
volume = {315},
number = {3},
pages = {e251704},
doi = {10.1148/radiol.251704},
pmid = {40552995},
issn = {1527-1315},
mesh = {Humans ; *Alzheimer Disease/diagnostic imaging/therapy ; Brain/diagnostic imaging ; *Diagnostic Imaging ; },
abstract = {"Just Accepted" papers have undergone full peer review and have been accepted for publication in Radiology. This article will undergo copyediting, layout, and proof review before it is published in its final version. Please note that during production of the final copyedited article, errors may be discovered which could affect the content.},
}

Humans
*Alzheimer Disease/diagnostic imaging/therapy
Brain/diagnostic imaging
*Diagnostic Imaging

@article {pmid40552707,
year = {2025},
author = {Siriwardhana, C and Gunaratnam, B and Kulasekera, KB},
title = {Personalized Treatment Selection for Multivariate Ordinal Scale Outcomes and Multiple Treatments.},
journal = {Pharmaceutical statistics},
volume = {24},
number = {4},
pages = {e70023},
doi = {10.1002/pst.70023},
pmid = {40552707},
issn = {1539-1612},
support = {R03AG075034/AG/NIA NIH HHS/United States ; 2U54MD007601-36/MD/NIMHD NIH HHS/United States ; },
mesh = {Humans ; *Precision Medicine/methods/statistics & numerical data ; Alzheimer Disease/drug therapy ; Treatment Outcome ; Computer Simulation ; Models, Statistical ; Clinical Trials as Topic/statistics & numerical data/methods ; Cystic Fibrosis/drug therapy ; Multivariate Analysis ; },
abstract = {In this study, we present an innovative approach for tailoring treatment selection on an individualized basis in the presence of correlated multiple responses, particularly those measured on ordinal scales, including binary responses. Our methodology involves the utilization of rank lists for treatments, generated from probabilities of observing responses of higher order than each level of the ordinal outcome, conditional on patient covariate measurements. We introduce a rank aggregation technique designed to amalgamate multiple lists of ranks, allowing for correlations both within these lists and among elements within each list. Our approach is versatile, accommodating any number of treatments and responses, and is applicable across a wide range of models. Our method offers flexibility by allowing the integration of response weights, enabling customization based on patient and clinician preferences on an individual case basis for optimal treatment decisions. To evaluate the performance of our proposed method in finite samples, we conducted a simulation study. Furthermore, we provide two illustrative examples using data from clinical trials on Cystic Fibrosis and Alzheimer's Disease, demonstrating the application of our proposed procedure in real-world scenarios.},
}

Humans
*Precision Medicine/methods/statistics & numerical data
Alzheimer Disease/drug therapy
Treatment Outcome
Computer Simulation
Models, Statistical
Clinical Trials as Topic/statistics & numerical data/methods
Cystic Fibrosis/drug therapy
Multivariate Analysis

@article {pmid40552323,
year = {2025},
author = {Wang, X and Li, Z and Ma, B and Jia, Q},
title = {Research progress on microglial pyroptosis and inflammasomes: a comprehensive analysis.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1582579},
pmid = {40552323},
issn = {1663-4365},
abstract = {BACKGROUND: Microglial pyroptosis and inflammasome activation play critical roles in neurodegenerative diseases, especially Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). In recent years, substantial attention has been directed toward elucidating their underlying mechanisms, diagnostic approaches, and prognostic implications. This study aimed to analyze the current research landscape, hotspots, and trends in this field.

METHODS: Articles published over the past decade on microglial pyroptosis and inflammasomes were retrieved from the Web of Science Core Collection (WoSCC) database. A comprehensive analysis was conducted, and high-impact articles were examined in depth.

RESULTS: A total of 958 articles were included. Among these, 664 originated from China, which also had the highest H-index (68), followed by 147 articles from the United States, with an H-index of 48 and the highest centrality (0.68). Southern Medical University (China) was the leading institution in terms of articles (47) and achieved the highest H-index (19). Journal of Neuroinflammation published the most articles (59) in this field. High-impact studies predominantly focused on the roles of microglial pyroptosis and inflammasomes in neurodegenerative diseases, neuroinflammation and therapeutic intervention strategies. Keywords such as "depression," "cell death," "recovery," and "pathogenesis" emerged as research hotspots over the past 3 years.

CONCLUSION: Microglial pyroptosis and inflammasome activation have become research hotspots in neurodegenerative disease, with China and the United States leading in article output and research influence in this field. Southern Medical University (China) is the most influential institution, and the Journal of Neuroinflammation is the most prolific journal. Current research hotspots emphasize elucidating the pathological mechanisms of microglial pyroptosis and inflammasome activation in neurodegenerative diseases, especially in AD, PD, and MS, and exploring potential therapeutic strategies such as MCC950, quercetin, MicroRNA-7, and melatonin. Future studies are expected to focus on mechanism elucidation, disease specificity, dynamic regulation, targeted interventions, and clinical translation to enhance treatment outcomes and prognosis for neurological disorders.},
}

@article {pmid40552150,
year = {2025},
author = {Ordaz, DA and Gupta, K and Bota, DA},
title = {The role of Poly-ADP ribose polymerase (PARP) enzymes in chemotherapy-induced cognitive impairments - parallels with other neurodegenerative disorders.},
journal = {Frontiers in pharmacology},
volume = {16},
number = {},
pages = {1615843},
pmid = {40552150},
issn = {1663-9812},
abstract = {Poly (ADP-ribose) polymerase (PARP) enzymes are critical in repairing DNA damage induced by chemotherapy and/or radiation. Due to PARP's role in DNA repair, inhibiting PARP leads to genomic instability and accumulation of damaged cells in cell cycle arrest. Previous studies have shown that PARP1 activation contributes to the development of various malignant disorders, and using PARP inhibitors is a promising intervention in these diseases. However, PARP activation is also common in neurological and inflammatory disorders. PARP inhibitors were studied in preclinical models of neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's Disease (AD). In neurodegenerative disorders like AD, activated PARP1 induces Aβ and forms Tau tangles, worsening cognitive symptoms. PARP inhibitors are currently used in combination therapy with chemotherapy drugs, including cisplatin and temozolomide, which are all described as having significant rates of central and peripheral nervous system side-effects, raising the potential question of using PARP inhibition not only as a cancer treatment but as an approach to mitigate the toxicity of the cancer drugs. This review will summarize evidence for the potential use of PARP inhibitors for neurologic disorders and discuss future prospects of how PARP inhibitors could be repurposed as neuroprotective agents against the cognitive complications of chemotherapeutic drugs.},
}

@article {pmid40551989,
year = {2025},
author = {Li, P and Gao, Y and Tao, Z and Mu, Z and Du, S and Zhao, X},
title = {PANoptosis: Cross-Talk Among Apoptosis, Necroptosis, and Pyroptosis in Neurological Disorders.},
journal = {Journal of inflammation research},
volume = {18},
number = {},
pages = {8131-8140},
pmid = {40551989},
issn = {1178-7031},
abstract = {Cell death mechanisms play a critical role in organismal development and homeostasis, primarily categorized into energy-dependent programmed cell death (PCD) and energy-independent necrotic cell death. PCD, regulated through various forms such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagic cell death, is essential for maintaining tissue stability and eliminating abnormal cells. Dysregulation of PCD is associated with numerous diseases, including cancer and neurodegenerative disorders. Recent studies have revealed extensive crosstalk and coordination among classical cell death pathways, leading to the identification of a novel programmed cell death mode termed PANoptosis. PANoptosis involves the dynamic assembly of the PANoptosome complex, which simultaneously activates apoptosis, pyroptosis, and necroptosis pathways in response to pathogen infection or tissue damage. In neurological diseases, PANoptosis exhibits dual roles: it can eliminate pathogen-infected cells but may also exacerbate neuroinflammation and neuronal death, contributing to the progression of neurodegenerative disorders. This review critically evaluates the molecular mechanisms of PANoptosis, its dual roles in neurological diseases (eg, Alzheimer's disease, Parkinson's disease, stroke, and glioma), and potential therapeutic strategies targeting PANoptosis, including small-molecule inhibitors, genome editing, and delivery technologies. By addressing conflicting evidence and outstanding questions, this review aims to provide a comprehensive framework for future research and clinical applications. Future research should focus on elucidating the molecular regulatory networks of PANoptosis, developing specific inhibitors, and advancing clinical applications to provide novel insights into the precise treatment of neurological diseases.},
}

@article {pmid40551964,
year = {2025},
author = {Beasley, BW},
title = {Why testing and diagnosis for Alzheimer's disease are mission critical.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70126},
pmid = {40551964},
issn = {2352-8737},
abstract = {The author, a physician who has younger-onset Alzheimer's disease (AD), recounts his recent lunch with a former coworker who has had a stroke. The author makes the point that because we now have an effective treatment for AD, and phosphorylated tau217 is a sensitive and specific screening test for AD, we should advocate for its usage in Medicare Wellness Visits, given that the adage "Time Is Brain" is just as apropos for AD as it has been in stroke care. However, at this time, Medicare is not paying for the lab test.},
}

@article {pmid40551529,
year = {2025},
author = {Shahrukh, M and Ahmad, S and Zaafar, M and Hasan, N and Ahmad, FJ},
title = {Management of Alzheimer's Disease With Nanotechnological Interventions and Novel Therapeutics.},
journal = {Drug development research},
volume = {86},
number = {5},
pages = {e70120},
doi = {10.1002/ddr.70120},
pmid = {40551529},
issn = {1098-2299},
support = {//The author would like to acknowledge the CSIR, for providing the CSIR-JRF fellowship to the first author (File No. 09/0591(16126)/2022-EMR-I). The author is also thankful to the Department of Science and Technology (DST), Govt of India for providing infrastructure under the DST-FIST program./ ; },
mesh = {*Alzheimer Disease/therapy/drug therapy ; Humans ; Drug Delivery Systems/methods ; Animals ; Genetic Therapy/methods ; Blood-Brain Barrier/metabolism ; Nanotechnology/methods ; Immunotherapy/methods ; Stem Cell Transplantation/methods ; },
abstract = {Alzheimer's disease (AD) is a progressive neurodegenerative condition marked by cognitive deterioration, β-amyloid plaque buildup, intracellular tangles, and significant neuronal loss. The increasing prevalence of AD, along with its substantial economic burden, underscores the urgent need for effective therapeutic strategies in the near future. The challenge is early diagnosis and management, hindered by the lack of reliable biomarkers. Currently, there is no definitive cure for AD. Attaining improved therapeutic outcomes necessitates delivering optimal drug concentrations to the central nervous system (CNS) by effectively penetrating the blood-brain barrier (BBB). Recently, nanotechnology has emerged as a promising approach to address this challenge, enhancing brain-targeted drug delivery while highlighting recent advancements and future potential. Additionally, novel targeted therapies such as genetic therapeutics, stem cell therapy, and immunotherapy approaches overcome AD-based challenges, enhance treatment efficacy, and improve patient compliance. This review highlights recent advancements in the treatment of AD, focusing on nanotechnology-based drug delivery systems, and also explores genetic therapeutics, stem cell therapy, and immunotherapy approaches. Overall, the review provides a comprehensive overview of these therapeutic approaches, shedding light on the evolving landscape of AD treatment and the challenges that lie ahead.},
}

*Alzheimer Disease/therapy/drug therapy
Humans
Drug Delivery Systems/methods
Animals
Genetic Therapy/methods
Blood-Brain Barrier/metabolism
Nanotechnology/methods
Immunotherapy/methods
Stem Cell Transplantation/methods

@article {pmid40551140,
year = {2025},
author = {Rehman, H and Yan, S and Saggu, S and Aida, M and Zhang, F and Shu, Y and Jones, A and Trang, A and Dew, E and Zhi, W and Claeboe, ET and Baucum, AJ and Wu, G and Jiao, K and Wang, Q},
title = {The PKCι-β-arrestin2 axis disrupts SORLA retrograde trafficking, driving its degradation and amyloid pathology in Alzheimer's disease.},
journal = {Molecular neurodegeneration},
volume = {20},
number = {1},
pages = {76},
pmid = {40551140},
issn = {1750-1326},
mesh = {*Alzheimer Disease/metabolism/pathology ; Animals ; Humans ; Mice ; *beta-Arrestin 2/metabolism ; *Membrane Transport Proteins/metabolism ; Protein Transport/physiology ; *LDL-Receptor Related Proteins/metabolism ; *Protein Kinase C/metabolism ; Disease Models, Animal ; Neurons/metabolism ; Amyloid beta-Peptides/metabolism ; Signal Transduction/physiology ; },
abstract = {BACKGROUND: Variants of SORL1 have been associated with both late and early onset of Alzheimer's disease (AD). SORL1 encodes the sorting-related receptor with A repeat (SORLA) protein, which belongs to the VPS10 receptor family. SORLA protects against AD pathogenesis through its sorting function, and reduced SORLA levels have been consistently observed in sporadic AD. Although the importance of SORLA in AD pathogenesis is well recognized, how it can be targeted for AD treatment remains to be established, owing to the inadequate understanding of its regulation by intracellular signaling.

METHODS: We employed combined biochemical, cell biological, and pharmacological approaches to investigate how SORLA trafficking and stability are regulated. Additionally, we used an AD mouse model, postmortem tissue samples, and iPSC-derived neurons to examine the functional outcomes of this regulation.

RESULTS: We identified a novel direct interaction between SORLA and β-arrestin2 (βARR2), which impedes the interaction of SORLA with the retromer complex, thus reducing the retrograde trafficking of SORLA. βARR2 promotes the interaction between SORLA and the ESCRT0 complex, leading to the lysosomal localization and degradation of SORLA. We also found that PKCι/λ induces SORLA phosphorylation and enhances its interaction with βARR2, promoting SORLA degradation. Importantly, blocking PKCι/λ with auranofin disrupts the SORLA-βARR2 interaction, elevates SORLA levels, decreases amyloidogenic processing of APP, and improves cognition in the App[NL-G-F/NL-G-F] AD mouse model. Furthermore, PKCι is hyperactive in human AD brains, and auranofin reduces Aβ production in AD iPSC-derived neurons through increasing SORLA levels.

CONCLUSION: Our study reveals the PKCι/λ-βARR2 axis as a key molecular mechanism that disrupts SORLA retrograde trafficking and drives its degradation. Our findings represent the first evidence that SORLA levels can be pharmacologically manipulated through blocking PKCι/λ to reduce Aβ production and alleviate AD-related phenotypes. Notably, repurposing auranofin, an FDA-approved drug for rheumatoid arthritis, may offer the potential for AD treatment.},
}

*Alzheimer Disease/metabolism/pathology
Animals
Humans
Mice
*beta-Arrestin 2/metabolism
*Membrane Transport Proteins/metabolism
Protein Transport/physiology
*LDL-Receptor Related Proteins/metabolism
*Protein Kinase C/metabolism
Disease Models, Animal
Neurons/metabolism
Amyloid beta-Peptides/metabolism
Signal Transduction/physiology

@article {pmid40551105,
year = {2025},
author = {Sun, X and Liu, H and Li, W and Li, L and Tian, Q and Cao, Q and Meng, Y and Shen, Y and Che, F and Chiu, JC and Yu, J and Hammock, BD},
title = {The soluble epoxide hydrolase inhibitor TPPU alleviates Aβ-mediated neuroinflammatory responses in Drosophila melanogaster and cellular models of alzheimer's disease.},
journal = {Journal of inflammation (London, England)},
volume = {22},
number = {1},
pages = {25},
pmid = {40551105},
issn = {1476-9255},
support = {(201919010)//This work was supported by a grant from Linyi Science and Technology Development Program, China./ ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a common neurodegenerative disease, and its pathogenesis is closely associated with neuroinflammation. The control of neuroinflammation in AD is the focus of current research. soluble epoxide hydrolase (sEH) protein is increased in the brain tissues of patients with AD and has been targeted by multiple genome wide association studies as a prime target for treating AD. Since sEH induces nerve inflammation by degrading epoxyeicosatrienoic acids (EETs), application of sEH inhibitor and sEH gene knockout are effective ways to improve the bioavailability of EETs and inhibit or even resolve neuroinflammation in AD. 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a potent sEH inhibitor that has been shown to be effective in preclinical animal models of a variety of chronic inflammatory diseases. This study aims to further explore whether TPPU can alleviate AD neuroinflammation.

METHODS: We established an Aβ42-transgenic Drosophila melanogaster model using the galactose-regulated upstream promoter element 4 (GAL4) / upstream active sequence (UAS) expression system and investigated the protective and anti-neuroinflammatory effects of TPPU against Aβ toxicity. We detected behavioral indexes (survival time, crawling ability, and olfactory memory) and biochemical indexes malondialdehyde (MDA) content and superoxide dismutase (SOD) activity in brain tissues of Aβ42 transgenic flies. Finally, we explored the anti-neuroinflammatory effect of TPPU and its possible mechanism by stimulating cocultures of human SH-SY5Y cells and HMC3 cells with Aβ(25-35) to model neuronal cell inflammation, and evaluated the cells by fluorescence microscopy, ELISA, Western Blot, and Real-time PCR.

RESULTS: We found that TPPU improved the survival time, crawling ability, and olfactory memory of Aβ42-transgenic flies. We also observed reduction of MDA content and elevation of SOD activity in the brain tissues of these flies. In human cell models, we found that TPPU improved cell viability, reduced cell apoptosis, decreased lipid oxidation, inhibited oxidative damage, thus playing a neuroprotective role. The inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-18 (IL-18) were downregulated, and the mRNA expression of the M2 microglia markers CD206 and SOCS3 were upregulated by TPPU; thus, TPPU inhibited neuroinflammatory responses. TPPU exerted neuroprotective and anti-inflammatory effects by decreasing the protein expression of the sEH-encoding gene EPHX2 and increasing the levels of 11,12-epoxyeicosatrienoic acid (11,12-EET) and 14,15-epoxyeicosatrienoic acid (14,15-EET). The inhibitory effect of TPPU on Aβ(25-35)-mediated neuroinflammation was associated with inhibition of the toll like receptor 4 (TLR4)/nuclear transcription factor-κB (NF-κB) pathway and p38 mitogen activated protein kinases (MAPK)/NF-κB pathway.

CONCLUSIONS: We report that the sEH inhibitor TPPU exerts neuroprotective and anti-neuroinflammatory effects in AD models, and it is expected that this drug could potentially be used for the prevention and treatment of AD.},
}

@article {pmid40550741,
year = {2025},
author = {Loi, SM and Kang, MJ},
title = {Donanemab: The dawn of disease-modifying treatment for Alzheimer's disease in Australia.},
journal = {Australasian psychiatry : bulletin of Royal Australian and New Zealand College of Psychiatrists},
volume = {},
number = {},
pages = {10398562251355157},
doi = {10.1177/10398562251355157},
pmid = {40550741},
issn = {1440-1665},
abstract = {On 22 May 2025, the Therapeutic Goods Administration (TGA) announced that the anti-amyloid monoclonal antibody donanemab (Eli Lilly, Kisunla) was approved in Australia for the treatment of Alzheimer's disease (AD). This has been heralded by some as a breakthrough for the treatment of AD, reflecting a turning point from symptomatic treatments to disease-modifying therapies. Psychiatrists should understand this scientific context, as it underpins both the hope and the limits of what donanemab can achieve. The roll-out of disease-modifying treatment comes with significant challenges but also provides a unique opportunity to improve care for people with AD and other dementias.},
}

@article {pmid40550256,
year = {2025},
author = {Gahr, M and Merz, B},
title = {[Trazodone in psychogeriatric care].},
journal = {Fortschritte der Neurologie-Psychiatrie},
volume = {},
number = {},
pages = {},
doi = {10.1055/a-2600-3773},
pmid = {40550256},
issn = {1439-3522},
abstract = {Trazodone is a dual serotonergic antidepressant with insignificant anticholinergic effects. It features sedative, hypnotic and anxiolytic effects in lower and antidepressive effects in higher doses. Its tolerability is good and the most important adverse drug reactions are orthostatic hypotension, drowsiness/sedation with increased risk of falls, dose-dependent moderate QTc prolongation with the risk of ventricular arrhythmias and priapism. Trazodone has evidence-based efficacy in elderly patients with depression and normal cognitive functioning, and there is evidence of antidepressive efficacy of trazodone also in patients with depression and dementia/cognitive dysfunction. In patients with dementia and sleep disturbances, trazodone improves sleep efficiency and increases total nocturnal sleep time. Although there is some evidence of efficacy of trazodone in the treatment of behavioral and psychological symptoms of dementia, particularly agitation, and trazodone is explicitly recommended for treatment of motor unrest in frontotemporal dementia, the evidence for this is rather weak. Results from studies in animal models indicate neuroprotective effects of trazodone by inhibition of overactivation of signalling in the unfolded protein response (UPR) which is typical of some neurodegenrative diseases. It was demonstrated that regular trazodone use is associated with delayed cognitive decline in humans with a diagnosis of Alzheimer's dementia. However, it is currently unclear if trazodone features significant neuroprotective effects in humans.},
}

@article {pmid40550228,
year = {2025},
author = {Tiwari, A and Singh, B and Singh, GK and Meena, J and Agrawal, AK and Kumar, S and Modi, G},
title = {Unveiling Exosome Potential: Transforming Treatments for Neurodegeneration.},
journal = {ACS applied bio materials},
volume = {},
number = {},
pages = {},
doi = {10.1021/acsabm.5c00096},
pmid = {40550228},
issn = {2576-6422},
abstract = {Exosomes, tiny extracellular vesicles, hold significant potential as biological nanocarriers for diverse therapeutic agents due to their exceptional ability to navigate through the barriers of biological systems. This comprehensive review delves into the capability of exosomes in the therapy of neurodegenerative disorders, concentrating on their potential for targeted drug delivery. It examines the complex processes involved in exosome-mediated drug delivery, including targeting, cellular uptake, intracellular trafficking, and therapeutic release. Insights from preclinical studies and clinical trials are exploited, highlighting the impactful applications of exosomes, particularly in the treatment of Parkinson's, Alzheimer's, ALS, and Huntington's diseases. The review also addresses challenges such as immunogenicity, scalability, and regulatory obstacles while exploring emerging technologies like advanced exosome engineering, personalized medicine, and the integration of nanotechnology. Overall, this review accentuates the potential impact of exosome-based treatments in biomedicine alongside the critical need to overcome existing barriers.},
}

@article {pmid40549373,
year = {2025},
author = {Clocchiatti-Tuozzo, S and Rivier, CA and Renedo, D and Huo, S and de Havenon, A and Hawkes, MA and Gilmore, E and Schwamm, LH and Sheth, KN and Gill, TM and Falcone, GJ},
title = {APOE ε4 and Risk of Intracranial Hemorrhage in Patients With Atrial Fibrillation Taking Apixaban.},
journal = {JAMA neurology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaneurol.2025.0182},
pmid = {40549373},
issn = {2168-6157},
abstract = {IMPORTANCE: The APOE ε4 variant is causally linked to cerebral amyloid angiopathy and is a risk factor for intracranial hemorrhage (ICH) among warfarin-treated patients with atrial fibrillation. Nevertheless, its impact on those treated with apixaban remains unknown.

OBJECTIVE: To test the hypothesis that APOE ε4 allele carriership is associated with an increased risk of ICH in patients with atrial fibrillation taking apixaban.

This cohort study involved data from the All of Us Research Program, a longitudinal, population-based study in the United States. Inclusion criteria were age older than 50 years, history of atrial fibrillation, and anticoagulation with apixaban. Participants with a history of ischemic stroke or ICH were excluded. Up to 3 years of follow-up data were available. Data were collected from 2017 to 2022 and analyzed from November 2023 to December 2024.

EXPOSURE: APOE ε2, ε3, and ε4 were ascertained using variants rs429358 and rs7412. APOE ε4 was modeled dichotomously (noncarriers [no alleles] vs carriers [1 or 2 alleles]).

MAIN OUTCOMES AND MEASURES: Incident ICH, including any new intraparenchymal, subdural, or subarachnoid hemorrhage after initiation of apixaban therapy.

RESULTS: Of 413 477 All of Us participants, 2038 were eligible. Their mean (SD) age was 71 (9) years; 918 (45%) were female, 1120 (55%) were male, and 1710 (83%) had European ancestry. Among these participants, 483 (23.7%) were carriers of at least 1 APOE ε4 allele. After a median follow-up of 2.9 years, 26 participants sustained an ICH (cumulative incidence, 1.5%; 95% CI, 1.0%-2.2%), of whom 12 (cumulative incidence, 3.1%; 95% CI, 1.7%-5.3%) were carriers and 14 (cumulative incidence, 1%; 95% CI, 0.6%-1.7%) were noncarriers (P = .007). Multivariable Cox proportional hazard models confirmed this association: compared with noncarriership, APOE ε4 carriership was associated with a 3-fold increase in the risk of ICH (hazard ratio, 3.07; 95% CI, 1.42-6.65). APOE information improved the discrimination of risk prediction scores (C statistic of 0.74 and 0.68 for models with and without APOE, respectively; P = .03).

CONCLUSIONS AND RELEVANCE: Further research is needed to evaluate whether cerebral amyloid angiopathy mediates the observed association and whether APOE e4 information improves clinical decision-making about anticoagulation therapy in patients with atrial fibrillation. The latter is important now that APOE information is used in clinical settings to guide antiamyloid treatment for Alzheimer disease and has been returned to millions of persons by direct-to-consumer genotyping companies.},
}

@article {pmid40549157,
year = {2025},
author = {Chen, F and Chen, Y and Feng, S and Chen, H and Deng, L and Ma, F and Ke, Q and Liang, Q and Chen, J and Peng, X and Lu, J and Liu, Y and Xie, Y and Cao, H and Sun, Y and Wu, W and Cui, L and Wang, Y},
title = {APOE4 triggers dysregulated synaptic vesicle release by disrupting SNARE complex assembly.},
journal = {Cellular and molecular life sciences : CMLS},
volume = {82},
number = {1},
pages = {248},
pmid = {40549157},
issn = {1420-9071},
support = {82071190//National Natural Science Foundation of China/ ; 82101269//National Natural Science Foundation of China/ ; 82301611//National Natural Science Foundation of China/ ; 2022A1515010593//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2023A1515010179//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2024A1515012844//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2024A1515011464//Basic and Applied Basic Research Foundation of Guangdong Province/ ; 2022M710848//China Postdoctoral Science Foundation/ ; 2023//Open Fund of Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases/ ; GCC2021010//Affiliated Hospital of Guangdong Medical University High Level talent research Launch project/ ; },
mesh = {*Synaptic Vesicles/metabolism ; *SNARE Proteins/metabolism ; Animals ; Vesicle-Associated Membrane Protein 2/metabolism ; *Apolipoprotein E4/metabolism/genetics ; Humans ; Mice ; Synaptic Transmission ; Rats ; Apolipoprotein E3/metabolism/genetics ; Protein Binding ; HEK293 Cells ; },
abstract = {The ε4 allele of the Apolipoprotein E (APOE) gene is an important genetic risk factor for several neurodegenerative diseases, while the common pathogenic mechanism is still unclear. Impaired synaptic transmission is one of the common pathogenic features of neurodegenerative diseases. By using proteomics analysis, co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assay, we demonstrated that APOE interacts with VAMP2, a core component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, in an APOE4 > APOE3 manner. Further in vitro and in vivo results suggest that APOE4 blocks SNARE complex assembly, which is likely driven by liquid-liquid phase separation (LLPS), negatively regulating synaptic vesicle release. Our study shows that APOE4 negatively regulates synaptic vesicle release by blocking the soluble SNARE complex assembly. Our data shed a light on how APOE polymorphism contributes to the risk for neurodegenerative diseases, and provides a theoretical basis for the future APOE targeted treatment of neurological diseases.},
}

*Synaptic Vesicles/metabolism
*SNARE Proteins/metabolism
Animals
Vesicle-Associated Membrane Protein 2/metabolism
*Apolipoprotein E4/metabolism/genetics
Humans
Mice
Synaptic Transmission
Rats
Apolipoprotein E3/metabolism/genetics
Protein Binding
HEK293 Cells

@article {pmid40548968,
year = {2025},
author = {Müller, DJ and Freitag, CM and Heilbronner, U and Nöthen, MM and Perneczky, R and Rietschel, M and Schulte, EC and Deckert, J and , },
title = {[Genetically informed treatment in psychiatry: new dynamics through APOE and antibody treatment of Alzheimer's disease].},
journal = {Der Nervenarzt},
volume = {},
number = {},
pages = {},
pmid = {40548968},
issn = {1433-0407},
abstract = {The European Medicines Agency has recommended testing for the ApoE-genotype prior to treatment of Alzheimer's disease with Lecanemab. The drug approval is limited to patients who are not homozygous for the ApoE epsilon 4 allele. This is to reduce the risk of undesired adverse effects in the patients treated with Lecanemab. With this recommendation for the first time a psychiatric therapy will be genetically informed.},
}

@article {pmid40547330,
year = {2025},
author = {Snider, BJ and Biffi, A and Bozeat, S and Clevenger, C and Farrar, G and Gitelman, D and Kolster, R and Mattke, S and Mielke, M and Mukherjee, D and Murphy, J and Okhravi, H and Rabinovici, GD and Rentz, D and Soria, J and Synder, H and Walker, G and Mahinrad, S and Carrillo, MC and Weber, CJ},
title = {System readiness and the patient care pathway for Alzheimer's disease diagnosis and treatment.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70094},
pmid = {40547330},
issn = {2352-8737},
abstract = {Promising therapeutic interventions that target the underlying pathophysiology are changing the landscape of Alzheimer's disease (AD) research. The AD care pathway must be transformed to meet the challenge of bringing these new therapies to the increasing number of people living with AD within the existing healthcare framework. Challenges include identifying patients who may benefit from treatment interventions early in the course of the disease, ensuring that diagnostic tools are accessible and accurate, and developing capabilities to monitor the effectiveness of interventions over time. These challenges must be addressed at all levels, from primary care settings to tertiary treatment centers; this will require collaborative efforts between health systems, drug manufacturers, and research institutions to navigate this evolving landscape and ensure system readiness for patients and their families with AD. The Spring 2024 Alzheimer's Association Research Roundtable (AARR) meeting gathered industry representatives and clinicians to discuss insights, challenges, and solutions that will help researchers and health systems identify patients in the early stages of AD and deliver emerging therapies efficiently and safely. In this paper, we provide highlights from the Spring 2024 AARR meeting.},
}

@article {pmid40547328,
year = {2025},
author = {Di Caro, V and Cho, E and North, HA and Caldwell, J and Pandey, K and Duong, D and Grundman, M and de Haan, W and Vijverberg, EG and Teunissen, CE and Caggiano, AO and Seyfried, NT and Hamby, ME},
title = {Identification of cerebrospinal fluid pharmacodynamic biomarkers and molecular correlates of brain activity in a Phase 2 clinical trial of the Alzheimer's disease drug candidate CT1812.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {11},
number = {2},
pages = {e70119},
pmid = {40547328},
issn = {2352-8737},
abstract = {INTRODUCTION: CT1812 (zervimesine) is an orally dosed modulator of the sigma-2 receptor (S2R) currently in clinical development for the treatment of Alzheimer's disease (AD). CT1812 has been shown in preclinical and early clinical trials to selectively prevent and displace binding of amyloid beta oligomers from their synaptic receptors and has improved cognitive function in animal models of AD.

METHODS: SEQUEL (NCT04735536) is a completed Phase 2, randomized, placebo-controlled 4-week crossover trial in adults with mild-to-moderate AD that investigated the effect of CT1812 on safety, synaptic function using quantitative electroencephalography (qEEG), and biomarkers. CT1812 improved established qEEG markers of spontaneous brain activity, suggesting improved neuronal and synaptic function. In the present study, cerebrospinal fluid (CSF)-based tandem mass tag mass spectrometry (TMT-MS) was performed on participant samples to investigate proteomic effects and identify potential biomarkers of CT1812.

RESULTS: Biomarkers found through proteomics analyses to be significantly differentially abundant in CT1812- versus placebo-treated participants supported pathway engagement and proof of mechanism for CT1812. Impacted proteins support a role for CT1812 at synapses, in vesicle trafficking, and in lipoprotein biology. Biomarkers correlated with the previously reported improvements in qEEG-based functional connectivity (inferred through alpha band Amplitude Envelope Correlations) with CT1812 treatment were also identified and may be potential early surrogate biomarkers of efficacy for CT1812. The processes and functions supported by biomarkers were congruent with those previously revealed in CSF proteomics analyses from phase 1 and 2 AD clinical trials with CT1812.

DISCUSSION: After 1 month of treatment, the identification of biomarkers supporting pathway engagement, the replication of biomarker findings from prior trials, and the discovery of molecular correlates of improved functional connectivity with CT1812 treatment bolster support for and expound upon the mechanism of action for CT1812 in displacing Aβ oligomers at neuronal synapses, as well as underscores the CT1812 relevance to AD.

HIGHLIGHTS: Exploratory proteomics identified candidate CSF biomarkers of CT1812 in SEQUEL.Molecular correlates of functional brain connectivity (qEEG) were identified.Proteins impacted by 1 month CT1812 treatment support target engagement.Pharmacodynamic changes found in synapse, immune, vesicle, and lipoprotein biologies.SEQUEL proteomics findings replicated previous trial findings with CT1812.},
}

@article {pmid40547197,
year = {2025},
author = {Yoshimura, T and Osawa, A and Maeshima, S and Ueda, I and Kawamura, K and Kamiya, M and Itoh, N and Arai, H},
title = {Unlocking the Value of Neuropsychological Assessments in Rehabilitation: Perspectives from Persons with Dementia and Their Caregivers.},
journal = {Current therapeutic research, clinical and experimental},
volume = {102},
number = {},
pages = {100781},
pmid = {40547197},
issn = {0011-393X},
abstract = {PURPOSE: Various neuropsychological or cognitive assessments are often conducted before rehabilitation to ascertain patients' function, disability, and environment. However, adequate assessments are not conducted for persons with dementia under the assumption that assessments would burden them. Therefore, this study investigated the perceptions of persons with dementia and their family caregivers regarding cognitive function assessments during hospital rehabilitation and reconsidered the significance of such assessments according to the opinions of those involved.

METHODS: This cross-sectional observational study was conducted over a 3-month period at a hospital-based rehabilitation center. We administered a semi-structured questionnaire to 31 older persons with dementia (13 men and 18 women; mean age [± SD]: 77 [± 5.7] (range: 66-87 years); mean years of education [± SD]: 12 [± 2.3]; (range: 9-16 years); Alzheimer's disease: 15; mild cognitive impairment (MCI): 15; corticobasal degeneration: 1) and 49 family caregiver dyads (24 men and 25 women, mean age [± SD]: 67 [± 11] years; age range: 46-90 years). The data were interpreted by employing descriptive statistics, and the χ[2], Fisher's exact, and Kruskal-Wallis tests.

FINDINGS: Both groups acknowledged the value of neuropsychological assessments, with 94% (95% CI 84.9-100%) of persons with MCI/dementia and 83% (95% CI 73.3-94.0%) of their family caregivers linking them directly to enhanced treatment and care quality. Their positive attitudes were significantly associated with the belief that such evaluations are integral for personalizing and optimizing rehabilitation strategies.

IMPLICATIONS: Most individuals with MCI/dementia and their caregivers value detailed neuropsychological assessments for understanding rehabilitation needs, highlighting the importance of integrating comprehensive evaluations into dementia care. However, the single-center nature of our study limits generalizability. Future research with diverse participants is needed to develop scalable, inclusive rehabilitation strategies.},
}

@article {pmid40546882,
year = {2025},
author = {Mohapatra, TK and Nayak, RR and Ganeshpurkar, A and Tiwari, P and Kumar, D},
title = {Navigating the treatment landscape of Alzheimer's disease: Current strategies and future directions.},
journal = {Ibrain},
volume = {11},
number = {2},
pages = {162-184},
pmid = {40546882},
issn = {2769-2795},
abstract = {Alzheimer's disease (AD), a neurodegenerative disease leading to dementia, lacks a single definitive diagnosis. While current medications only manage symptoms, the ideal treatment would restore cognition. Traditional therapies targeting beta-amyloid haven't yielded significant results, while new approaches target tau protein tangles, protein degradation pathways, inflammation, and neurotrophic factor depletion. Autophagy, a cellular degradation and recycling process, has emerged as a crucial hallmark and contributor to the pathogenesis of AD. Notably, autophagy induction has emerged as a promising therapeutic approach, with inducers like celastrol and caudatin promoting the degradation of toxic protein aggregates. Additionally, innovative drug formulations, such as nanoparticles, are being explored for targeted drug delivery. Research is increasingly focusing on neuroinflammation and developing multi-targeted drugs to address various aspects of AD, potentially leading to preventive strategies in the early stages. This review summarizes the current state and emerging trends in AD drug development.},
}

@article {pmid40546877,
year = {2025},
author = {Wu, W and Yan, Y and Yi, T and Wei, Y and Gao, J and Gong, Q},
title = {Lithocarpus polystachyus Rehd. leaves aqueous extract inhibits learning and memory impairment in Alzheimer's disease rats: Involvement of the SIRT6/NLRP3 signaling pathway.},
journal = {Ibrain},
volume = {11},
number = {2},
pages = {228-244},
pmid = {40546877},
issn = {2769-2795},
abstract = {Alzheimer's disease (AD) is a chronic and progressive neurodegenerative condition that is influenced by multiple factors along with neuroinflammation and oxidative stress. Our previous study proved that Lithocarpus polystachyus Rehd. aqueous extract (sweet tea aqueous extract, STAE) effectively inhibits hydrogen peroxide-induced neuronal cell injury. However, it is not clear whether STAE can protect against AD, and its underlying mechanisms are still uncertain. Therefore, the present study was designed to evaluate the possible behavioral and neurochemical effects of STAE on Aβ 25-35-induced AD rats administered STAE (20, 40, 80 mg/mL) for 14 days. We showed that STAE administration significantly and dose-dependently ameliorated the cognitive deficits in the AD rat models, assessed in the Morris water maze (MWM) test, Y-maze test, and novel object recognition (NOR) test. The results of hematoxylin and eosin (H&E) staining and Nissl staining showed that after treatment with STAE, the pathological damage to the hippocampal CA1, CA3, and dentate gyrus (DG) neurons of rats was significantly improved. Furthermore, STAE dose-dependently inhibited microglia and astrocyte activation in the hippocampus of rats accompanied by increased protein expression of silent mating-type information regulation 2 homolog 6 (SIRT6) and decreased protein expression of nod-like receptor thermal protein domain-associated protein 3 (NLRP3) and its downstream pyroptosis-related genes after following Aβ 25-35. In summary, our findings indicate that STAE effectively inhibits Aβ 25-35-induced learning and memory impairment in rats, and the mechanism is, at least partially, related to the regulation of SIRT6/NLRP3 signaling pathway.},
}

@article {pmid40546798,
year = {2025},
author = {Lai, G and Wu, H and Yang, K and Hu, K and Zhao, W and Chen, X and Li, J and Wang, H and Lv, Z and Xie, G and Wu, X},
title = {Potential Applications of Natural Components of Traditional Chinese Medicine Delivery via Nanoparticle Drug Delivery Systems in the Treatment of Alzheimer's Disease.},
journal = {International journal of nanomedicine},
volume = {20},
number = {},
pages = {7781-7810},
pmid = {40546798},
issn = {1178-2013},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; Medicine, Chinese Traditional/methods ; Animals ; *Nanoparticle Drug Delivery System/chemistry ; Blood-Brain Barrier/metabolism ; Neuroprotective Agents/administration & dosage/pharmacokinetics ; *Drugs, Chinese Herbal/administration & dosage/pharmacokinetics/chemistry ; *Drug Delivery Systems/methods ; *Nanoparticles/chemistry ; Biological Availability ; },
abstract = {Alzheimer's disease (AD), a primary neurodegenerative disorder, is characterized by amyloid-β plaques and tau hyperphosphorylation-induced neurofibrillary tangles. Current treatments only alleviate symptoms, and Aβ monoclonal antibodies raise safety concerns in clinical use. Natural components (NCs) of Traditional Chinese Medicine (TCM) (eg, curcumin, quercetin, berberine, resveratrol) exhibit multi-target neuroprotective effects in AD, but poor blood-brain barrier (BBB) penetration and low bioavailability limit clinical use. Recent strategies to enhance TCM delivery include NP-based nanoparticle (NP) drug delivery systems (NDDS), structural modifications, and combination therapies. NDDS demonstrate superior performance in enabling brain-targeting delivery via passive (paracellular/transcellular) and active (adsorption-/receptor-/carrier-mediated transcytosis) approaches, improving NCs' stability, controlled release, and bioavailability. With NCs of TCM delivery via NDDS, it is possible to develop intelligent therapeutic systems that combine multi-target regulation with precise drug delivery. This review summarizes the diverse neuroprotective effects of NCs of TCM in AD treatment and discusses the commonly used types of NPs for AD therapy. It particularly focuses on these NCs of TCM delivery via NDDS, covering aspects such as NPs types, fabrication techniques, characteristics, administration routes, and advantages. Finally, the challenges and potential solutions for NCs of TCM were examined, along with comparative advantages and limitations among different NPs and future research directions. Collectively, NCs of TCM delivery via NDDS demonstrate promising therapeutic potential for AD treatment.},
}

*Alzheimer Disease/drug therapy
Humans
Medicine, Chinese Traditional/methods
Animals
*Nanoparticle Drug Delivery System/chemistry
Blood-Brain Barrier/metabolism
Neuroprotective Agents/administration & dosage/pharmacokinetics
*Drugs, Chinese Herbal/administration & dosage/pharmacokinetics/chemistry
*Drug Delivery Systems/methods
*Nanoparticles/chemistry
Biological Availability

@article {pmid40546469,
year = {2025},
author = {Kalochristianaki, S and Vlotinou, P and Bablekos, G and Katsouri, IG and Tsiakiri, A and Georgousopoulou, V and Tsakni, G},
title = {Cost Estimation Analysis of Dementia: A Scope Review.},
journal = {Cureus},
volume = {17},
number = {5},
pages = {e84547},
pmid = {40546469},
issn = {2168-8184},
abstract = {Dementia is a progressive neurodegenerative condition, primarily caused by Alzheimer's disease, predominantly affecting elderly individuals. Under these circumstances, dementia care focuses on assisting patients with daily living, either in nursing facilities or at home. The condition imposes substantial economic burdens on patients, caregivers, and healthcare systems, particularly in Europe and North America, where precise cost assessments are essential. This review examines the economic impact of dementia care by integrating diverse cost estimation sources to evaluate the cost-effectiveness of preventive care for high-risk individuals and providing meta-analytic estimates of annual medical, non-medical, and informal care costs per patient, and compares these costs with care effectiveness. The analysis focuses on Europe and the United States, with a greater emphasis on Europe, aiming to encourage further research on preventive strategies and caregiver support. Dementia presents a significant economic challenge globally, driven by rising healthcare costs and an aging population. The disparities between direct and indirect costs in the US and Europe highlight the impact of healthcare systems and cultural practices on dementia care costs. Preventive measures could significantly reduce long-term treatment costs, making them a crucial investment to alleviate future financial burdens.},
}

@article {pmid40546334,
year = {2025},
author = {Cruz, MV and Jamal, S and Sethuraman, SC},
title = {A Comprehensive Survey of Brain-Computer Interface Technology in Health care: Research Perspectives.},
journal = {Journal of medical signals and sensors},
volume = {15},
number = {},
pages = {16},
pmid = {40546334},
issn = {2228-7477},
abstract = {The brain-computer interface (BCI) technology has emerged as a groundbreaking innovation with profound implications across diverse domains, particularly in health care. By establishing a direct communication pathway between the human brain and external devices, BCI systems offer unprecedented opportunities for diagnosis, treatment, and rehabilitation, thereby reshaping the landscape of medical practice. However, despite its immense potential, the widespread adoption of BCI technology in clinical settings faces several challenges. These include the need for robust signal acquisition and processing techniques and optimizing user training and adaptation. Overcoming these challenges is crucial to unleashing the complete potential of BCI technology in health care and realizing its promise of personalized, patient-centric care. This review work underscores the transformative potential of BCI technology in revolutionizing medical practice. This paper offers a comprehensive analysis of medical-oriented BCI applications by exploring the various uses of BCI technology and its potential to transform patient care.},
}

@article {pmid40546257,
year = {2025},
author = {Yu, X and Lu, F and Chen, J and Liu, X and Chen, Q},
title = {A bibliometric analysis of acupuncture treatment and cognitive impairment.},
journal = {Frontiers in neurology},
volume = {16},
number = {},
pages = {1495191},
pmid = {40546257},
issn = {1664-2295},
abstract = {Cognitive impairment, a prevalent neurological disorder characterized by multisystem dysregulation within the nervous system, has prompted substantial scientific inquiry into complementary therapies. This scientometric investigation systematically examines the evolving bilingual (Chinese-English) research paradigm of acupuncture interventions for cognitive impairment through comparative analysis of 510 publications from the China National Knowledge Infrastructure (CNKI) and 633 articles from Web of Science Core Collection, processed via CiteSpace 6.4.R2. Our multidimensional analysis reveals three principal dimensions: (1) Spatiotemporal evolution demonstrating that scholarly contributions in this domain are predominantly clustered within China. Longitudinal bibliometric analysis demonstrates sustained scholarly productivity in this domain, with annual bilingual (Chinese-English) publication outputs consistently exceeding 40 peer-reviewed articles per annum throughout the 2000-2025 observation window, establishing a robust baseline for continuous knowledge advancement; (2) Network analysis atlas of the research institutions and authors reveals that both research output density and institutional affiliations concentrated in Chinese academic hubs and most authors come from China; (3) Divergent thematic trajectories between linguistic cohorts - Chinese studies emphasize vascular mechanisms, oxidative stress modulation, and pharmacological synergies, whereas English literature prioritizes gut-brain axis interactions, postoperative cognitive recovery, and neuroinflammatory pathways. These findings provide evidence-based insights into acupuncture's therapeutic mechanisms in cognitive impairment while establishing a conceptual framework to guide future translational studies and clinical protocol optimization in integrative neurology.},
}

@article {pmid40546239,
year = {2025},
author = {Liang, J and Dong, X and Yang, J and Hu, N and Luo, X and Cong, S and Chen, J and Zhao, W and Liu, B},
title = {Buyang Huanwu Decoction Modulates the Gut Microbiota-C/EBPβ/AEP Axis to Ameliorate Cognitive Impairment in Alzheimer's Disease Mice.},
journal = {CNS neuroscience & therapeutics},
volume = {31},
number = {6},
pages = {e70480},
doi = {10.1111/cns.70480},
pmid = {40546239},
issn = {1755-5949},
support = {2024yjscx013//Innovative Research Project for Postgraduate Students of Heilongjiang University of Traditional Chinese Medicine/ ; LH2022H059//Natural Science Foundation of Heilongjiang Province of China/ ; LH2023H073//Natural Science Foundation of Heilongjiang Province of China/ ; },
mesh = {Animals ; *Gastrointestinal Microbiome/drug effects/physiology ; *Drugs, Chinese Herbal/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology/psychology ; Mice ; *Cognitive Dysfunction/drug therapy/metabolism ; Mice, Transgenic ; *CCAAT-Enhancer-Binding Protein-beta/metabolism ; Male ; Fecal Microbiota Transplantation ; Mice, Inbred C57BL ; Signal Transduction/drug effects ; },
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and behavioral disturbances. Buyang Huanwu Decoction (BYHWD), a traditional Chinese herbal formulation, has demonstrated potential neuroprotective effects. This study aims to evaluate the therapeutic impact of BYHWD on cognitive impairments in 3×Tg mice and to investigate its underlying mechanism through modulation of the gut microbiota-C/EBPβ/AEP signaling pathway.

METHODS: In two independent experiments, we assessed the effects of BYHWD and its derived fecal microbiota transplantation (FMT-BYHWD) on behavioral performance, neuropathological alterations, and signaling pathways in 3×Tg mice.

RESULTS: Treatment with BYHWD significantly improved cognitive function in 3×Tg mice and mitigated AD-like pathological changes. By suppressing the C/EBPβ/AEP signaling pathway, BYHWD reduced pathological Aβ plaque deposition, diminished tau hyperphosphorylation, and inhibited the release of pro-inflammatory cytokines. Further analysis revealed that BYHWD restored gut microbiota balance and suppressed the activation of the C/EBPβ/AEP pathway in the hippocampus. Moreover, transplanting FMT-BYHWD from BYHWD-treated mice to germ-free 3×Tg mice also ameliorated their cognitive deficits and AD-like pathology, suggesting that the anti-AD effects of BYHWD are mediated through the gut-brain axis by regulating the interplay between gut microbiota and the C/EBPβ/AEP signaling pathway.

CONCLUSION: This study uncovers the mechanism by which BYHWD improves cognitive deficits and neuropathological changes in 3×Tg mice via the gut-brain axis, mediated by the modulation of the gut microbiota-C/EBPβ/AEP signaling pathway, providing a novel therapeutic strategy for AD.},
}

Animals
*Gastrointestinal Microbiome/drug effects/physiology
*Drugs, Chinese Herbal/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology/psychology
Mice
*Cognitive Dysfunction/drug therapy/metabolism
Mice, Transgenic
*CCAAT-Enhancer-Binding Protein-beta/metabolism
Male
Fecal Microbiota Transplantation
Mice, Inbred C57BL
Signal Transduction/drug effects

@article {pmid40545618,
year = {2025},
author = {Kuzma, A and Valladares, O and Greenfest-Allen, E and Nicaretta, H and Kirsch, M and Ren, Y and Katanic, Z and White, H and Wilk, A and Bass, L and Brettschneider, J and Carter, L and Cifello, J and Chuang, WH and Clark, K and Gangadharan, P and Haut, J and Ho, PC and Horng, W and Iqbal, T and Jin, Y and Keskinen, P and Rose, AL and Moon, MK and Manuel, J and Qu, L and Robbins, F and Saravanan, N and Sha, J and Tate, S and Zhao, Y and , and Cantwell, L and Gardner, J and Chou, SY and Tzeng, JY and Bush, W and Naj, A and Kuksa, P and Lee, WP and Leung, YY and Schellenberg, G and Wang, LS},
title = {NIAGADS: A data repository for Alzheimer's disease and related dementia genomics.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70255},
doi = {10.1002/alz.70255},
pmid = {40545618},
issn = {1552-5279},
support = {U24AG041689/AG/NIA NIH HHS/United States ; U54AG052427/AG/NIA NIH HHS/United States ; U01AG032984/AG/NIA NIH HHS/United States ; U01AG058654/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/genetics ; *Genomics ; United States ; *Databases, Genetic ; National Institute on Aging (U.S.) ; *Dementia/genetics ; Genome-Wide Association Study ; Information Dissemination ; },
abstract = {The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is the National Institute on Aging-designated national data repository for human genetics research on Alzheimer's disease and related dementias (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis, including whole genome and exome sequence data from the Alzheimer's Disease Sequencing Project and other genotype/phenotype data, encompassing 211,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a Federal Information Security Modernization Act moderate compliant cloud-based platform that fully supports the National Institutes of Health Genomic Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. As a one-stop access portal for Alzheimer's disease (AD) genetics, NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of AD. HIGHLIGHTS: The National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) is a data repository for the storage of genetics and genomics data. NIAGADS houses data for Alzheimer's disease, related dementias, and healthy aging. NIAGADS offers open and qualified access data and knowledgebases to explore open access data. The Alzheimer's Disease Sequencing Project dataset is the largest Alzheimer's disease and related dementias joint called whole genome sequencing dataset (≈ 58,000 whole genomes).},
}

Humans
*Alzheimer Disease/genetics
*Genomics
United States
*Databases, Genetic
National Institute on Aging (U.S.)
*Dementia/genetics
Genome-Wide Association Study
Information Dissemination

@article {pmid40545559,
year = {2025},
author = {Cummings, J and Cohen, S and Murphy, J and Brothers, HM and Nejati, M and Forrestal, F and de Moor, C and O'Gorman, J and Harrison, J and Jaeger, J and Mummery, CJ and Porsteinsson, AP and Potashman, M and Tian, Y and Yang, L and He, P and Haeberlein, SB},
title = {Evaluation of cognitive, functional, and behavioral effects observed in EMERGE, a phase 3 trial of aducanumab in people with early Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70224},
doi = {10.1002/alz.70224},
pmid = {40545559},
issn = {1552-5279},
support = {//Biogen/ ; },
mesh = {Humans ; *Alzheimer Disease/drug therapy/genetics/psychology ; *Antibodies, Monoclonal, Humanized/therapeutic use ; Male ; Female ; Aged ; Disease Progression ; *Cognition/drug effects ; Treatment Outcome ; Apolipoprotein E4/genetics ; Double-Blind Method ; Neuropsychological Tests ; },
abstract = {INTRODUCTION: In EMERGE (NCT02484547), participants receiving aducanumab had significantly less progression versus placebo on all prespecified clinical endpoints at week 78. Here, we explicate the clinical meaningfulness of these treatment effects by analyzing item-level data and the persistence of treatment benefit.

METHODS: Participants with early Alzheimer's disease (AD) were stratified by apolipoprotein E (APOE) ε4 status and randomized (1:1:1) to receive low- or high-dose aducanumab, or placebo. Prespecified principal component analyses (PCAs) per the Statistical Analysis Plan were followed by post hoc examination of individual domains/items across all five clinical endpoints. Progression analysis assessed reduction in clinical decline.

RESULTS: High-dose aducanumab demonstrated clinically meaningful slowing of progression across clinical endpoints measuring cognition, daily function, and behavioral symptoms. Delay of progression over 18 months was consistent across measures; treatment effects increased over time.

DISCUSSION: Across multiple analyses aducanumab slowed cognitive decline, prolonged functional independence, and attenuated behavioral symptoms in participants with early AD. These outcomes comprise the elements of a clinically meaningful response to treatment.

HIGHLIGHTS: Endpoints in EMERGE assessed different aspects of cognition, daily function, and behavioral symptoms. Treatment benefits were observed across subdomains on all five clinical endpoints. Aducanumab meaningfully slowed disease progression in participants with early AD.},
}

Humans
*Alzheimer Disease/drug therapy/genetics/psychology
*Antibodies, Monoclonal, Humanized/therapeutic use
Male
Female
Aged
Disease Progression
*Cognition/drug effects
Treatment Outcome
Apolipoprotein E4/genetics
Double-Blind Method
Neuropsychological Tests

@article {pmid40544930,
year = {2025},
author = {Geng, D and Liu, A and Yan, Y and Zheng, W},
title = {Intermittent ELF-MF exposure effectively ameliorates pathologic features associated with adult AD mice.},
journal = {Brain research},
volume = {},
number = {},
pages = {149796},
doi = {10.1016/j.brainres.2025.149796},
pmid = {40544930},
issn = {1872-6240},
abstract = {OBJECTIVE: Extremely low frequency magnetic fields (ELF-MF) have been confirmed to have potentially positive effects on Alzheimer's disease (AD). However, the therapeutic effects are influenced by the exposure mode and the pathological process. Currently, there is no optimized treatment plan for the pathological process of AD. This study aims to optimize the exposure mode of ELF-MF to improve the therapeutic effect on AD mice with different degrees of dementia.

METHOD: This study employed 40 Hz, 10mT continuous pulsed ELF-MF stimulation, intermittent (stimulating for 30 min every 12 h) and continuous (stimulating for 60 min every 24 h) ELF-MF exposure. Through calculating various behavioral data, the changes in spatial working memory (SWM) of each group of mice were compared; the time-frequency distribution analysis method was applied to compare the changes in the theta band and gamma band neural oscillations of local field potentials (LFPs) signals in the CA1 region of the hippocampus during the object location task (OLT) of each group of mice; by analyzing the immunofluorescence images of Amyloid-beta 42 (Aβ42) and dynamin-related protein 1 (Drp1) in the hippocampal region of each group of mice, the changes in Aβ42 and Drp1 contents were compared.

RESULTS: ELF-MF stimulation can improve the SWM ability of AD model mice. Among them, intermittent stimulation in the adult group shows a better effect, while continuous stimulation in the aged group is superior. Further LFPs analysis reveals that AD leads to a decrease in theta and gamma frequency band energy in the CA1 area of the hippocampus, while ELF-MF stimulation can significantly enhance its energy. Moreover, in the adult group, the improvement of theta and gamma frequency bands under intermittent stimulation is more obvious, and in the aged group, the improvement of theta frequency band under continuous stimulation is more significant. The results of immunofluorescence detection indicate that ELF-MF stimulation can reduce the abnormal accumulation of Aβ42 and Drp1 in the hippocampus, and the effect of intermittent stimulation in the adult group is more significant.

CONCLUSION: Intermittent ELF-MF exposure may be an effective therapeutic strategy, especially in adult AD mice. This study highlights the potential significance of the ELF-MF exposure pattern in AD treatment and reveals the heterogeneous effects of ELF-MF exposure on the physiological and pathological conditions of AD mice, which has important guiding significance for the formulation of personalized treatment plans in the future.},
}

@article {pmid40544795,
year = {2025},
author = {León-Arcia, K and Pérez-Leal, G and Quintero-Álvarez, H and Zamora-Loyarte, DI and López-Armenteros, M and de la Caridad Sánchez-Quesada, A and Vázquez-Mojena, Y},
title = {Dual Aβ/tau epitope vaccines: a poorly explored strategy for Alzheimer's disease immunotherapy.},
journal = {Vaccine},
volume = {61},
number = {},
pages = {127414},
doi = {10.1016/j.vaccine.2025.127414},
pmid = {40544795},
issn = {1873-2518},
abstract = {Alzheimer's disease (AD) presents a growing public health challenge that urgently requires effective disease-modifying therapies. Active immunotherapy appears to be a promising strategy in AD drug development, offering advantages over passive immunization in terms of prophylactic potential and cost-effectiveness. We systematically reviewed anti-Aβ and anti-tau active immunization strategies over the past 25 years, identifying 577 unique antigenic formulations. Only 3.5 % have progressed to clinical trials, with none yet approved. Notably, only three strategies targeted both Aβ and tau epitopes (Aβ1-11 and tau2-18), despite the potential of multi-target approaches for AD's multifactorial pathology. Given the synergistic role of Aβ and tau in disease progression, dual-target vaccines remain a critical and underinvestigated area with significant therapeutic promise. This review underscores the need to expand research into multi-target immunotherapies that better address AD's complexity, potentially improving prevention and treatment outcomes.},
}

@article {pmid40544750,
year = {2025},
author = {Yang, LY and Hsu, CH and Cheng, YW and Chen, KW and Chou, SC and Chen, YR and Chen, YT and Deng, CR and Chen, IC and Kuo, MF and Wang, KC},
title = {Antroquinonol mitigates Tau hyperphosphorylation, neuronal damage and cognitive impairments in a chronic cerebral ischemia rat model.},
journal = {Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie},
volume = {189},
number = {},
pages = {118271},
doi = {10.1016/j.biopha.2025.118271},
pmid = {40544750},
issn = {1950-6007},
abstract = {Chronic cerebral ischemia (CCI) induced hyperphosphorylated Tau has been associated with an increased risk of neurodegenerative disorders such as Alzheimer's and vascular dementia. This study investigated the neuroprotective effects of Antroquinonol (AQ), an ubiquinone derivative from Antrodia camphorata with anti-inflammatory and antioxidant properties. Bilateral internal carotid artery ligation (BICAL) in male Wistar rats and mixed rat primary neuron/glia co-cultures exposed to a hypoxia and hypoglycemia (HH) environment were used as experimental CCI models to investigate the therapeutic effects and mechanisms of AQ. AQ was administered daily at low or high doses for 28 days after BICAL induction. Two and four weeks after BICAL surgery, the functional and cognitive outcomes were evaluated by rotarod test, open field test (OFT), novel object recognition (NOR) and Y-maze test. Nissl, TUNEL, IHC and ICC staining, and Western blot analysis were used to evaluate the effects and underlying mechanisms of AQ in the treatment of CCI. The results showed that both low and high doses of AQ treatment significantly ameliorated motor deficits, anxiety-like behavior, and cognitive impairments in BICAL rats at 2 or 4 weeks post-CCI. Histological and molecular analyses revealed that AQ reduced neuronal injury, microglia activation, apoptosis, and Tau hyperphosphorylation in the cortex and hippocampus regions. We also found that AQ inhibited HH-induced hyperphosphorylation of Tau by modulating protein kinases (p-GSK3β Y216 and p-mTOR), LC3II, and p-NRF2 proteins in cultured cells, suggesting roles in kinase regulation, autophagy, and antioxidation. These findings support AQ as a promise therapeutic candidate for treating CCI-related neurodegenerative disorders.},
}

@article {pmid40544243,
year = {2025},
author = {Mao, R and Shu, S and Sun, M and Chen, J and Hu, M and Ye, L and Xu, S and Jia, J and Shao, W and Bao, X and Xu, Y and Zhu, X},
title = {Edaravone-Dexborneol slows down pathological progression and cognitive decline via inhibiting S100A9 in APPswe/PS1dE9 mice.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {139},
pmid = {40544243},
issn = {1758-9193},
support = {82271480//the National Natural Science Foundation of China/ ; 82471460//the National Natural Science Foundation of China/ ; BK20230053//the Natural Science Foundation of Jiangsu Province of China/ ; BK20231120//the Natural Science Foundation of Jiangsu Province of China/ ; 2022ZD0211800//the STI2030-Major Projects/ ; ZKX22025//Nanjing Medical Science and Technology Development Foundation/ ; },
abstract = {BACKGROUND: Edaravone-Dexborneol (EDB) presents therapeutic effects due to its anti-inflammatory, antioxidant and anti-apoptotic properties, and has been widely used in ischemic stroke. However, the detailed efficacy and potential target of EDB in Alzheimer's disease (AD) are still elusive.

METHODS: Male APPswe/PS1dE9 mice were administered with EDB intraperitoneally from 3.5 to 8 months of age. The cognition of mice was assessed by behavioral tests. Synaptic alternations in the hippocampus were detected by electrophysiology and Golgi staining. β-amyloid (Aβ) pathology was mainly observed by immunofluorescence. Oxidative stress-related indicators were evaluated by dedicated kits, while quantitative PCR and ELISA were used to detect pro-inflammatory factors. Proteomics analysis further identified the potential target of EDB.

RESULTS: EDB was capable of delaying the cognitive decline and ameliorating the synaptic loss in APPswe/PS1dE9 mice. In addition to the anti-inflammation and anti-oxidation effects, EDB treatment mightily ablated the Aβ plaque by promoting microglial phagocytosis. Particularly, we first discovered that EDB could directly bind to S100A9, a pathological molecule that aggravates Aβ pathology and induces oxidative stress and neuroinflammation. EDB inhibited the expression, functional threonine phosphorylation and self-assembly of S100A9.

CONCLUSION: Our results indicate that EDB can improve cognitive function and slow down AD progression, and it may serve as a potential agent for AD and other S100A9-related diseases.},
}

@article {pmid40544093,
year = {2025},
author = {Moon, H and Chen, X and , },
title = {Plasma p-tau217 predicting brain-wide tau accumulation in preclinical AD.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {},
number = {},
pages = {100252},
doi = {10.1016/j.tjpad.2025.100252},
pmid = {40544093},
issn = {2426-0266},
abstract = {BACKGROUND: Recently developed blood test of Alzheimer's disease (AD) has been recognized as a promising alternative to CSF and PET, as it is noninvasive, cost-effective, and more accessible. Particularly, plasma p-tau217 shows high sensitivity in detecting β-amyloid (Aβ) and tau positivity in early AD. However, the potential value of p-tau217 in revealing Aβ and tau distribution and predicting future development has not been studied.

OBJECTIVES: We investigated the dose-response associations between p-tau217 and regional Aβ and tau measured by PET, as well as the longitudinal prediction of p-tau217 for prospective Aβ and tau accumulation measured by longitudinal PET.

DESIGN: Cross-sectional and longitudinal analyses.

SETTING: We used data in Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) study (N = 333) for primary analyses and Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 410) for validation.

PARTICIPANTS: Cognitively unimpaired older adults (N = 333) from A4 study and cognitively unimpaired older adults (N = 222), mild cognitive impairment (N = 114), and dementia (N = 74) from ADNI.

MEASUREMENTS: Plasma p-tau217 was measured using Lilly (A4) and Fujirebio (ADNI) assays. [18-F]Florbetapir PET and [18-F]Flortaucipir PET measured regional Aβ and tau.

RESULTS: Plasma p-tau217 was associated with concurrent Aβ in most cortical regions and tau in temporo-parietal cortices. Longitudinally, p-tau217 predicted brain-wide tau accumulation in widespread cortical regions in preclinical AD, but not Aβ change anywhere.

CONCLUSIONS: Plasma p-tau217 shows dose-response, brain-wide relationships with concurrent Aβ and future tau development in preclinical AD, suggesting its potential in disease trajectory monitoring and large-scale screening for individuals approaching certain biological stages of AD in clinical trials.},
}

@article {pmid40543791,
year = {2025},
author = {Feng, M and Wang, Q and Lei, M and Zhang, D and Yu, Q and Yan, C},
title = {Structural analysis and anti-neuroinflammatory activity of the water-soluble heteropolysaccharide PTTBP-2-2 from Pinellia ternata.},
journal = {International journal of biological macromolecules},
volume = {},
number = {},
pages = {145268},
doi = {10.1016/j.ijbiomac.2025.145268},
pmid = {40543791},
issn = {1879-0003},
abstract = {Neuroinflammation is closely linked to Alzheimer's disease, where the deposition of amyloid-beta activates microglia, triggering multiple processes that lead to neuronal damage and cognitive decline. However, studies have shown that water extract of Pinellia ternata can improve cognitive function and reduce inflammatory response in the brain injury of mice. Herein, a water-soluble polysaccharide, PTTBP-2-2. with a molecular weight of 11.7 kDa, consisting of D-Glc, D-Gal, D-Xyl, and L-Ara, was isolated from P. ternata. Methylation analysis, partial acid hydrolysis, and nuclear magnetic resonance revealed that the of PTTBP-2-2 backbone consisted of →4)-α-D-Glcp-(1→, →4,6)-α-D-Glcp-(1→, and →6)-α-D-Galp-(1 → residues, with side chains substituted at O-2, O-3, and O-6 positions of →4)-α-D-Glcp-(1→. In vitro experiments demonstrated that PTTBP-2-2 significantly reduced nitrous oxide levels in BV2 microglia cells and suppressed the expression of pro-inflammatory genes, including COX2, iNOS, TNF-α, IL-1β, and IL-6. These factors are key mediators of neuroinflammation. Mechanistic investigations revealed that the anti-neuroinflammatory activity of PTTBP-2-2 was mediated through the regulation of NF-κB and Nrf2/HO-1 signaling pathways. Overall, PTTBP-2-2 shows potential as a therapeutic agent for the treatment of neuroinflammation.},
}

@article {pmid40543641,
year = {2025},
author = {Chen, X and Cao, YG and Hao, FX and Liu, YL and Chi, FG and Niu, Y and Lu, D and Zhao, BX and Chen, L and Zheng, XK and Feng, WS},
title = {Alkaloids from the tubers of Pinellia pedatisecta.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114597},
doi = {10.1016/j.phytochem.2025.114597},
pmid = {40543641},
issn = {1873-3700},
abstract = {Nine undescribed alkaloids (1, 3, 4, 7, 8 and 10-13) and four undescribed natural products (2, 5, 6 and 9), together with eight known components, were isolated from the tubers of Pinellia pedatisecta Schott. Their structures were elucidated based on spectroscopic data, Rh2(OCOCF3)4-induced ECD spectral analysis, DP4+ analysis, ECD analysis and interpretation of their optical rotation data. The protective effects of all compounds against Aβ25-35-induced PC-12 cell injury were tested by MTT method, and the results indicated that compounds 1, 2, 5-10 and 16-20 exhibited obviously protective effects. In addition, the action mechanisms of compounds 2 and 5 were investigated by flow cytometry and cellular immunofluorescence, and the results indicated that compounds 2 and 5 ameliorated Aβ25-35-induced PC-12 cell injury via the NMDAR/p-CamK II/PKG signaling pathway. This study provided experimental basis for researching the chemical composition of P. pedatisecta and developing natural medicines for the treatment of Alzheimer's disease in the future.},
}

@article {pmid40543640,
year = {2025},
author = {Chen, X and Cao, YG and Chi, FG and Liu, YL and Ye, KL and Zheng, XK and Feng, WS},
title = {Norsesquiterpenes from the stems and leaves of Pinellia pedatisecta Schott.},
journal = {Phytochemistry},
volume = {},
number = {},
pages = {114590},
doi = {10.1016/j.phytochem.2025.114590},
pmid = {40543640},
issn = {1873-3700},
abstract = {A chemical investigation of the stems and leaves of Pinellia pedatisecta Schott afforded forty norsesquiterpenes, including eleven undescribed compounds (1-6, 10-13, and 23) and twenty-nine known analogues. Their structures were elucidated using detailed spectroscopic and comparative literature data analysis. The Mo2(OAc)4-induced ECD spectral analysis, DP4+ and ECD analysis were used to determine the absolute configuration of undescribed isolates. In addition, the results of the bioactivity evaluation indicated that components 3-6, 8-10, 12, 14, 15, 17-19, 21-22, 25-29, 33, and 39 significantly improved Aβ25-35-induced PC-12 cell damage. The network pharmacology results showed that STAT3, NFKB1, HIF1A, EGFR, CASP3 were the correlated targets of compounds 3-6, 10, and 12 against AD, with Ras, PI3K-Akt, and MAPK as the potential signaling pathways. This study provided experimental basis for the treatment of Alzheimer's disease and we will further explore mechanisms in cells and mice to find accurate targets and pathways in the future.},
}

@article {pmid40542938,
year = {2025},
author = {Cherait, A and Xifró, X and Reglodi, D and Vaudry, D},
title = {More Than Three Decades After Discovery of the Neuroprotective Effect of PACAP, What Is Still Preventing Its Clinical Use?.},
journal = {Journal of molecular neuroscience : MN},
volume = {75},
number = {3},
pages = {80},
pmid = {40542938},
issn = {1559-1166},
abstract = {Discovered in 1989, pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with strong neuroprotective properties, as shown in various neurodegenerative preclinical models of Parkinson, Alzheimer, or Huntington diseases. PACAP neuroprotection has also been reported in animal models of cerebral ischemia and traumatic brain injury. The neuroprotective effect of PACAP occurs through its capacity to modulate most of the multiphasic aspects of neuronal diseases, such as oxidative stress, neuronal cell death, and inflammation. However, more than three decades after its discovery, and although PACAP neurotrophic and neuroprotective activities have now been largely documented, its clinical use is still awaited. Thus, the aim of this manuscript is to discuss the main reasons which limit the use of PACAP as a therapeutic agent for the treatment of neuronal diseases. To achieve this objective, an opinion survey has been conducted among experts in the field of PACAP, and a bibliographic investigation was carried out.},
}

@article {pmid40542726,
year = {2025},
author = {Lv, Y and Song, X and He, J and Jiang, X and Lu, L and Fan, M and Guo, Z and Zhang, C and Xie, Y},
title = {3-Hydroxyquinolin-2-Ones Act as Dual Inhibitors of Ferroptosis and Monoamine Oxidase B: Reducing Alzheimer's Disease-Related Amyloid Precursor Protein and Hyperphosphorylated Tau In Vivo.},
journal = {Journal of medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.jmedchem.5c00502},
pmid = {40542726},
issn = {1520-4804},
abstract = {The challenges in the current treatment landscape for Alzheimer's disease (AD) underscore the urgent need for novel therapeutic strategies targeting multiple pathological pathways. Recent studies have implicated iron in ROS-dependent neuronal injury through ferroptosis. Additionally, overexpression of monoamine oxidase B (MAO-B) induces oxidative stress and decreases cognitive function. In this study, we presented the novel dual inhibitors of ferroptosis and MAO-B for AD management, aiming to address both the symptomatic and neurodegenerative aspects of this disease. Compound 21d emerged as a promising candidate, exhibiting potent and selective MAO-B inhibitory activity (IC50 = 87.47 nM, SI > 229), as well as excellent antiferroptosis activity through modulation of the iron metabolic pathway and GSH-GPX4 axis in vitro. Importantly, 21d normalized cognitive and memory impairments in a 3×Tg (APP/Tau/Ps1) AD mouse model and reduced levels of AD-related proteins, including amyloid precursor protein and phosphorylated Tau protein, in the brains of AD mice.},
}

@article {pmid40542704,
year = {2025},
author = {Aly, HF and Fouad, GI and Khalil, WKB and Kamel, NN and El-Rigal, NS and Ahmed, KA and Taha, DA and Shalaby, MB and Abd El-Karim, SS and Abou Baker, DH and Rizk, MZ},
title = {Evaluating the therapeutic efficacy of a Benzofuran-Enaminone derivative for the management of Alzheimer's disease (AD)-like pathology in rats through regulating the expression of apoptosis and AD-related genes.},
journal = {Neurological research},
volume = {},
number = {},
pages = {1-15},
doi = {10.1080/01616412.2025.2520021},
pmid = {40542704},
issn = {1743-1328},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a progressive age-related neurodegenerative disorder. There is currently no promising cure for AD; the available treatments can only alleviate the symptoms.

OBJECTIVES: The Benzofuran-Enaminone derivative '(E)-1-(benzofuran-2-yl)-3-((2-hydroxyphenyl)amino)prop-2-en-1-one (5)' was synthesized as a potential anti-AD candidate in Aluminum chloride (AlCl3)-induced AD in rats.

METHODS: In vivo and in vitro acute and chronic studies were conducted to examine the potential toxicity, as well as the antioxidant and anti-acetylcholinesterase (AChE) activities of compound 5. Then, rats were divided into four groups: (1) negative control; (2) AD-induced rats; (3) AD-induced rats treated with compound 5; and (4) AD-induced rats treated with Donepezil. Behavioral, biochemical, and molecular investigations were conducted. The expression of insulin 1 gene, apoptotic genes, and the AD-related genes were estimated.

RESULTS: The selected dose of compound 5 (10 mg/kg) was based on an acute toxicity test, then it was applied for a chronic study for 1 month; no toxicological features were stimulated. In vitro, compound 5 demonstrated antioxidant and anti-AChE activities. The expression of apoptotic genes (Bcl-2, Bax, and Caspase-3), AD-related genes (Amyloid precursor protein (APP) and Tau), and the insulin 1 gene were altered in AD-induced rats versus control rats. Treatment of AD rats with compound 5 counteracted the AlCl3-induced neurotoxicity.

CONCLUSION: This study could be regarded as an initial step in drug discovery for testing this new chemical entity as a potent anti-AD therapeutic agent.},
}

@article {pmid40542425,
year = {2025},
author = {Liu, Y and Hong, T and Lv, M and Guo, X and Zhang, P and Yan, A and Wei, W},
title = {Delphinidin attenuates cognitive deficits and pathology of Alzheimer's disease by preventing microglial senescence via AMPK/SIRT1 pathway.},
journal = {Alzheimer's research & therapy},
volume = {17},
number = {1},
pages = {138},
pmid = {40542425},
issn = {1758-9193},
support = {82302417//National Natural Science Foundation of China/ ; 82201565//National Natural Science Foundation of China/ ; QMRC2203//the Qingmiao Talent Program of Huadong Hospital/ ; 24ZR1420800//Natural Science Foundation of Shanghai Municipality/ ; 21YF1411600//Shanghai Sailing Program/ ; HDLC2022003//the Investigator Initiated Research Projects of Huadong Hospital/ ; SHDC22022304//the Shanghai Hospital Development Center Foundation/ ; },
abstract = {BACKGROUND: Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy.

OBJECTIVES: This study aimed to investigate whether delphinidin, a naturally occurring anthocyanin, can alleviate AD-related pathologies by mitigating microglial senescence and to elucidate the underlying molecular mechanisms.

METHODS: We employed APP/PS1 mice, naturally aged mice, and an in vitro model using Aβ42-induced senescent BV2 microglia. Delphinidin's effects were evaluated through assessments of cognitive function, synaptic integrity (synapse loss), Aβ plaque burden, senescent microglia gene signatures, and cellular senescence markers (including senescence-associated β-galactosidase activity, SASP factor expression, oxidative stress, and cyclin p21/p16 levels). Mechanistic studies involved analyzing the AMPK/SIRT1 signaling pathway, testing direct delphinidin-SIRT1 interaction, and using the AMPK inhibitor Compound C.

RESULTS: Delphinidin treatment significantly alleviated cognitive deficits, synapse loss, Aβ peptides plaques of APP/PS1 mice via downregulated senescent microglia gene signature, prevented cell senescence, including senescence-associated β-galactosidase activity, senescence-associated secretory phenotype (SASP), oxidative stress, cyclin p21 and p16. And delphinidin treatment also prevented microglial senescence in naturally aged mice. In vitro, delphinidin treatment attenuated cell senescence induced by Aβ42 in BV2 microglia cells. Further research indicated that delphinidin treatment enhanced the AMPK/SIRT1 signaling pathway. Additionally, delphinidin was found to directly interact with SIRT1. It's noteworthy that AMPK inhibitor Compound C inversed the protective effect of delphinidin against microglial senescence.

CONCLUSION: Our study reveals for the first time that delphinidin effectively improved cognitive deficits, alleviated synapse loss and Aβ pathology in APP/PS1 mice by mitigating microglial senescence. These findings highlight delphinidin as a promising natural anti-aging agent against the development of aging and age-related diseases.},
}

@article {pmid40541947,
year = {2025},
author = {Guan, P and Ruan, Q and Li, J and Xi, M and Qi, W and Ko, KI and Ni, J},
title = {Ferroptosis in periodontitis: mechanisms, impacts, and systemic connections.},
journal = {Cell death discovery},
volume = {11},
number = {1},
pages = {283},
pmid = {40541947},
issn = {2058-7716},
support = {2025A1515012494//Natural Science Foundation of Guangdong Province (Guangdong Natural Science Foundation)/ ; A2022522//Guangdong Medical Research Foundation (Guangdong Province Medical Research Foundation)/ ; B2022262//Guangdong Medical Research Foundation (Guangdong Province Medical Research Foundation)/ ; A223450//Guangdong Medical Research Foundation (Guangdong Province Medical Research Foundation)/ ; },
abstract = {Periodontitis is a chronic inflammatory disease initiated by plaque microorganisms, with the regulatory mechanisms of its progression being a primary research focus. Ferroptosis, a unique form of cell death driven by iron-dependent lipid peroxidation, has been increasingly recognized for its crucial role in modulating chronic inflammation. This study focused on the molecular mechanisms by which plaque microorganisms and the inflammatory microenvironment trigger ferroptosis in periodontal cells, elucidating how ferroptosis in these cells promotes periodontitis progression. Additionally, the potential exacerbation of periodontitis through ferroptosis in systemic diseases such as Alzheimer's disease, nonalcoholic steatohepatitis, chronic obstructive pulmonary disease, and type 2 diabetes is discussed. This review aims to provide new theoretical foundations and strategies for the treatment of periodontitis.},
}

@article {pmid40541595,
year = {2025},
author = {Alkhammash, A and Alotaibi, G},
title = {Epigenetic Reprogramming as a Therapeutic Strategy for Neurodegenerative Diseases: A Complex and Novel Approach.},
journal = {European journal of pharmacology},
volume = {},
number = {},
pages = {177853},
doi = {10.1016/j.ejphar.2025.177853},
pmid = {40541595},
issn = {1879-0712},
abstract = {Epigenetic reprogramming has emerged as a promising therapeutic strategy for neurodegenerative diseases by targeting reversible gene expression changes without altering the underlying DNA sequence. This review explores key epigenetic mechanisms, including DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, that contribute to neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Pharmacological interventions such as DNA methylation modulators, histone deacetylase (HDAC) inhibitors, and non-coding RNA therapies have shown potential in restoring normal gene function. Advanced approaches, including CRISPR-dCas9 epigenetic editing, synthetic transcription factors (STFs), and Yamanaka factor-mediated cellular rejuvenation, offer precise control over disease-associated gene expression. Despite these advancements, several challenges and controversies remain, including off-target effects, delivery limitations, long-term safety concerns, and ethical implications. Emerging research focuses on multi-target combination therapies, integrating epigenetic interventions with stem cell therapy, immune checkpoint inhibitors, and AI-driven precision medicine. Future directions involve the development of non-invasive drug delivery systems, AI-powered biomarker discovery, and personalized epigenome-based treatments to enhance therapeutic outcomes. As research advances, epigenetic reprogramming holds the potential to revolutionize neurodegenerative disease treatment, providing more effective, individualized, and disease-modifying interventions.},
}

@article {pmid40541584,
year = {2025},
author = {Tao, X and Wang, L and Gong, W},
title = {Untargeted metabolomics reveals the mechanisms of luteolin and exercise combination treatment against cognitive impairments in AD mice through modulating autophagy.},
journal = {The Journal of nutritional biochemistry},
volume = {},
number = {},
pages = {110011},
doi = {10.1016/j.jnutbio.2025.110011},
pmid = {40541584},
issn = {1873-4847},
abstract = {BACKGROUND: Alzheimer's disease (AD) yields a dramatic burden on patients and their families, with no complete cure yet. Our group has previously found that AD-related cognitive impairment (ARCI) could be alleviated after luteolin and exercise combination treatment (Lut + Exe), but the potential mechanisms require further exploration.

PURPOSE: This work used untargeted metabolomics to uncover the mechanisms Lut + Exe protects against ARCI.

METHODS: Utilizing an Aβ1-42-oligomers-induced AD model, the Morris water maze (MWM) test was performed. Metabolomics of plasma was performed to identify differential metabolites. KEGG and MetaboAnalyst were used to enrich the metabolic pathways. Then, the autophagy inhibitor chloroquine (CQ) was utilized to verify the potential role of autophagy in the Lut+ Exe efficacy against ARCI.

RESULTS: The results showed that Lut + Exe alleviated the ARCI in mice. The in-depth analysis showed that Lut + Exe could significantly affect purine metabolism, retinol metabolism, thiamine metabolism, histidine metabolism, and cysteine and methionine metabolism, indicating that the energy metabolism disorder was alleviated. Based on the close relationship between autophagy and energy metabolism, further study found that Lut + Exe could reverse the significant reduction of key autophagy proteins of AD model mice, while the effects of it on the MWM performance and neurogenesis of AD model mice could be blocked by CQ.

CONCLUSION: This study reveals the crucial role of autophagy in the mechanisms of Lut + Exe against ARCI using untargeted metabolomics. Our work provides a novel paradigm to promote the use of combination treatment in curing AD.},
}

@article {pmid40541317,
year = {2025},
author = {Frecska, E and Kovács, A and Szabo, A},
title = {The protective effect of DMT against neurodegeneration.},
journal = {International review of neurobiology},
volume = {181},
number = {},
pages = {395-420},
doi = {10.1016/bs.irn.2025.04.010},
pmid = {40541317},
issn = {2162-5514},
abstract = {This paper explores the therapeutic potential of DMT in neuroprotective strategies, particularly concerning ischemia-reperfusion injury (IRI) and neurodegenerative disorders. Besides its potent serotonin receptor actions, DMT is also an endogenous agonist of the sigma-1 receptor (Sig-1R). Sigma receptors are a unique family of proteins with high expression in the brain and spinal cord and have been involved in the etiology, symptom course and treatment of several central nervous system disorders. Our previous theoretical and experimental work strongly suggest that targeting sigma (and serotonin) receptors via DMT may be particularly useful for treatment in a number of neurological conditions like stroke, global brain ischemia, Alzheimer's disease, and amyotrophic lateral sclerosis. In this article, we briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of our previous preclinical (in vitro and in vivo) DMT studies aiming at mitigating IRI and related cellular neuropathologies. We conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest. The multiple neuroprotective mechanisms facilitated by DMT may position it as a model molecule for developing pharmacological treatments for neurodegenerative disorders.},
}

@article {pmid40541177,
year = {2025},
author = {Habich, C and Kowalski, A and Wachter, A and Heimann, MJ and Wolf, M and Kummer, MP and Nicolaisen, N and Sliwinski, C and Reinhardt, L and Heil, V and Lange, T and Untucht, C and Miller, LN and Korffmann, J and Geist, D and Schöndorf, D and Lee, H and Bahnassawy, L and Mielich-Süss, B and Brennan, MS and Wilkens, R and Röwe, J and Weidling, I and Rudolf, R and Hafner, M and Manos, JD and Cik, M and Reinhardt, P},
title = {BMP, MEK, and WNT inhibition with NGN2 expression for rapid generation of hiPSC-derived neurons amenable to regional patterning.},
journal = {Stem cell reports},
volume = {},
number = {},
pages = {102539},
doi = {10.1016/j.stemcr.2025.102539},
pmid = {40541177},
issn = {2213-6711},
abstract = {Human induced pluripotent stem cells (hiPSCs) are a promising tool for studying neurological diseases and developing therapies for neurodegenerative diseases. Differentiation of hiPSCs into neurons can be achieved by dual SMAD inhibition (dSMADi) or by induced neurogenin 2 (NGN2) overexpression ("iNGN2"). Starting directly from hiPSCs, iNGN2 shortens the time to a neuronal stage but leads to neurons partially resembling peripheral or posterior fates while dSMADi more faithfully recapitulates telencephalic development. To modify the iNGN2 approach, we applied an accelerated induction paradigm that is dependent on the inhibition of BMP, MEK, and WNT pathways ("BMWi"), to commit hiPSCs into a telencephalic fate before iNGN2. The resulting neurons showed strong expression of telencephalic markers, with decreased levels of peripheral and posterior marker genes compared to iNGN2 alone. The resulting telencephalic neurons are suitable for a tau aggregation assay. Furthermore, we could demonstrate that during BMWi treatment, the cells are amenable to additional regional patterning cues. This allowed the generation of neurons from different regions of the CNS and peripheral nervous system (PNS), which will significantly facilitate in vitro modeling of a range of neurodevelopmental and neurodegenerative disorders.},
}

@article {pmid40541115,
year = {2025},
author = {Pinheiro, PSM and de Chirico, F and Loi, M and Trazzi, S and Ciani, E and Rodrigues, DA and Alves, MA and Lima, LM and Milelli, A and Monti, B and Manssour Fraga, CA and Bolognesi, ML},
title = {Design, synthesis and pharmacological evaluation of multitarget GPR40 agonists/HDAC6 inhibitors for Alzheimer's disease.},
journal = {European journal of medicinal chemistry},
volume = {296},
number = {},
pages = {117868},
doi = {10.1016/j.ejmech.2025.117868},
pmid = {40541115},
issn = {1768-3254},
abstract = {The discovery of new therapeutic agents for the treatment of neurodegenerative diseases-particularly Alzheimer's disease (AD) -remains one of the most challenging areas in medicinal chemistry. Given the multifactorial nature of these disorders, the rational design of multitarget-directed ligands (MTDLs) is gaining increasing attention, underscoring the importance of exploring novel target combinations. In this study, we report the design of the first-in-class multitarget compounds that function as dual GPR40 agonists and HDAC6 inhibitors-a novel strategy aimed at modulating neuroinflammation in AD. Among them, compound 4e exhibited potent activity, with an EC50 of 22 nM for GPR40 activation and an IC50 of 73 nM for HDAC6 inhibition. This balanced dual profile was corroborated in cell-based assays, where compound 4e significantly increased acetylated tubulin and ERK phosphorylation levels in SH-SY5Y cells. Furthermore, compound 4e demonstrated immunomodulatory effects on microglia, highlighting its potential as a chemical starting point for targeting neuroinflammation and, ultimately, neurodegeneration.},
}

@article {pmid40540716,
year = {2025},
author = {Zhang, QL and Liu, Y and Tu, T and Yan, XX},
title = {The Comorbidity of AD and PD: Exploring Clinical, Pathological, and Biomarker Interactions.},
journal = {Aging and disease},
volume = {},
number = {},
pages = {},
doi = {10.14336/AD.2025.0301},
pmid = {40540716},
issn = {2152-5250},
abstract = {Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative disorders, primarily characterized by cognitive decline and motor dysfunction, respectively. The comorbidity of AD and PD further increases disease complexity and presents significant challenges for clinical diagnosis and treatment. Due to substantial clinical overlaps in the advanced stage of AD and PD, comorbid cases are frequently misdiagnosed as a single disease, which hinders early recognition and timely intervention. Based on pathological observations from patients with comorbidity of AD and PD, this review discusses the prevalence and clinical features of AD-PD comorbidity, the spatiotemporal progression and potential interactions of key pathological proteins, including β-amyloid (Aβ), phosphorylated tau (pTau), and α-synuclein (α-syn). The aim of this review is to update potential new insights and strategies to improve diagnostic accuracy, advance personalized therapeutic approaches, and guide future research into the underlying mechanisms of comorbidity.},
}

@article {pmid40540273,
year = {2025},
author = {Jeong, SM and Jung, W and Cho, H and Choi, HL and Jeon, KH and Nam, KW and Lee, YG and Kim, B and Han, K and Shin, DW},
title = {Alzheimer Disease in Breast Cancer Survivors.},
journal = {JAMA network open},
volume = {8},
number = {6},
pages = {e2516468},
doi = {10.1001/jamanetworkopen.2025.16468},
pmid = {40540273},
issn = {2574-3805},
abstract = {IMPORTANCE: Cancer-related cognitive impairment is a common concern after breast cancer treatment. However, the association between breast cancer survivorship and the risk of Alzheimer dementia (AD) remains unclear.

OBJECTIVE: To evaluate the risk of AD among breast cancer survivors compared with cancer-free controls and examine the potential association of cancer treatments with AD risk.

This retrospective cohort study used data from the Korean National Health Insurance Service. A total of 70 701 patients who underwent breast cancer surgery between January 1, 2010, and December 31, 2016, were included and matched with cancer-free controls (1:3). Participants were followed up for a median (IQR) of 7.3 (5.7-9.0) years. Data analysis was performed from January 2024 to June 2024.

EXPOSURES: Breast cancer diagnosis, surgery, and subsequent treatments, including anthracycline chemotherapy and radiation therapy.

MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of AD. Subdistribution hazard ratios (SHRs) and 95% CIs were calculated using competing risk regression models, adjusting for sociodemographic factors and comorbidities.

RESULTS: Among 70 701 breast cancer survivors (mean [SD] age, 53.1 [8.5] years), 1229 cases of AD were detected, with an incidence rate of 2.45 per 1000 person-years. Survivors exhibited a slightly lower risk of AD compared with cancer-free controls (SHR, 0.92; 95% CI, 0.86-0.98), especially among individuals 65 years or older (SHR, 0.92; 95% CI, 0.85-0.99). However, landmark analyses found that this lower risk did not persist beyond 5 years of survival. Cancer treatment with radiation therapy (adjusted HR, 0.77; 95% CI, 0.68-0.87) was associated with reduced risk of AD among survivors.

CONCLUSIONS AND RELEVANCE: This cohort study of breast cancer survivors found a lower risk of AD compared with cancer-free controls, despite common concerns about cognitive decline after treatment. The findings suggest certain cancer treatments potentially have benefits for lower AD risk. Further research is needed to assess the long-term risk of AD in this population.},
}

@article {pmid40540149,
year = {2025},
author = {Zhang, X and Zhong, G and Wu, H},
title = {Exploring the pharmacological mechanisms and therapeutic implications of galangin against neurological disorders.},
journal = {Pharmacological reports : PR},
volume = {},
number = {},
pages = {},
pmid = {40540149},
issn = {2299-5684},
support = {2022-92//Foshan Famous Traditional Chinese Medicine Inheritance Studio Construction Project/ ; 20241300//Scientific Research Project of Guangdong Provincial Bureau of Traditional Chinese Medicine/ ; 2017A020213015//Guangdong Provincial Science and Technology Project Plan/ ; },
abstract = {Neurological disorders represent a leading cause of mortality and disability worldwide, encompassing a broad spectrum of prevalent conditions such as Alzheimer's disease, epilepsy, and stroke. In recent years, natural compounds have garnered increasing attention as potential therapeutic and preventive agents for neurological disorders. Galangin, a naturally occurring flavonoid primarily derived from Alpinia officinarum Hance, exhibits diverse biological properties, including notable neuroprotective, anti-tumor, and anti-inflammatory effects. Emerging evidence indicates that galangin exerts significant neuroprotective effects through multiple mechanisms. This review systematically summarizes the in vivo metabolism and pharmacokinetics of galangin, elucidates its mechanism of action, and highlights recent advances in its application for neurological disorders. Furthermore, the prospect of nanodrug carriers for enhancing the therapeutic efficacy of galangin is explored. Additionally, this review addresses the current research limitations and outlines future research directions to provide a theoretical foundation for its clinical application in neurological disorders. Collectively, the findings underscore the extensive pharmacological properties and therapeutic potential of galangin, highlighting its promise as a novel candidate for the treatment and prevention of neurological disorders and warranting further in-depth investigation and development.},
}

@article {pmid40539354,
year = {2025},
author = {Qin, Y and Deng, X and Zhang, S},
title = {Cognition, Diagnosis, and Treatment of Alzheimer's Disease: A Review.},
journal = {Recent patents on biotechnology},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118722083358924250606173812},
pmid = {40539354},
issn = {2212-4012},
abstract = {As the global population ages, the health of older adults has become a growing concern. Alzheimer's disease (AD) is a common ailment affecting older adults, but the diagnosis and treatment of AD are difficult given our insufficient understanding of the disease. This review aims to provide reliable information for patients and their families by presenting a detailed overview of the pathogenic factors, diagnostic methods, and clinical manifestation of AD, as well as advances in drug and physical therapies. The information presented here should help provide a more comprehensive understanding of AD for patients and their families and encourage family- or self-screening based on clinical manifestations, thus improving early AD detection. In addition, the current treatment methods for AD are summarized. Although a gold-standard treatment for AD is yet to be developed, controlled-release therapies and medications that slow disease progression or improve cognitive function are available. The appropriate treatment method depends on the patient's diagnosis and the local medical level, and the effectiveness of the treatments may vary. Therefore, improving our understanding of AD and cognition-related symptoms in the public is necessary to improve early AD diagnoses. This review provides information that will facilitate self-screening for AD based on clinical manifestations, which can improve the early clinical diagnosis rate.},
}

@article {pmid40539231,
year = {2025},
author = {Espay, AJ and Sturchio, A and Imarisio, A and Hill, EJ and Williamson, B and Montemagno, K and Hoffmann, C and Roy, HL and Milovanovic, D and Manfredsson, FP},
title = {Physics of Protein Aggregation in Normal and Accelerated Brain Aging.},
journal = {BioEssays : news and reviews in molecular, cellular and developmental biology},
volume = {},
number = {},
pages = {e70030},
doi = {10.1002/bies.70030},
pmid = {40539231},
issn = {1521-1878},
abstract = {Protein aggregation is a normal response to age-related exposures. According to the thermodynamic hypothesis of protein folding, soluble proteins precipitate into amyloids (pathology) under supersaturated conditions through a process similar to crystallization. This soluble-to-insoluble phase transition occurs via nucleation and may be catalyzed by ectopic surfaces such as lipid nanoparticles, microbes, or chemical pollutants. The increasing prevalence of these exposures with age correlates with the rising incidence of pathology over the lifespan. However, the formation of amyloid fibrils does not inherently cause neurodegeneration. Neurodegeneration emerges when the levels of functional monomeric proteins, from which amyloids form, fall below a critical threshold. The preservation of monomeric proteins may explain neurological resilience, regardless of the extent of amyloid deposition. This biophysical framework challenges the traditional clinicopathological view that considers amyloids intrinsically toxic, despite the absence of a known mechanism of toxicity. Instead, it suggests that chronic exposures driving persistent nucleation consume monomeric proteins as they aggregate. In normal aging, replacement matches loss; in accelerated aging, it does not. A biophysical approach to neurodegenerative diseases has important therapeutic implications, refocusing treatment strategies from removing pathology to restoring monomeric protein homeostasis above the threshold needed to sustain normal brain function.},
}

@article {pmid40538861,
year = {2025},
author = {Wu-Chung, EL and Bonomo, ME and Brandt, AK and Denny, BT and Karmonik, C and Frazier, JT and Blench, K and Fagundes, CP},
title = {Music-induced cognitive change and whole-brain network flexibility: a pilot study.},
journal = {Frontiers in neuroscience},
volume = {19},
number = {},
pages = {1567605},
pmid = {40538861},
issn = {1662-4548},
abstract = {INTRODUCTION: Cognitive impairment that exceeds age-related cognitive decline is a risk factor for Alzheimer's disease and related dementias. As the older adult population is notably increasing every year, significant efforts are being made to preserve cognitive function in older adulthood. Non-pharmaceutical approaches such as music interventions have noticeable benefits for cognition. Music engagement utilizes multiple brain regions dually involved in higher cognitive functions. Yet the neurobiology of music-induced cognitive change remains understudied. Complex human behavior and cognition likely depend on continuous communication across brain regions rather than localized activity in one region. Given that music creativity engages a wide range of mental processes, whole-brain network indices quantifying the brain's tendency to create functional communities (modularity) and then dynamically reorganize these communities (flexibility) may be relevant for assessing music-related cognitive change. Using a semi-randomized clinical trial design (ClinicalTrials.gov; NCT04137913), we examined whether (1) music creativity altered whole-brain network indices (modularity, flexibility) and (2) whether music-related effects on cognition depended on whole-brain network indices.

METHODS: Fifty-two older adults (Mean age = 75 years; 54% female; 84% White) were randomized to a 6-week music creativity intervention (n = 25) or a no-treatment control condition (n = 27) and completed resting-state fMRI scans and the Montreal Cognitive Assessment at baseline and follow-up (post-intervention).

RESULTS: The music creativity intervention did not alter network flexibility or modularity over time. However, the relationship between group assignment and change in global cognitive function depended on baseline flexibility: music creativity improved global cognition more than the control condition, only among individuals who had higher than average network flexibility.

DISCUSSION: Findings suggest that having a dynamic brain network, which has previously been linked to better executive functioning performance, may be necessary for music-related benefits on cognition. This pilot study is innovative as it is among the first to identify possible neural mechanisms underlying why music creativity interventions confer a more significant cognitive benefit for some older adults than others.},
}

@article {pmid40538392,
year = {2025},
author = {Yuan, L and An, L and Xie, R and Cai, J and Li, D and Chen, X and Guo, W and Lin, Y and Zhu, C and Chang, Y and Wang, K and Han, W and Han, L},
title = {Correlation study of 5-HT in brain with cognitive function and anxious-like behavior in APP/PS1 transgene mice.},
journal = {Sleep and biological rhythms},
volume = {23},
number = {3},
pages = {319-329},
pmid = {40538392},
issn = {1446-9235},
abstract = {Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive decline in cognitive function and emotional disturbances. The amygdala is an important connectivity structure in the brain and is responsible for emotional responses. 5-HT is involved in various neurodevelopmental processes in the brain. In this study, correlation study of 5-HT in brain with cognitive function and anxious-like behavior was investigated in APP/PS1 transgene mice. Multiple behavioral tests were performed to examine the cognitive function and anxiety behavior of AD mice. In vivo hippocampus long-term potentiation (LTP) was recorded to reflect synaptic plasticity. 5-HT levels in hippocampus and amygdala were determined. Further, we explored the correlation between 5-HT levels in hippocampus and amygdala and long-term cognitive behaviors and anxiety behaviors in the AD mice using linear regression analysis. Our results demonstrated that there was close linear correlation between 5-HT level in brain and spatial cognition and anxiety behavior of APP/PS1 transgene mice. 5-HT influences spatial learning and memory by regulating the synaptic plasticity in hippocampus of APP/PS1 transgenic mice. These results indicate that 5-HT might be potentially beneficial in the treatment of AD.},
}

@article {pmid40537813,
year = {2025},
author = {Hoffmann, J and Machule, ML and Kreye, J and Stöffler, L and Körtvelyessy, P and Buthut, M and Rößling, R and Bacher, P and Scheffold, A and Prüss, H},
title = {Frequency of synaptic antigen-specific CD4[+] T cells in dementia is age-dependent but not correlated with cognitive impairment.},
journal = {Immunity & ageing : I & A},
volume = {22},
number = {1},
pages = {23},
pmid = {40537813},
issn = {1742-4933},
support = {HIL-A03 BaoBab//Helmholtz-Fonds/ ; FOR3004, PR1274/9-1, clinical research unit 5023/1 'BECAUSE-Y' [project number 504745852]//Deutsche Forschungsgemeinschaft/ ; Connect-Generate 16GW0279K//Bundesministerium für Bildung und Forschung/ ; },
abstract = {Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. Autoimmune mechanisms have been increasingly considered to contribute to disease progression, e.g. by enhancing protein misfolding or pro-inflammatory immune responses. Understanding this contribution may lead to novel treatment options beyond removing neurodegeneration-associated proteins. We hypothesized that CD4[+] TH cells against synaptic proteins may play a role in dementia, given the profound changes of synaptic proteins in the disease. We investigated TH cell frequencies and phenotypes after antigen-reactive T cell enrichment (ARTE) using three important synaptic antigens known to play a role in cognitive function, N-Methyl-D-Aspartate receptor (NMDAR), Leucine-rich, glioma inactivated 1 (LGI1) and metabotropic glutamate receptor 5 (mGluR5). Our data revealed that synaptic autoantigen-specific TH cells occurred in all cohorts and were similarly frequent in patients with dementia and sex- and age-matched controls. However, they were significantly reduced compared to young healthy subjects, indicating strong age-related effects ('immune senescence'). Compared to the ubiquitously available Candida albicans antigen, synaptic autoantigen-specific TH cell responses were strongly driven by IFNγ-producing T cells, expression of which markedly decreased with age. Patients with dementia had significantly less IL-17-producing synaptic autoantigen-specific TH cells than aged healthy controls. This first direct ex vivo quantitative and qualitative analysis of circulating T cells autoreactive to three synaptic autoantigens in dementia shows no correlation with cognitive impairment. It suggests that synaptic autoantigen-specific TH cells decline with age and are not a major driver of dementia development.},
}

@article {pmid40537027,
year = {2025},
author = {Wu, Z and Zhao, Y and Hao, S and An, M and Song, C and Li, J},
title = {Role of peroxisome proliferator-activated receptor alpha in neurodegenerative diseases and other neurological disorders: Clinical application prospects.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01371},
pmid = {40537027},
issn = {1673-5374},
abstract = {Peroxisome proliferator-activated receptor alpha is a member of the nuclear hormone receptor superfamily and functions as a transcription factor involved in regulating cellular metabolism. Previous studies have shown that PPARα plays a key role in the onset and progression of neurodegenerative diseases. Consequently, peroxisome proliferator-activated receptor alpha agonists have garnered increasing attention as potential treatments for neurological disorders. This review aims to clarify the research progress regarding peroxisome proliferator-activated receptor alpha in nervous system diseases. Peroxisome proliferator-activated receptor alpha is present in all cell types within adult mouse and adult neural tissues. Although it is conventionally believed to be primarily localized in the nucleus, its function may be regulated by a dynamic balance between cytoplasmic and nuclear shuttling. Both endogenous and exogenous peroxisome proliferator-activated receptor alpha agonists bind to the peroxisome proliferator-activated response element to exert their biological effects. Peroxisome proliferator-activated receptor alpha plays a significant therapeutic role in neurodegenerative diseases. For instance, peroxisome proliferator-activated receptor alpha agonist gemfibrozil has been shown to reduce levels of soluble and insoluble amyloid-beta in the hippocampus of Alzheimer's disease mouse models through the autophagy-lysosomal pathway. Additionally, peroxisome proliferator-activated receptor alpha is essential for the normal development and functional maintenance of the substantia nigra, and it can mitigate motor dysfunction in Parkinson's disease mouse models. Furthermore, peroxisome proliferator-activated receptor alpha has been found to reduce neuroinflammation and oxidative stress in various neurological diseases. In summary, peroxisome proliferator-activated receptor alpha plays a crucial role in the onset and progression of multiple nervous system diseases, and peroxisome proliferator-activated receptor alpha agonists hold promise as new therapeutic agents for the treatment of neurodegenerative diseases, providing new options for patient care.},
}

@article {pmid40537002,
year = {2025},
author = {Brooks, NAH and Riar, I and Klegeris, A},
title = {Mitochondrial damage-associated molecular patterns: Neuroimmunomodulators in central nervous system pathophysiology.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01459},
pmid = {40537002},
issn = {1673-5374},
abstract = {Neuroinflammation contributes to a wide range of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. It is driven by non-neuronal glial cells, mainly microglia and astrocytes. Microglia are the resident immune cells of the central nervous system, while astrocytes are the main support cells for neuronal functions but can also participate in neuroimmune responses. Both these glial cell types can become reactive upon detection of certain endogenous intracellular molecules that appear in the extracellular space under specific circumstances; these can be pathology-associated abnormal structures, such as amyloid β proteins, or damage-associated molecular patterns released from injured cells, including their mitochondria. Once in the extracellular space, damage-associated molecular patterns act as ligands for specific pattern recognition receptors expressed by glia inducing their reactivity and neuroimmune responses. This review considers the following mitochondrial damage-associated molecular patterns: heme, cytochrome c, cardiolipin, adenosine triphosphate, mitochondrial DNA, mitochondrial transcription factor A, N-formyl peptides, and the tricarboxylic acid cycle metabolites: succinate, fumarate, and itaconate. We describe their well-established functions as damage-associated molecular patterns of the peripheral tissues before summarizing available evidence indicating these molecules may also play significant roles in the neuroimmune processes of the central nervous system. We highlight the pattern recognition receptors that mitochondrial damage-associated molecular patterns interact with and the cellular signaling mechanisms they modulate. Our review demonstrates that some mitochondrial damage-associated molecular patterns, such as cytochrome c, adenosine triphosphate, and mitochondrial transcription factor A, have already demonstrated significant effects on the central nervous system. In contrast, others including cardiolipin, mitochondrial DNA, N-formyl peptides, succinate, fumarate, and itaconate, will require additional studies corroborating their roles as damageassociated molecular patterns in the central nervous system. For all of the reviewed mitochondrial damage-associated molecular patterns, there is a shortage of studies using human cells and tissues, which is identified as a significant knowledge gap. We also assess the need for targeted research on the effects of mitochondrial damage-associated molecular patterns in the central nervous system pathologies where their roles are understudied. Such studies could identify novel treatment strategies for multiple neurodegenerative diseases, which are characterized by chronic neuroinflammation and currently lack effective therapies.},
}

@article {pmid40538761,
year = {2024},
author = {Cheng, R and Shu, J and Chen, H and Li, M and Cheng, X and Liu, L},
title = {DNA Methylation in Aging and Alzheimer's Disease.},
journal = {Human brain (Hong Kong)},
volume = {3},
number = {3},
pages = {},
pmid = {40538761},
issn = {2957-6296},
abstract = {DNA methylation undergoes significant changes with age. These alterations play a pivotal role in the development of age-related diseases, including Alzheimer's disease (AD). Recent advancements in DNA methylome profiling have revealed global hypomethylation patterns, particularly within repetitive elements, as well as gene-specific changes that are associated with neurodegeneration. Age-related alterations in DNA methylation have been implicated in the disruption of key cellular processes, such as inflammation and proteostasis, both central to AD pathology. However, several challenges persist in this field. One major issue is the inconsistency of findings across different brain regions and tissue types, which complicates result interpretation. Furthermore, the limited understanding of cell-type specificity raises concerns about the generalizability of findings from bulk tissue analyses. Key questions remain in DNA methylation research related to aging and AD, including elucidating the precise mechanisms driving methylation changes, exploring cell-type specificity, determining the functional consequences of these alterations, and investigating cross-tissue correlations. A deeper understanding of the spatiotemporal dynamics of methylation changes, the underlying mechanisms, and their therapeutic implications is essential to the development of novel prevention and treatment strategies. This review will delve into these findings and challenges, offering insights into future research directions.},
}

@article {pmid40536997,
year = {2025},
author = {Zhang, F and Meng, Y and Zhang, W},
title = {Deep brain stimulation for the treatment of Alzheimer's disease: A safer and more effective strategy.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01088},
pmid = {40536997},
issn = {1673-5374},
abstract = {Alzheimer's disease is the most common type of cognitive disorder, and there is an urgent need to develop more effective, targeted and safer therapies for patients with this condition. Deep brain stimulation is an invasive surgical treatment that modulates abnormal neural activity by implanting electrodes into specific brain areas followed by electrical stimulation. As an emerging therapeutic approach, deep brain stimulation shows significant promise as a potential new therapy for Alzheimer's disease. Here, we review the potential mechanisms and therapeutic effects of deep brain stimulation in the treatment of Alzheimer's disease based on existing clinical and basic research. In clinical studies, the most commonly targeted sites include the fornix, the nucleus basalis of Meynert, and the ventral capsule/ventral striatum. Basic research has found that the most frequently targeted areas include the fornix, nucleus basalis of Meynert, hippocampus, entorhinal cortex, and rostral intralaminar thalamic nucleus. All of these individual targets exhibit therapeutic potential for patients with Alzheimer's disease and associated mechanisms of action have been investigated. Deep brain stimulation may exert therapeutic effects on Alzheimer's disease through various mechanisms, including reducing the deposition of amyloid-β, activation of the cholinergic system, increasing the levels of neurotrophic factors, enhancing synaptic activity and plasticity, promoting neurogenesis, and improving glucose metabolism. Currently, clinical trials investigating deep brain stimulation for Alzheimer's disease remain insufficient. In the future, it is essential to focus on translating preclinical mechanisms into clinical trials. Furthermore, consecutive follow-up studies are needed to evaluate the long-term safety and efficacy of deep brain stimulation for Alzheimer's disease, including cognitive function, neuropsychiatric symptoms, quality of life and changes in Alzheimer's disease biomarkers. Researchers must also prioritize the initiation of multi-center clinical trials of deep brain stimulation with large sample sizes and target earlier therapeutic windows, such as the prodromal and even the preclinical stages of Alzheimer's disease. Adopting these approaches will permit the efficient exploration of more effective and safer deep brain stimulation therapies for patients with Alzheimer's disease.},
}

@article {pmid40536954,
year = {2025},
author = {Hu, M and Yi, H and Wang, S and Kang, X and Liu, Y and Liu, Z and Huang, H and Qin, Q and Yuan, L and Cai, W and Qiu, W and Lu, Z and Liu, S},
title = {Bone marrow mesenchymal stem cells protect against cerebral amyloid angiopathy by enhancing neutrophil mitocytosis.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01273},
pmid = {40536954},
issn = {1673-5374},
abstract = {Current treatments for cerebral amyloid angiopathy are mainly symptomatic and have limited efficacy, and there is a lack of targeted therapies. Mesenchymal stem cell transplantation improves cognitive and motor function in conditions such as Alzheimer's disease, acute ischemic stroke, and Parkinson's disease. In addition, mesenchymal stem cell therapy modulates the immune system, reduces neuroinflammation, and improves resolution of brain lesions by cells of the macrophage lineage. Cerebral amyloid angiopathy and Alzheimer's disease share similar pathologic changes involving amyloid-beta deposition, which contributes to the progression of both diseases and exacerbates cognitive deficits through impaired vascular integrity and neuroinflammation. Therefore, we hypothesized that mesenchymal stem cell therapy could also ameliorate the pathological changes seen in cerebral amyloid angiopathy by modulating the immune response. In this study, we show that bone marrow mesenchymal stem cells have a protective effect in a mouse model of cerebral amyloid angiopathy (Tg-SwDI/B). Bone marrow mesenchymal stem cell treatment improved cognitive function, reduced neuroinflammation, and maintained blood-brain barrier integrity in Tg-SwDI/B mice. Mechanistically, bone marrow mesenchymal stem cell treatment enhanced the expulsion of damaged mitochondria from neutrophils via migrasomes, in a process known as mitocytosis, thereby preserving mitochondrial quality within the neutrophils. Mitochondrial damage in neutrophils leads to cellular injury, including the generation of reactive oxygen species and the formation of neutrophil extracellular traps. Neutrophils activate mitocytosis to promote mitochondrial renewal, which further enhances their own clearance by macrophage lineage cells. Our findings demonstrate that bone marrow mesenchymal stem cells are a promising therapeutic candidate for cerebral amyloid angiopathy, as they play a significant role in migrasome-dependent mitochondrial quality control in neutrophils.},
}

@article {pmid40536931,
year = {2025},
author = {Li, K and Chen, R and Wang, R and Fan, W and Zhao, N and Yang, Z and Yan, J},
title = {Neuroinflammation in neurodegenerative diseases: Focusing on the mediation of T lymphocytes.},
journal = {Neural regeneration research},
volume = {},
number = {},
pages = {},
doi = {10.4103/NRR.NRR-D-24-01539},
pmid = {40536931},
issn = {1673-5374},
abstract = {Neurodegenerative diseases are a group of illnesses characterized by the gradual deterioration of the central nervous system, leading to a decline in patients' cognitive, motor, and emotional abilities. Neuroinflammation plays a significant role in the progression of these diseases. However, there is limited research on therapeutic approaches to specifically target neuroinflammation. The role of T lymphocytes, which are crucial mediators of the adaptive immune response, in neurodegenerative diseases has been increasingly recognized. This review focuses on the involvement of T lymphocytes in the neuroinflammation associated with neurodegenerative diseases. The pathogenesis of neurodegenerative diseases is complex, involving multiple mechanisms and pathways that contribute to the gradual degeneration of neurons, and T cells are a key component of these processes. One of the primary factors driving neuroinflammation in neurodegenerative diseases is the infiltration of T cells and other neuroimmune cells, including microglia, astrocytes, B cells, and natural killer cells. Different subsets of CD4+ T cells, such as Th1, Th2, Th17, and regulatory T cells, can differentiate into various cell types and perform distinct roles within the neuroinflammatory environment of neurodegenerative diseases. Additionally, CD8+ T cells, which can directly regulate immune responses and kill target cells, also play several important roles in neurodegenerative diseases. Clinical trials investigating targeted T cell therapies for neurodegenerative diseases have shown that, while some patients respond positively, others may not respond as well and may even experience adverse effects. Targeting T cells precisely is challenging due to the complexity of immune responses in the central nervous system, which can lead to undesirable side effects. However, with new insights into the pathophysiology of neurodegenerative diseases, there is hope for the establishment of a solid theoretical foundation upon which innovative treatment strategies that target T cells can be developed in the future.},
}

@article {pmid40536624,
year = {2025},
author = {Owona, BA and Ngoungoure, VN and Tchamba, JT and Njayou, FN and Moundipa, PF},
title = {Cola acuminata extract's inhibition of NLRP3 inflammasome in THP-1 cells as a potential treatment option for Parkinson's disease.},
journal = {Metabolic brain disease},
volume = {40},
number = {6},
pages = {229},
pmid = {40536624},
issn = {1573-7365},
mesh = {Humans ; *NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism ; *Inflammasomes/metabolism/antagonists & inhibitors/drug effects ; *Plant Extracts/pharmacology/therapeutic use ; THP-1 Cells ; *Parkinson Disease/drug therapy/metabolism ; Macrophages/drug effects/metabolism ; },
abstract = {Neuroinflammation has been described as one of the multiple clinical manifestations of Parkinson's and Alzheimer's diseases (PD and AD). Moreover, it was reported that amyloid-β deposition is associated with cognitive decline in PD. Here, Cola acuminata (CA) extract was used to inhibit NLRP3 inflammasome in THP-1 macrophages in vitro. CA showed significant anti-inflammatory effect by inhibiting nitric oxide (NO) release from cells after stimulation with LPS and Nigericin. Phagocytosis of amyloid-β by THP-1 cells showed that at 100 µg/ml, CA increases phagocytic activity of macrophages in vitro. Moreover, activation of NLRP3 inflammasome and subsequent treatment with CA showed a reduction of IL1-β and IL-18 cytokines release in ELISA assay. Furthermore, NLRP3, caspase-1, IL1-β and NF-kB expressions were significantly inhibited at the gene and protein levels as shown by RTqPCR and western blot assays respectively. Interestingly, colocalization analysis of activated inflammasome confirmed our results suggesting that CA disaggregates inflammasome assembly. Mass spectrometry analysis of CA has identified epicatechin, catechin, chlorogenic acid, quercetin and stigmasterol known as inflammasome inhibitors among the extract chemical constituents. Together, our results indicate that CA can inhibit inflammasome activation in macrophage, thereby opening future perspectives for PD treatment.},
}

Humans
*NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors/metabolism
*Inflammasomes/metabolism/antagonists & inhibitors/drug effects
*Plant Extracts/pharmacology/therapeutic use
THP-1 Cells
*Parkinson Disease/drug therapy/metabolism
Macrophages/drug effects/metabolism

@article {pmid40535825,
year = {2025},
author = {Sharma, A and Gugulothu, D and Virmani, T and Sharma, A and Kumar, G and Singh, K and Jain, D and Bhuia, MS and Chowdhury, R and Ahammed, NT and Islam, MT},
title = {Ethnopharmacological Profile, Phytochemistry and Therapeutic Potential of Aegle marmelos L. for the Treatment of Neurological Disorders.},
journal = {Journal of nutrition and metabolism},
volume = {2025},
number = {},
pages = {2275526},
pmid = {40535825},
issn = {2090-0724},
abstract = {Aegle marmelos (L.) Corrêa, commonly known as the bael fruit tree, is a member of the Rutaceae family and holds significance in Ayurvedic herbal medicine due to its myriad therapeutic properties. This paper seeks to delve into the diverse benefits offered by the bael fruit tree, exploring various plant parts, including leaves, fruit, bark, and seeds, all of which contain bioactive compounds with therapeutic potential. The bael fruit, with its diverse phytochemical profile, exhibits potential health benefits ranging from radioprotection and antibacterial properties to antioxidant and hepatoprotective effects. Additionally, this review highlights the limited preclinical studies on AMs' efficacy in treating neurological disorders, emphasizing the need for more clinical trials to validate its potency and safety. Specifically, the effects and mechanisms of AM extract in addressing Alzheimer's disease, anxiety, depression, epilepsy and Parkinson's disease are explored. In conclusion, AM emerges as a plant of considerable nutritional and pharmacological value, with the potential to contribute significantly to the treatment of neurological disorders. Despite its promising attributes, the limited preclinical studies necessitate further clinical trials to confirm its efficacy. This review consolidates relevant studies, offering insights into AMs' ethnobotany, chemical constituents, pharmacological properties and potential application in neurological disorders. The comprehensive examination underscores the need for continued research to unlock the full therapeutic potential of this versatile plant.},
}

@article {pmid40535822,
year = {2025},
author = {Hossain, MS and Patwary, MAM and Rupa, SA and Kazi, M and Kumar, A and Alghamdi, KM and Matin, MM and Rahman, MR},
title = {In vitro antioxidant, anticholinesterase, and antiproliferative activities of methanol extracts of Crateva religiosa bark.},
journal = {Journal of Cancer},
volume = {16},
number = {8},
pages = {2492-2502},
pmid = {40535822},
issn = {1837-9664},
abstract = {Background: C. religiosa has traditionally been applied to treat heart disease, chronic weight loss, improved digestion, memory loss, convulsion and epilepsy, psychological problems, and neurologic pains. Purpose: Prior studies have already elucidated the potential therapeutic effects of C. religiosa. However, in this work, the bark extract of C. religiosa was studied systematically to investigate its antioxidant, anticholinesterase, and antiproliferative activities, focusing on potential applications in treating Alzheimer's disease (AD) and cancer. Study Design and Methods: The dried coarse powder of C. religiosa bark was cold-extracted in methanol and evaporated to dryness. It was then successively fractionated into petroleum ether (PEF), dichloromethane (DMF), and ethyl acetate (EEF) fractions. The Folin-Ciocalteu reagent and AlCl3 approaches were utilized to evaluate the total phenol and flavonoid contents, respectively, and the DPPH (2,2-diphenyl-1-picrylhydrazyl) and phosphomolybdenum assays were employed to determine the antioxidant activity of each fraction. The DMF was tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by employing the Ellman method, while all fractions were tested for antiproliferative activity against HepG2 and A549 cell lines by MTT assay. Results: The DMF displayed the highest phenolic content (124.8 ± 17.5 mg gallic acid equivalent/g of dry extract) and flavonoid content (211.1 ± 4.8 mg quercetin equivalent/g of dry extract). In the phosphomolybdenum assay, its antioxidant IC50 value was 25 ± 1 µg/mL. Additionally, the DMF fraction exhibited significant inhibition activity against AChE and BChE, with IC50 values of 455 ± 1 and 450 ± 1 μg/mL, respectively. In terms of anti-proliferative activity, the DMF exhibited an IC50 value of 29.2 µM against the HepG2 cell line, while the EAF showed IC50 values of 24.7 µM in the A549 cell line. Conclusion: The potent activity of C. religiosa as an antioxidant, along with its significant inhibition of AChE and BChE, positions it as a promising candidate for Alzheimer's disease treatment. Furthermore, its robust inhibition of human liver and lung cancer cells suggests its potential as a therapeutic agent against cancer.},
}

@article {pmid40534898,
year = {2025},
author = {Xiao, W and Chen, LZ and Chang, J and Xiao, YW},
title = {Discovery of Novel Anti-Acetylcholinesterase Peptides Using a Machine Learning and Molecular Docking Approach.},
journal = {Drug design, development and therapy},
volume = {19},
number = {},
pages = {5085-5098},
pmid = {40534898},
issn = {1177-8881},
mesh = {*Machine Learning ; *Cholinesterase Inhibitors/chemistry/pharmacology ; *Molecular Docking Simulation ; *Acetylcholinesterase/metabolism ; Humans ; *Peptides/chemistry/pharmacology ; *Drug Discovery ; Alzheimer Disease/drug therapy ; Structure-Activity Relationship ; },
abstract = {OBJECTIVE: Alzheimer's disease poses a significant threat to human health. Currenttherapeutic medicines, while alleviate symptoms, fail to reverse the disease progression or reduce its harmful effects, and exhibit toxicity and side effects such as gastrointestinal discomfort and cardiovascular disorders. The major challenge in developing machine learning models for anti-acetylcholinesterase peptides discovery is the limited availability of active peptide data in public databases. This study primarily aims to address this challenge and secondarily to discover novel, safer, and less toxic anti-acetylcholinesterase peptides for better Alzheimer's disease treatment.

METHODS: A Random Forest Classifier model was constructed from a hybrid dataset of non-peptide small molecules and peptides. It was applied to screen a custom peptide library. The binding affinities of the predicted peptides to acetylcholinesterase were assessed via molecular docking, and top ranked peptides were selected for experimental assay.

RESULTS: The top six peptides (IFLSMC, WCWIYN, WIGCWD, LHTMELL, WHLCVLF, and VWIIGFEHM) were selected for experimental validation. Their inhibitiory effects on acetylcholinesterase were determined to be 0.007, 3.4, 1.9, 10.6, 1.5, and 3.9 μmol/L, respectively.

DISCUSSION: Predicting anti-acetylcholinesterase peptides is challenging due to the absence of a comprehensive, publicly accessible peptide database. Traditional approaches using only non-peptide small molecules for model construction often have poor performance on predicting active peptides. Here, we developed a machine-learning model from a hybrid dataset of non-peptide small molecules and peptides, which find six potent peptides. This model was as/superior accuracy compared to small-molecule-only models reported before, but has a significant higher capability of discriminating active peptides. Our work shows that hybrid datasets can boost machine-learning model prediction in peptide drug discovery.},
}

*Machine Learning
*Cholinesterase Inhibitors/chemistry/pharmacology
*Molecular Docking Simulation
*Acetylcholinesterase/metabolism
Humans
*Peptides/chemistry/pharmacology
*Drug Discovery
Alzheimer Disease/drug therapy
Structure-Activity Relationship

@article {pmid40532357,
year = {2025},
author = {Wang, Y and Sheng, H and Wang, X},
title = {Recognition and diagnosis of Alzheimer's Disease using T1-weighted magnetic resonance imaging via integrating CNN and Swin vision transformer.},
journal = {Clinics (Sao Paulo, Brazil)},
volume = {80},
number = {},
pages = {100673},
doi = {10.1016/j.clinsp.2025.100673},
pmid = {40532357},
issn = {1980-5322},
abstract = {PURPOSE: Alzheimer's disease is a debilitating neurological disorder that requires accurate diagnosis for the most effective therapy and care.

METHODS: This article presents a new vision transformer model specifically created to evaluate magnetic resonance imaging data from the Alzheimer's Disease Neuroimaging Initiative dataset in order to categorize cases of Alzheimer's disease. Contrary to models that rely on convolutional neural networks, the vision transformer has the ability to capture large relationships between far-apart pixels in the images. The suggested architecture has shown exceptional outcomes, as its precision has emphasized its capacity to detect and distinguish significant characteristics from MRI scans, hence enabling the precise classification of Alzheimer's disease subtypes and various stages. The model utilizes both the elements from convolutional neural network and vision transformer models to extract both local and global visual patterns, facilitating the accurate categorization of various Alzheimer's disease classifications. We specifically focus on the term 'dementia in patients with Alzheimer's disease' to describe individuals who have progressed to the dementia stage as a result of AD, distinguishing them from those in earlier stages of the disease.

RESULTS: Precise categorization of Alzheimer's disease has significant therapeutic importance, as it enables timely identification, tailored treatment strategies, disease monitoring, and prognostic assessment.

CONCLUSION: The stated high accuracy indicates that the suggested vision transformer model has the capacity to assist healthcare providers and researchers in generating well-informed and precise evaluations of individuals with Alzheimer's disease.},
}

@article {pmid40532315,
year = {2025},
author = {Wu, QL and Yang, X and Luo, JX and Liu, L and Zhou, Y and Lu, MH},
title = {Microglia energy metabolism: A new perspective on Alzheimer's disease treatment.},
journal = {Journal of the neurological sciences},
volume = {475},
number = {},
pages = {123585},
doi = {10.1016/j.jns.2025.123585},
pmid = {40532315},
issn = {1878-5883},
abstract = {Alzheimer's disease (AD) is a progressive age-associated neurodegenerative disorder characterized by systemic cerebral metabolic disturbances. Neuroimaging and biochemical analyses reveal three hallmark features: decreased glucose utilization, mitochondrial bioenergetic deficits, and impaired energy homeostasis within hippocampal circuits. Emerging evidence highlights the pivotal role of microglia, the brain's specialized immune guardians, whose metabolic plasticity forms a self-reinforcing pathological cycle with AD progression. During early disease stages, oxidative phosphorylation (OXPHOS)-dependent M2 microglia mediate neuroprotective functions through efficient β-amyloid (Aβ) phagocytosis. However, progressive metabolic reprogramming drives a pathological shift toward glycolysis-dominant M1, characterized by heightened proinflammatory cytokine secretion and compromised clearance capacity. Notably, AD-associated pathological aggregates disrupt microglial metabolic adaptation, suppress mitophagy processes, and perpetuate sustained neuroinflammatory responses. The metabolic flexibility of microglia allows them to adapt to different energy demands. This study reviews the roles of major metabolic pathways and metabolic regulators of microglia in AD and the link between AD pathology and microglia energy metabolism, and describes the potential of relevant drugs and non-drug approaches in AD treatment, revealing metabolic regulation as a new target for AD therapy.},
}

@article {pmid40531514,
year = {2025},
author = {Fang, R and Jin, L and Lu, H and Xie, Q and Yang, X and Kueckelhaus, M},
title = {A Novel Microsurgical Model of Cervical Lymph Node-to-Vein Anastomosis (LNVA) for Studying Brain Lymphatic Outflow.},
journal = {The Journal of craniofacial surgery},
volume = {},
number = {},
pages = {},
doi = {10.1097/SCS.0000000000011535},
pmid = {40531514},
issn = {1536-3732},
abstract = {BACKGROUND: Cervical lymphaticovenous bypass has recently emerged as an innovative surgical approach to enhance brain lymphatic clearance for the treatment of Alzheimer disease (AD). Although early clinical findings are promising, the absence of a reproducible preclinical model has hindered mechanistic investigations and translational advancements.

OBJECTIVE: This study aimed to establish the first rat model for cervical LVA, addressing technical challenges and providing a standardized platform for preclinical research on lymphatic clearance and its role in neurodegeneration.

METHODS: Rats underwent bilateral cervical LNVA using high-magnification supermicrosurgical techniques. After identification of the deep cervical lymph nodes, end-to-side lymph node-to-venous anastomosis was performed. Anastomotic patency was confirmed intraoperatively by direct visualization without leakage. Indocyanine green (ICG) lymphangiography, performed through nasal administration, demonstrated fluorescence drainage into the external jugular vein.

RESULTS: With progressive refinement of microsurgical skills and improved anatomic familiarity, procedural stability was achieved. In the final cohort of 5 rats, all LVA procedures resulted in successful anastomotic patency.

CONCLUSION: This study is the first to establish a rat model of cervical deep lymph node-venous anastomosis (LNVA), offering a novel microsurgical platform with dual value. On one hand, it serves as a technically demanding and reproducible model for advanced training in plastic and lymphatic surgery. On the other, it provides a structurally precise, gain-of-function approach for targeted intervention of the deep cervical lymph nodes-an anatomic hub increasingly implicated in brain lymphatic clearance and neurodegeneration. As such, this model may contribute meaningfully to future mechanistic studies on glymphatic function and its modulation.},
}

@article {pmid40531439,
year = {2025},
author = {Hossain, MS and Hussain, MH},
title = {Multi-Target Drug Design in Alzheimer's Disease Treatment: Emerging Technologies, Advantages, Challenges, and Limitations.},
journal = {Pharmacology research & perspectives},
volume = {13},
number = {4},
pages = {e70131},
doi = {10.1002/prp2.70131},
pmid = {40531439},
issn = {2052-1707},
mesh = {*Alzheimer Disease/drug therapy ; Humans ; *Drug Design ; Animals ; Blood-Brain Barrier/metabolism ; Drug Delivery Systems ; Machine Learning ; Nanomedicine ; Polypharmacology ; Artificial Intelligence ; },
abstract = {Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disorder, recognized as the most prevalent form of dementia. It is characterized by multiple pathological processes, including amyloid-beta accumulation, neurofibrillary tangles, and neuroinflammation. The therapeutic efficacy of traditional single-target drugs has been limited, failing to cure, halt, or reverse disease progression. Therefore, this complex disease warrants comprehensive therapeutic strategies like multi-target drug design (MTDD). MTDD represents a promising strategy to target multiple pathological pathways concurrently. The integration of advanced technologies, including artificial intelligence, machine learning, and nanomedicine, can further enhance the precision and effectiveness of MTDD. This review explores various MTDD approaches, including multi-target-directed ligands, multi-target compound combinations, and polypharmacology. These strategies aim to address the multifaceted nature of AD pathology more effectively than single-target approaches. MTDD offers key advantages, including pathway-level synergy, broader therapeutic scope, and potential for improved efficacy. However, MTDD faces various challenges and limitations, such as the complexity of drug design, difficulty of crossing the blood-brain barrier, and regulatory hurdles. Despite these challenges, recent advancements in computational methods and drug delivery systems show promise in overcoming these barriers. Future research should focus on optimizing delivery systems, improving in silico modeling, and translating multi-target strategies into clinically viable therapies for AD. This review addresses these needs by critically analyzing recent technologies, advantages, challenges, limitations, and future directions of MTDD, underscoring its potential to transform AD treatment.},
}

*Alzheimer Disease/drug therapy
Humans
*Drug Design
Animals
Blood-Brain Barrier/metabolism
Drug Delivery Systems
Machine Learning
Nanomedicine
Polypharmacology
Artificial Intelligence

@article {pmid40531190,
year = {2025},
author = {McIntyre, RS},
title = {Acetylcholine and muscarinic receptor targeting in bipolar disorder: does xanomeline-trospium chloride and other investigational muscarinic agonists hold promise as a mechanistically informed therapeutic treatment for mania, mixed features and cognitive deficits in bipolar disorder?.},
journal = {Expert opinion on investigational drugs},
volume = {},
number = {},
pages = {},
doi = {10.1080/13543784.2025.2522885},
pmid = {40531190},
issn = {1744-7658},
abstract = {INTRODUCTION: Xanomeline-trospium chloride (Cobenfy, KarXT) received FDA approval on 26 September 2024, for the treatment of adults with schizophrenia. Xanomeline-trospium chloride is the first muscarinic M1, M4 acetylcholine receptor partial agonist approved to treat schizophrenia. Preliminary evidence indicates that xanomeline-trospium chloride improves measures of cognition in Alzheimer's disease and schizophrenia.

AREAS COVERED: Acetylcholine's physiology and evidence implicating disturbance in acetylcholine and its canonical receptors in mania and cognitive impairment in bipolar disorder are synthesized. Extant efficacy, safety and tolerability data for xanomeline-trospium chloride in adults with schizophrenia are reviewed. Xanomeline-trospium chloride's clinical and pharmacological profile provides rationale for investigating its efficacy, safety and tolerability in the treatment of manic episodes and cognitive impairment associated with bipolar disorder.

EXPERT OPINION: Xanomeline-trospium chloride is a mechanistically novel treatment for schizophrenia targeting cholinergic receptors as opposed to dopamine receptors and may have transdiagnostic efficacy in mania and/or cognitive impairment in bipolar disorder. Xanomeline-trospium chloride is safe and generally well tolerated and does not appear to have depressogenic effects and/or increased suicidality in adults with schizophrenia. Whether other investigational muscarinic agonists (e.g. positive allosteric modulator [PAM] of M4) are potentially efficacious in mania and cognitive impairment in bipolar disorder is a future research avenue.},
}

@article {pmid40530895,
year = {2025},
author = {Aitken, L and Baillie, G and Pannifer, A and Morrison, A and Major, LL and Alphey, MS and Sethi, R and Timmerman, M and Robinson, J and Riley, J and Shishikura, Y and Koekemoer, L and Von Delft, F and Rutjes, H and Read, KD and Jones, PS and McElroy, SP and Smith, TK and Gunn-Moore, FJ},
title = {High-Throughput Screening of Potent Drug-like Molecules Targeting 17β-HSD10 for the Treatment of Alzheimer's Disease and Cancer.},
journal = {ACS chemical biology},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschembio.5c00110},
pmid = {40530895},
issn = {1554-8937},
abstract = {In this study, the first industrial-scale high-throughput screening of nearly 350,000 drug-like molecules targeting the enzyme 17β-HSD10, a promising therapeutic target for Alzheimer's disease and cancers, is presented. Two novel series of potent 17β-HSD10 inhibitors that demonstrate low nanomolar potency against both the enzyme and in vivo cellular assays with minimal cytotoxicity were identified. These inhibitors were characterized further through a series of assays demonstrating ligand-protein interactions and co-crystallography, revealing un-/non-competitive inhibition with respect to the cofactor NADH, unlike previously published inhibitors. This work significantly advances the development of 17β-HSD10-targeting therapeutics, offering new potential leads for treating Alzheimer's disease and cancers.},
}

@article {pmid40530328,
year = {2025},
author = {Cellular Longevity, OMA},
title = {RETRACTION: Classic Prescription, Kai-Xin-San, Ameliorates Alzheimer's Disease as an Effective Multitarget Treatment: From Neurotransmitter to Protein Signaling Pathway.},
journal = {Oxidative medicine and cellular longevity},
volume = {2025},
number = {},
pages = {9868970},
pmid = {40530328},
issn = {1942-0994},
abstract = {[This retracts the article DOI: 10.1155/2019/9096409.].},
}

@article {pmid40529430,
year = {2025},
author = {Chen, R and Li, R and Jiang, J and Zhou, L and Zhao, S and Zhang, Y and Xia, Q and Yang, Z},
title = {Coconut oil derived medium-chain triglycerides ameliorated memory deficits via promoting neurite outgrowth and maintaining gut homeostasis in 5×FAD mice.},
journal = {Frontiers in nutrition},
volume = {12},
number = {},
pages = {1585640},
pmid = {40529430},
issn = {2296-861X},
abstract = {Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by neurite atrophy, neuronal loss, and memory impairment. Medium-chain triglycerides (MCT), a type of fatty acid predominantly found in coconut oil, have been shown to improve metabolic syndrome as well as cognitive performance via ketone production in humans. Here, we investigated the protective effects of MCT on neurite atrophy and memory deficits in 5×FAD mice and elucidated the underlying mechanisms. First, virgin coconut oil (VCO), refined, bleached, and deodorized coconut oil (RBDCO), and MCT were orally administered to 6-8 months old 5×FAD mice for 9 consecutive weeks, the effects on cognition were then evaluated. MCT demonstrated superior effects compared to RBDCO and VCO in reducing Aβ levels, inhibiting hyperactivated microglia and astroglia, protecting neurons, and mitigating memory decline. Further, metagenomic analysis and RT-qPCR results revealed that MCT intervention increased the relative abundance of Akkermansia, reduced intestinal permeability, and elevated the concentration of short-chain fatty acids in the brain. Additionally, MCT treatment significantly protected primary cortical neurons against Aβ25-35-induced apoptosis and promoted neurite regeneration. Transcriptome and RT-qPCR data suggested that Ucp1 and Flor1 may be potential targets through which MCT exerts its neuroprotective effects. Our findings suggest that MCT may help prevent the progression of AD by promoting neurite outgrowth and maintaining gut homeostasis in 5×FAD mice, offering a theoretical foundation for the development of dietary therapies for AD.},
}

@article {pmid40529210,
year = {2025},
author = {Untu, I and Davidson, M and Stanciu, GD and Rabinowitz, J and Dobrin, RP and Vieru, DS and Tamba, BI},
title = {Neurobiological and therapeutic landmarks of depression associated with Alzheimer's disease dementia.},
journal = {Frontiers in aging neuroscience},
volume = {17},
number = {},
pages = {1584607},
pmid = {40529210},
issn = {1663-4365},
abstract = {Depression in Alzheimer's disease (AD) dementia has become an increasingly recognized public health concern due to its high prevalence and substantial impact on patient outcomes. Despite extensive research having been conducted over the past decades, the precise causal mechanisms and the nature of the relationship between depression and AD dementia remain incompletely understood. This narrative review examines the bidirectional interaction between depression and Alzheimer's disease, emphasizing shared neurobiological pathways, including neurotransmitter dysregulation, neuroinflammation, abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis, and deficits in neuroplasticity. These mechanisms likely contribute to the acceleration of neurodegeneration in AD and the onset or worsening of depressive symptoms. Current therapeutic approaches remain largely nonspecific, with a lack of targeted therapies that address the unique pathophysiological context of depression in AD. While progress has been made, key research gaps remain, particularly in understanding the complex biological interactions between these two conditions. Future research should focus on identifying specific biomarkers and developing personalized treatment strategies tailored to the neurobiological features of both depression and AD. By addressing these neurobiological mechanisms, we can develop more effective and targeted interventions, ultimately improving patient outcomes and advancing clinical care for this dual pathology.},
}

@article {pmid40529145,
year = {2025},
author = {He, C and Shen, Y and Zhang, M and Zhou, X},
title = {Integrating genetic and immune profiles for personalized immunotherapy in Alzheimer's disease.},
journal = {Frontiers in medicine},
volume = {12},
number = {},
pages = {1603553},
pmid = {40529145},
issn = {2296-858X},
abstract = {Alzheimer's disease (AD) is the most frequent cause of dementia worldwide, and it is estimated that the number of patients will increase to 131 million by 2050. Most of the current methods of dealing with AD are designed to alleviate the symptoms, and there is no effective way of stopping the progression of the disease. Personalized immunotherapy has the potential to be highly effective and cut down on side effects because it can be targeted accurately and intervened early. Considering the genetic factors, many studies are increasingly looking at taking the immune status into account. This article further discusses the genetic and immune characteristics of AD, the methods of integrating multiple histological data, the identification of biomarkers, the stratification of patients, the precise treatment plans, and the application and future trends of immunotherapy, giving new directions for the future treatment of AD. In this mini-review, the authors address the critical role that genetic background and immune status play in shaping therapeutic strategies for AD, noting that there is a unique immune response in carriers of the APOEε4 allele compared to non-carriers, and that this difference may affect the course of the disease as well as the efficacy of immunotherapy. The aim of this review is to give an overview of the current understanding of the influence of genetic and immune factors on each other in AD, focusing on the impact of the APOEε4 allele on the immune response and its implications for immunotherapy.},
}

@article {pmid40528277,
year = {2025},
author = {Goodwin, GJ and Mehrzad, S and Cummings, JL and Renn, BN and Kinney, JW and John, SE},
title = {Comparing clinical features of behavioral variant frontotemporal dementia and Alzheimer's disease using network analysis.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {21},
number = {6},
pages = {e70361},
doi = {10.1002/alz.70361},
pmid = {40528277},
issn = {1552-5279},
support = {R35AG71476/AG/NIA NIH HHS/United States ; R25AG083721-01/AG/NIA NIH HHS/United States ; U24 AG072122/NH/NIH HHS/United States ; P30 AG062429/AG/NIA NIH HHS/United States ; P30 AG066468/AG/NIA NIH HHS/United States ; P30 AG062421/AG/NIA NIH HHS/United States ; P30 AG066509/AG/NIA NIH HHS/United States ; P30 AG066514/AG/NIA NIH HHS/United States ; P30 AG066530/AG/NIA NIH HHS/United States ; P30 AG066507/AG/NIA NIH HHS/United States ; P30 AG066444/AG/NIA NIH HHS/United States ; P30 AG066518/AG/NIA NIH HHS/United States ; P30 AG066512/AG/NIA NIH HHS/United States ; P30 AG066462/AG/NIA NIH HHS/United States ; P30 AG072979/AG/NIA NIH HHS/United States ; P30 AG072972/AG/NIA NIH HHS/United States ; P30 AG072976/AG/NIA NIH HHS/United States ; P30 AG072975/AG/NIA NIH HHS/United States ; P30 AG072978/AG/NIA NIH HHS/United States ; P30 AG072977/AG/NIA NIH HHS/United States ; P30 AG066519/AG/NIA NIH HHS/United States ; P30 AG062677/AG/NIA NIH HHS/United States ; P30 AG079280//NIA-funded Alzheimer's Disease Research Centers/ ; P30 AG062422/AG/NIA NIH HHS/United States ; P30 AG066511/AG/NIA NIH HHS/United States ; P30 AG072946/AG/NIA NIH HHS/United States ; P30 AG062715/AG/NIA NIH HHS/United States ; P30 AG072973/AG/NIA NIH HHS/United States ; P30 AG066506/AG/NIA NIH HHS/United States ; P30 AG066508/AG/NIA NIH HHS/United States ; P30 AG066515/AG/NIA NIH HHS/United States ; P30 AG072947/AG/NIA NIH HHS/United States ; P30 AG072931/AG/NIA NIH HHS/United States ; P30 AG066546/AG/NIA NIH HHS/United States ; P30 AG086401/AG/NIA NIH HHS/United States ; P30 AG086404/AG/NIA NIH HHS/United States ; P20 AG068082/AG/NIA NIH HHS/United States ; P30 AG072958/AG/NIA NIH HHS/United States ; P30 AG072959/AG/NIA NIH HHS/United States ; RO1NS139383/NS/NINDS NIH HHS/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Ted and Maria Quirk Endowment/ ; //Joy Chambers-Grundy Endowment/ ; P20GM109025/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/psychology/diagnosis/physiopathology ; *Frontotemporal Dementia/psychology/diagnosis/physiopathology ; Female ; Male ; Middle Aged ; Aged ; Neuropsychological Tests/statistics & numerical data ; },
abstract = {INTRODUCTION: Clinical characterization of behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) is challenging due to overlapping neuropsychiatric symptoms and cognitive profiles between the two conditions.

METHODS: We used clinical network analysis to characterize and compare clinical profiles in AD and bvFTD using initial visit data from the National Alzheimer's Coordinating Center.

RESULTS: The final matched sample included 890 patients per group (AD: mean age  = 63.02, standard deviation [SD] = 9.34, 36.4% female; bvFTD: mean age  = 62.87, SD = 9.46, 36.52% female). Both networks were densely connected, reflecting comorbidity between neuropsychiatric symptoms and cognitive scores. Memory performance, hallucinations, and motor disturbance were bridge symptoms in the AD network, whereas elation was the sole bridge symptom in the bvFTD network.

DISCUSSION: Distinct networks highlight unique clinical profiles in AD and bvFTD. Treatment of bridge symptoms may relieve overall symptom burden. Findings can advance clinical characterization of AD and bvFTD, leading to development of targeted interventions.

HIGHLIGHTS: We compared clinical features of Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Clinical networks showed comorbidity between neuropsychiatric symptoms and cognitive manifestations. Clinical networks significantly differed between AD and bvFTD, highlighting unique behavioral and cognitive profiles. Distinct symptoms were important for overall symptom comorbidity. Findings can be used to characterize AD and bvFTD and inform targeted treatment.},
}

Humans
*Alzheimer Disease/psychology/diagnosis/physiopathology
*Frontotemporal Dementia/psychology/diagnosis/physiopathology
Female
Male
Middle Aged
Aged
Neuropsychological Tests/statistics & numerical data

@article {pmid40527437,
year = {2025},
author = {Almazán, JL and Cortes-Flores, E and Ramírez-Olvera, A and Palomero-Rivero, M and Camacho-Concha, N and Guerra-Crespo, M and Aleph Prieto, G and Pérez-Martínez, L and Pedraza-Alva, G},
title = {TNFR2 contributes to synaptic potentiation failure in hippocampal synapses and memory loss in a familial Alzheimer's disease mouse model.},
journal = {Brain, behavior, and immunity},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.bbi.2025.06.019},
pmid = {40527437},
issn = {1090-2139},
abstract = {Alzheimer's disease (AD) is a critical health problem with a projected increase in prevalence, demanding more efforts to find an effective treatment. AD is characterized by amyloid-β (Aβ) accumulation, which drives neuroinflammation. Aβ-mediated caspase-1-dependent neuroinflammation fuels memory loss through pro-inflammatory cytokines signaling. For instance, TNF promotes synaptic plasticity dysfunction impairing long-term potentiation (LTP), an early hallmark of AD. Thus, targeting TNF receptors (TNFR1 and TNFR2) with antagonists/agonists is a promising therapeutic strategy. Here, we found that intrahippocampal administration of a TNFR2-specific blocking antibody improved recognition memory, spatial memory, and synaptic potentiation in response to chemically induced LTP (cLTP) in 5xFAD mice. Additionally, we found that TNFR2 predominates over TNFR1 on the surface of hippocampal synaptosomes from wild-type mice and that TNFR2 levels increased on the synaptosomal surface of 5xFAD mice in a caspase-1-dependent manner. Notably, caspase-1 deletion and TNFR2 blocking improved synaptic potentiation of hippocampal synaptosomes from 5xFAD mice in response to cLTP. TNF signaling via TNFR2 also reduced cell viability and impaired BDNF-mediated neurite outgrowth in SN56 cholinergic cells. Thus, our data reveal that TNFR2 contributes to neuron- and synapse-specific deleterious effects, impacting the memory of 5xFAD mice, suggesting that TNFR2-dependent signaling at the synapsis should be considered for AD treatment.},
}

@article {pmid40527057,
year = {2025},
author = {Danta, CC and Chaudhari, P and Nefzi, A},
title = {Targeting Acetylcholinesterase with Oxytocin: A New Avenue in Alzheimer's Disease Therapeutics.},
journal = {ACS chemical neuroscience},
volume = {},
number = {},
pages = {},
doi = {10.1021/acschemneuro.5c00383},
pmid = {40527057},
issn = {1948-7193},
abstract = {Oxytocin, the so-called natural love hormone, is a neuropeptide comprising nine amino acids with an active aliphatic disulfide bond forming the cyclic ring through cysteine[1]-cysteine[6] residues. Oxytocin synthesizes in hypothalamus and acts as a neurotransmitter. Oxytocin receptors are present in many areas of brain such as the hypothalamus that involve in the pathophysiology of Alzheimer's disease (AD). Since 1987, it has been postulated that oxytocin could be useful in the treatment of AD as it showed some positive outcomes when injected into the hypothalamus in experimental animals. However, in recent years, some reports suggested that oxytocin decreases the amyloid-β (Aβ) and tau deposition in AD animal experiments and exhibited antioxidant and anti-inflammatory properties, therefore, acting as a neuroprotective agent. In addition, even though evidence is limited, recently, it has also been reported that oxytocin is capable of inhibiting acetylcholinesterase (AChE) and can reverse learning and memory impairment in AD animal models but the in vitro enzyme inhibition data have not been reported yet. Therefore, as it is well documented that AChE inhibition leads to an increase of acetylcholine level and a decrease of Aβ and tau deposition in brain, discovery and development of oxytocin and its analogues as potential future drug candidates for the treatment of AD would be an attractive and promising approach.},
}

@article {pmid40526360,
year = {2025},
author = {Sharma, P and Sharma, T and Bashir, B and Andotra, N and Awasthi, A and Patel, P and Subramaniyan, V and Chellappan, DK and Gupta, G and Vishwas, S and Singh, SK},
title = {Role of Galangin for the Treatment of Alzheimer's Disease: Journey So Far and Road Ahead.},
journal = {Current nutrition reports},
volume = {14},
number = {1},
pages = {80},
pmid = {40526360},
issn = {2161-3311},
}

@article {pmid40526193,
year = {2025},
author = {Tang, T},
title = {Pyroptosis in Alzheimer's Disease: Mechanisms and Therapeutic Potential.},
journal = {Cellular and molecular neurobiology},
volume = {45},
number = {1},
pages = {57},
pmid = {40526193},
issn = {1573-6830},
mesh = {*Pyroptosis/physiology/drug effects ; Humans ; *Alzheimer Disease/pathology/metabolism/therapy/drug therapy ; Animals ; Inflammasomes/metabolism ; Signal Transduction ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid plaques, neurofibrillary tangles (NFTs), and neuroinflammation. Recent research has revealed that pyroptosis, an inflammatory programmed cell death (PCD), plays a crucial role in AD pathology. The pyroptosis signaling cascade triggered by β-amyloid (Aβ) and hyperphosphorylated tau protein leads to the release of proinflammatory cytokines, forming a "neuroinflammation-neurodegeneration" vicious cycle. Therapeutic strategies targeting the pyroptosis signaling pathway show promise, with evidence suggesting that inhibition of inflammasomes, caspase-1, or gasdermin D (GSDMD) can alleviate AD-related pathological features. However, the specificity of the existing inhibitors is insufficient, and research on non-classical pyroptosis pathway remains in its early stages. More mechanisms and therapeutic strategies targeting pyroptosis-related pathway need to be explored to enhance the therapeutic efficacy. Targeting the pyroptosis pathway provides a novel direction for AD treatment. Exploring and summarizing its mechanisms along with the clinical translational applications of targeted inhibitors will offer fresh perspectives for moving beyond traditional "symptom control" therapies and achieving "pathology-modifying" interventions, holding significant scientific and clinical importance.},
}

*Pyroptosis/physiology/drug effects
Humans
*Alzheimer Disease/pathology/metabolism/therapy/drug therapy
Animals
Inflammasomes/metabolism
Signal Transduction
Amyloid beta-Peptides/metabolism

@article {pmid40526097,
year = {2025},
author = {Ingle, RG and M Elossaily, G and Ansari, MN and Makhijani, S},
title = {Unlocking the potential: advancements and applications of gene therapy in severe disorders.},
journal = {Annals of medicine},
volume = {57},
number = {1},
pages = {2516697},
doi = {10.1080/07853890.2025.2516697},
pmid = {40526097},
issn = {1365-2060},
mesh = {Humans ; *Genetic Therapy/methods/trends ; Genetic Vectors ; Gene Editing/methods ; *Genetic Diseases, Inborn/therapy/genetics ; Neoplasms/therapy/genetics ; },
abstract = {INTRODUCTION: Several severe disorders, such as inherited diseases (e.g. cystic fibrosis and beta thalassemia), genetic diseases (e.g. malignant tumors and diabetes), and infectious diseases (e.g. HIV) are pose significant challenges to human health.

BACKGROUND: Over the past few decades, researchers have been working on gene therapies, and currently, terrible dreams have come true. To date, the Food and Drug Administration (FDA) has approved multiple gene therapies such as Kynamro for familial hypercholesterolaemia, Exondys51 for duchenne muscular dystrophy, Spinraza for spinal muscular atrophy, etc., rest for cancer, infectious diseases, and rare diseases.

DISCUSSION: The authors have summarized recent advances in gene therapy, its background, molecular basis (e.g. viral and non-viral vectors), gene-editing techniques (e.g. CRISPR/Cas9, TALEN, ZFN), and its foremost applications in severe disorders, such as cancer, monogenic disorders (e.g. spinal muscular atrophy), polygenic disorders (e.g. autism), neurogenic disorders (e.g. Parkinson disease and Alzheimer's disease), and infectious diseases (e.g. HIV).

CHALLENGES: In addition, we explored the major challenges faced by gene therapies during targeted delivery, immunogenicity, efficacy, and safety.

CONCLUSION: To date, most of the promising approaches, such as different vectors, target cell populations, and both in vivo and ex vivo have paved the foundation for applications of gene therapies. Additionally, advances in enhancing the immune system that would certainly lower the healthcare costs. This review highlights the translatory potential of gene therapy in revolutionizing the treatment landscape for severe disorders.},
}

Humans
*Genetic Therapy/methods/trends
Genetic Vectors
Gene Editing/methods
*Genetic Diseases, Inborn/therapy/genetics
Neoplasms/therapy/genetics

@article {pmid40525437,
year = {2025},
author = {Kumar, R and Tyagi, N},
title = {Pharmacological Characterization of Ruellia tuberosa Ethanolic Extract in a Rodent Model of Cognitive Impairment.},
journal = {Recent advances in inflammation & allergy drug discovery},
volume = {},
number = {},
pages = {},
doi = {10.2174/0127722708364435250604032539},
pmid = {40525437},
issn = {2772-2716},
abstract = {INTRODUCTION: Cognitive impairment linked to neurodegenerative diseases poses a considerable challenge, requiring the exploration of plant-derived therapeutic alternatives. Ruellia tuberosa, a medicinal plant recognized for its anti-oxidant and anti-inflammatory properties, was examined for its therapeutic potential in a rodent model of memory impairment.

METHOD: The present study aimed to evaluate the effects of Ruellia tuberosa ethanolic extract (RTEE) on aluminium chloride (AlCl3)-induced Alzheimer's disease (AD) in adult Wistar rats. In-vitro cell line study showed decreased formation of reactive oxygen species (ROS), decreased levels of IL-6 (Interleukin-6), and suppressed NF-κB (Nuclear factor kappa-B) translocation, which further confirmed RTEE's antioxidant and anti-inflammatory characteristics. Following the objective, thirty adult Wistar rats were taken and divided into five groups (n=6). They were treated with Normal saline, AlCl3 (100 mg/kg), DPZ (Donepezil- 3 mg/kg), and RTEE (100 and 200 mg/kg), respectively, for 35 days.

RESULTS: Various behavioral and biochemical parameters, along with the oxidative and inflammatory biomarkers, were assessed to determine the effects of RTEE. The plant extract at both the doses (100 and 200 mg/kg) demonstrated increased body weight, improved motor coordination as demonstrated by an increase in fall-off time on the Rota rod apparatus, decreased escape latency in the Morris water maze test, reduced transfer latency (TL) in the elevated plus maze test, increased time spent in the target quadrant, and increased exploration time in the novel object recognition test. Furthermore, RTEE treatment exhibited decreased levels of malondialdehyde (MDA) and acetylcholinesterase (AChE) activity and increased levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and total protein. Additionally, RTEE reduced levels of inflammatory cytokines, such as TNF-α and IL-1β, which decreased neuroinflammation and amyloid-beta levels. Additionally, the extract exhibited cholinergic system modulation, as observed by improved acetylcholinesterase activity, suggesting its potential role in neurotransmitter regulation. Histopathological study further confirmed its neuroprotective potential by reducing neuronal degeneration in brain regions (hippocampus and cortex).

CONCLUSION: According to the study's findings, memory impairment in the AlCl3-induced rat model of AD was ameliorated by both doses of RTEE. However, further studies need to be conducted to establish its therapeutic effects in neurodegenerative diseases.},
}