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Bibliography on: Alzheimer Disease — Treatment

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 03 Apr 2025 at 01:37 Created: 

Alzheimer Disease — Treatment

Alzheimer's disease is an irreversible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. In most people with Alzheimer's, symptoms first appear in their mid-60s. Alzheimer's is the most common cause of dementia among older adults. Dementia is the loss of cognitive functioning — thinking, remembering, and reasoning — and behavioral abilities to such an extent that it interferes with a person's daily life and activities. Dementia ranges in severity from the mildest stage, when it is just beginning to affect a person's functioning, to the most severe stage, when the person must depend completely on others for basic activities of daily living. Scientists don't yet fully understand what causes Alzheimer's disease in most people. There is a genetic component to some cases of early-onset Alzheimer's disease. Late-onset Alzheimer's arises from a complex series of brain changes that occur over decades. The causes probably include a combination of genetic, environmental, and lifestyle factors. The importance of any one of these factors in increasing or decreasing the risk of developing Alzheimer's may differ from person to person. Because of this lack of understanding of the root cause for Alzheimer's Disease, no direct treatment for the condition is yet available. However, this bibliography specifically searches for the idea of treatment in conjunction with Alzheimer's to make it easier to track literature that explores the possibility of treatment.

Created with PubMed® Query: ( alzheimer*[TIAB] AND treatment[TIAB] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2025-04-02
CmpDate: 2025-04-02

Wang A, Since M, Dallemagne P, et al (2025)

Implication of Central β2 Adrenergic Receptor for the Development of Novel Drugs Against Alzheimer's Disease.

Archiv der Pharmazie, 358(4):e2400750.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive onset of symptoms, including memory loss, accompanied by other neurological impairments. This progression is attributed to the deterioration of neuronal connections and a decrease in neurotransmission. Although this phenomenon has been extensively studied in the cholinergic system, it also affects other neurobiological pathways, particularly adrenergic transmission. In this context, the use of agonists, in particular, β2-adrenergic receptor (β2AR) agonists, may represent a promising therapeutic approach. After reviewing the main pharmacological aspects related to these receptors, we will first present the different existing modulators and their peripheral effects. We will then analyze the results of studies investigating their use in disease models. Finally, we will discuss the conditions and prospects for the development of a new treatment for Alzheimer's disease using a β2AR agonist.

RevDate: 2025-04-02

Wang Y, Wu Z, Zheng Y, et al (2025)

Unraveling the genetic underpinnings of mitochondrial traits and associated circulating inflammatory proteins in Alzheimer's disease: Mitochondrial HtrA2-T cell CD5 negative axis.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundPrevious studies with limited sample sizes have indicated a link between mitochondrial traits, inflammatory proteins, and Alzheimer's disease. The exact causality and their mediation relationships remain unclear.ObjectiveOur study aimed to delve into the genetic underpinnings of mitochondrial function and circulating inflammatory proteins in the pathogenesis of Alzheimer's disease.MethodsWe leveraged aggregated data from the largest genome-wide association study, including 69 mitochondrial traits, 91 circulating inflammatory proteins, and Alzheimer's disease. Bidirectional mendelian randomization (MR) analyses were performed to investigate their primary causal relationships. Thereafter a two-step MR mediation analysis was utilized to clarify the modulating effects of inflammatory proteins on mitochondria and Alzheimer's disease.ResultsOur study identified mitochondrial phenylalanine-tRNA ligase and 4-hydroxy-2-oxoglutarate aldolase as risk factors for Alzheimer's disease, and serine protease HtrA2 and carbonic anhydrase 5A as protective factors against Alzheimer's disease. Four inflammatory proteins (T-cell surface glycoprotein CD5, C-X-C motif chemokine 11, TGF-α, and TNF-related apoptosis-inducing ligand) played protective roles against Alzheimer's disease. Axin-1 and IL-6 increased the risk of Alzheimer's disease. Furthermore, T-cell surface glycoprotein CD5 was found to be a significant mediator between mitochondrial serine protease HTRA2 and Alzheimer's disease with the two-step MR method, accounting for 10.83% of the total effect.ConclusionsOur study emphasized mitochondrial HtrA2-T cell CD5 as a negative axis in Alzheimer's disease, offering novel perspectives on its etiology, pathogenesis, and treatment.

RevDate: 2025-04-01

Lapid MI, Pagali SR, Basso MR, et al (2025)

A pilot randomized controlled double-blind trial of intermittent theta burst stimulation (iTBS) repetitive transcranial magnetic stimulation (rTMS) to improve memory in mild cognitive impairment (MCI): a study protocol.

Pilot and feasibility studies, 11(1):35.

BACKGROUND: Mild cognitive impairment (MCI), prevalent among older adults, often precedes Alzheimer's disease (AD) or Alzheimer's disease-related dementias (ADRD), emphasizing the need for effective interventions. Early intervention in MCI is crucial, not only to alleviate symptoms but to potentially delay the progression of cognitive decline. The lack of definitive treatments for MCI has prompted the exploration into alternative non-pharmacological therapeutic approaches. Specifically, noninvasive brain stimulation using repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in improving cognition in MCI and AD.

OBJECTIVES: Our study will test the feasibility of using intermittent theta burst stimulation (iTBS) technique of rTMS in MCI, pilot test the study design, and collect pilot data on the effect of iTBS over three different brain regions on working memory, new learning, and executive function in MCI. Exploratory objectives are to assess the feasibility and usefulness of functional magnetic resonance imaging (fMRI), high-density electroencephalography (HD-EEG), and sleep architecture as potential biomarkers in response to iTBS.

METHODS: A pilot randomized double-blind controlled cross-over trial of iTBS on 20 MCI participants randomized to 10 days of active iTBS (left dorsolateral prefrontal cortex or left lateral parietal cortex) or control (vertex). After 4-6-week washout period, they cross over to the alternative treatment arm for another 10 days. Each participant will undergo a total of 20 iTBS sessions. Pre- and post-iTBS assessments include neuropsychological tests, fMRI, HD-EEG, and sleep architecture.

DISCUSSION: This innovative study aims to test the feasibility of iTBS as a cognitive enhancement strategy in MCI. If our study is feasible, it could lead to a future larger trial to further test whether iTBS can modulate underlying neurobiology and offer a therapeutic avenue to remediate cognitive decline in MCI or ultimately delay progression to dementia.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT05327257. Registered 04 April 2022.

RevDate: 2025-04-01

Lee M, Lee KJ, Kim J, et al (2025)

Low-density lipoprotein cholesterol levels and risk of incident dementia: a distributed network analysis using common data models.

Journal of neurology, neurosurgery, and psychiatry pii:jnnp-2024-334708 [Epub ahead of print].

BACKGROUND: The link between low-density lipoprotein cholesterol (LDL-C) levels and dementia risk is poorly understood, with conflicting evidence on the role of LDL-C and the impact of statin therapy on cognitive outcomes. Thus, we aimed to examine the association between low-density LDL-C levels and the risk of dementia and assess the influence of statin therapy.

METHODS: We retrospectively analysed data from 11 university hospitals participating in the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Participants with a prior diagnosis of dementia or those with <180 days of observation before cohort inclusion, and those included in both cohorts were excluded. The primary outcome was all-cause dementia, with the secondary outcome being Alzheimer's disease-related dementia (ADRD). The study utilised 1:1 propensity score matching to compare individuals with LDL-C levels below 70 mg/dL (1.8 mmol/L) against those with levels above 130 mg/dL (3.4 mmol/L), resulting in a primary analysis cohort of 108 980 matched patients. Secondary analyses further examined LDL-C thresholds below 55 mg/dL (1.4 mmol/L) and the influence of statin use.

RESULTS: The LDL-C levels below 70 mg/dL (1.8 mmol/L) were associated with a 26% reduction in the risk of all-cause dementia and a 28% reduction in the risk of ADRD, compared with levels above 130 mg/dL (3.4 mmol/L). For LDL-C levels below 55 mg/dL (1.4 mmol/L), there was an 18% risk reduction for both outcomes. Among those with LDL-C <70 mg/dL (<1.8 mmol/L), statin use was associated with a 13% reduction in all-cause dementia risk and a 12% decrease in ADRD risk compared with non-users.

CONCLUSION: Low LDL-C levels (<70 mg/dL (<1.8 mmol/L)) are significantly associated with a reduced risk of dementia, including ADRD, with statin therapy providing additional protective effects. These findings support the necessity of targeted lipid management as a preventive strategy against dementia, indicating the importance of personalised treatment approaches.

RevDate: 2025-04-01

Wattanalaorsomboon S, Mansalai P, Payaka A, et al (2025)

The inhibition effect of oleamide for acetylcholinesterase and α-glucosidase from edible wild mushroom by in vitro, in silico and fluorescence analysis.

International journal of biological macromolecules pii:S0141-8130(25)03233-7 [Epub ahead of print].

Lipid compounds from edible wild mushrooms have been reported for their biological activities related to Alzheimer's disease (AD) and diabetes mellitus (DM) treatment. This research investigated purified oleamide (PEWM) from edible wide mushroom and determined its antioxidant activity and inhibition potential against acetylcholinesterase (AChE) and α-glucosidase. The PEWM was purified by preparative thin-layer chromatography (PTLC) with methanol: chloroform: water (6:6:1 v/v). The antioxidant activity against ABTS[·+] and DPPH· radical of crude extracts (CEWM) had higher potent than PEWM. On the other hand, the inhibition potential of PEWM against AChE and α-glucosidase had higher potency than CEWM. Moreover, the inhibition potency of PEWM and oleamide against AChE was higher than α-glucosidase. The inhibition mode of CEWM, PEWM and oleamide exhibited mixed-type inhibition on AChE and α-glucosidase. Inhibition constant (Ki) also supported that CEWM, PEWM and oleamide have the highest potent on AChE. CEWM, PEWM and oleamide showed fluorescence quenching by increasing the inhibitors' concentration against AChE and α-glucosidase. Docking analysis revealed that oleamide was located in peripheral anionic sites of AChE. The results suggest that edible wild mushrooms as the source of lipids related to AChE and α-glucosidase inhibitory activity might be applied for AD and DM management.

RevDate: 2025-04-01

Ambamba BDA, Paka GD, Takuissu GRN, et al (2025)

Glycosyl terpenoid-rich fraction of TeMac™ attenuates oxidative stress, inhibits cholinesterases enzyme activities, and protects brain against scopolamine-induced histopathological alterations in rats.

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 186:118010 pii:S0753-3322(25)00204-5 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is the most commonly diagnosed form of senile dementia, with limited therapeutic options. Neuronal damage is caused by factors secreted by inflammatory cells but also, the lack of antioxidants to prevent oxidative stress and help maintain neuronal integrity, which is crucial for cognition and memory are mediators of AD. Terminalia macroptera barks contain glycosyl terpenoids, known for their strong antioxidant properties. This study investigated the antioxidant and neuroprotective effects of the glycosylic terpenoid-rich fraction of Terminalia macroptera (GT-TeMac™) in scopolamine-treated rats.

METHODS: Glycosylic terpenoids were identified by LC-MS and antiradical activity tests (DPPH and ORAC) were performed. Cholinergic cognitive dysfunction and oxidative stress were induced in male wistar rats, by intraperitoneal injection of scopolamine (1 mg/kg BW/day) for seven consecutive days. GT-TeMac™ at 100 mg/kg and Donepezil at 5 mg/kg body weight were administered orally 60 min after scopolamine. After treatment, rat were sacrificed and brains were collected for the evaluation of cholinergic enzyme activity, oxidative stress markers and histopathological analysis. In vitro study was carried out to assess the ability of GT-TeMac™ to scavenge free radicals and suppress H2O2-induced ROS production in SK-N-SH cells. In addition, the ability of GT-TeMac™ to restore cell viability reduced by acrolein was performed.

RESULTS: Chebuloside II, Sericoside, 24-deoxysericoside, arjunglucoside 1 and 23-galloylarjunolic acid 28-O-glucopyranosylester were identified by LC-MS. GT-TeMac™ has a SC50 of 9.54 μg/mL and an ORAC value of 1130 µM Trolox equivalent per mg of GT-TeMac™. The administration of GT-TeMac™ protected against cognitive decline in AD by inhibiting cholinesterase metabolism, modulating oxidative stress parameters and protecting hippocampal areas. Additionally, GT-TeMac™ absorbed and eliminated ROS produced by hydrogen peroxide in SKNSH cells and restored cell viability reduced by acrolein.

CONCLUSION: These findings suggest that the active ingredients in GT-TeMac™ are promising drug candidates for the treatment of cognitive disorders associated with oxidative stress in AD.

RevDate: 2025-04-01
CmpDate: 2025-04-01

Yang W, Wei Z, T Wang (2025)

Unraveling the Role of LRP1 in Alzheimer's Disease: A Focus on Aβ Clearance and the Liver-Brain Axis.

Journal of molecular neuroscience : MN, 75(2):43.

Alzheimer's disease (AD) is the most prevalent form of dementia, significantly contributing to the global health burden. The progressive accumulation of amyloid-beta (Aβ) plaques and tau tangles triggers neuroinflammation, oxidative stress, and neuronal damage, highlighting the critical need for effective clearance mechanisms. Recent research has identified low-density lipoprotein receptor-related protein 1 (LRP1) as a key factor in the regulation of Aβ clearance, neuroinflammation, and blood-brain barrier integrity, particularly in relation to the liver-brain axis. This review provides a comprehensive examination of the role of LRP1 in AD, focusing on its expression in the brain and liver, its contribution to Aβ metabolism, and its potential as a therapeutic target. Using a systematic literature review, LRP1's multifaceted roles across various biological processes were explored, including its involvement in Aβ transport, clearance via the liver, and modulation of neuroinflammation. Additionally, the impact of physical exercise, pharmacological interventions, and dietary factors on LRP1 expression levels was investigated, elucidating how these approaches may enhance Aβ clearance. The findings demonstrate that LRP1 expression decreases progressively as AD advances, and that augmenting LRP1 activity-particularly through exercise and drug therapies-can improve Aβ clearance and reduce neuroinflammatory responses. Furthermore, LRP1's involvement in the liver-brain axis reveals its broader systemic role in AD pathology. In conclusion, targeting LRP1 offers a promising avenue for AD prevention and treatment, providing new insights into the therapeutic potential of enhancing Aβ clearance pathways through the liver-brain axis.

RevDate: 2025-04-01
CmpDate: 2025-04-01

Sharma V, Sharma P, TG Singh (2025)

Ferroptosis and Alzheimer's: unveiling new avenues for the treatment and prevention.

Metabolic brain disease, 40(4):167.

Alzheimer's disease (AD), one of the most prevalent neurodegenerative illnesses worldwide, has a devastating effect on individual, families and society. Despite the extensive research and effort, various clinical trials aimed against amyloid-β, which is suspected to have a causative role in the illness, have not yet shown any clinically significant success to date. Emerging evidence suggests that ferroptosis, a kind of programmed cell death triggered by lipid peroxidation and dependent on iron, plays a role in AD. There is a complex relationship between AD and ferroptosis. In both the processes iron dysregulation, altered anti-oxidant mechanisms and lipid peroxidation is involved. Ferroptotic processes contributes to the neuro-inflammation, oxidative stress and damage to the neurons as observed in AD. Additionally, amyloid-β, a hallmark of AD, may influence the ferroptosis, further linked the two pathways. Numerous signalling pathways such as Phospho inositide 3-kinase, Glycogen synthase kinase-3β, 5'-AMP-activated protein kinase, nuclear factor erythroid 2-related factor-2 and Sirtuin pathway plays a part in the pathophysiology of AD. Through a comprehensive review of current research and experimentation, this investigation elucidates the interactions between novel pharmacological agents (ferroptotic inhibitors) and AD-related pathways. Furthermore, this review highlights the various ferroptotic inhibitors as the therapeutic agents for the slowing down the progression of AD. The crosstalk between these processes could unveil the potential therapeutic targets for the AD treatment.

RevDate: 2025-04-01
CmpDate: 2025-04-01

Abbas K, Mustafa M, Alam M, et al (2025)

Multi-target approach to Alzheimer's disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid- modulating mechanisms.

Neurogenetics, 26(1):39.

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline, posing a significant global health challenge. Growing evidence suggests that dietary polyphenols may reduce the risk and progression of AD through multifaceted neuroprotective mechanisms. Polyphenols regulate amyloid proteostasis by inhibiting β/γ-secretase activity, preventing Aβ aggregation, and enhancing clearance pathways. Their strong antioxidant properties neutralize reactive oxygen species, chelate redox-active metals, and activate cytoprotective enzymes via Nrf2 signaling. This review examines the potential therapeutic targets, signaling pathways, and molecular mechanisms by which dietary polyphenols exert neuroprotective effects in AD, focusing on their roles in modulating amyloid proteostasis, oxidative stress, neuroinflammation, and cerebrovascular health. Polyphenols mitigate neuroinflammation by suppressing NF-κB signaling and upregulating brain-derived neurotrophic factor, supporting neuroplasticity and neurogenesis. They also enhance cerebrovascular health by improving cerebral blood flow, maintaining blood-brain barrier integrity, and modulating angiogenesis. This review examines the molecular and cellular pathways through which polyphenols exert neuroprotective effects, focusing on their antioxidant, anti-inflammatory, and amyloid-modulating roles. We also discuss their influence on key AD pathologies, including Aβ deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Insights from clinical and preclinical studies highlight the potential of polyphenols in preventing or slowing AD progression. Future research should explore personalized dietary strategies that integrate genetic and lifestyle factors to optimize the neuroprotective effects of polyphenols.

RevDate: 2025-04-01

Tewolde S, Rosenberg SB, Estrada JAG, et al (2025)

Epidemiology of Alzheimer Disease and Related Dementia Among Medicare and Medicaid Enrolled Autistic Adults, 2011-2019.

Autism research : official journal of the International Society for Autism Research [Epub ahead of print].

Alzheimer's disease and related dementias (ADRD) are burdensome and lethal conditions that have been hypothesized to be related to autism through shared genetic etiologies and environmental risk factors. Our objective was to use longitudinal Medicaid and Medicare data to describe the epidemiology of ADRD in publicly insured autistic adults. We used all claims and encounters from 2011 to 2019 to identify autism and ADRD. We calculated prevalence, incidence, age at onset, and created survival curves. There were 90,229 autistic adults ≥ 30 years of age and enrolled for at least 1 year in Medicaid and/or Medicare and 267 ADRD cases. Prevalence of ADRD was 2.09% (95% CI: 1.99%, 2.20%) in 2011 and 8.11% (95% CI: 7.92%, 8.30%) in 2019. Mean age at ADRD onset was 59.3 years (SD: 14.2). Mean age among men was 58.3 years (SD: 13.8) and 61.0 years among females. Incidence of ADRD was higher in autistic adults with intellectual disability with no difference by sex. ADRD is a prevalent condition in middle- and older-aged adults identified with autism in the Medicaid and Medicare system. Understanding the diagnostic process and phenotype of ADRD will be important to improve identification and treatment.

RevDate: 2025-04-01
CmpDate: 2025-04-01

Guo L, Wang D, Lai X, et al (2025)

Relationship Between Peripheral Serum Adiponectin and Cerebrospinal Fluid TNF-α, IL-1β, Lactic Acid, Pyruvic Acid and Perioperative Neurocognitive Dysfunction in Elderly Patients Undergoing Hip Arthroplasty.

Clinical interventions in aging, 20:381-393.

BACKGROUND: Postoperative neurocognitive dysfunction (PND) represents a form of cognitive impairment related to surgery and anesthesia, which may manifest hours or even weeks after the surgical procedure, persist, and potentially progress into Alzheimer's disease. The etiology of PND is intricate, with central nervous inflammation playing a crucial role. The clinical manifestations of PND are not distinctive, no obvious image alterations are observable, and the diagnosis rate is relatively low, thereby influencing prognosis and augmenting postoperative complications and mortality. The optimal treatment approach for PND lies in timely identification and management of the high-risk factors causing PND and implementing early prevention. We hypothesize that the level of peripheral blood adiponectin (APN) is correlated with PND, potentially through inhibiting the central inflammatory response and regulating brain energy metabolism.

METHODS: Fifty elderly patients undergoing elective hip arthroplasty under continuous epidural spinal anesthesia (CESA) were included. Cognitive function was assessed using the Mini-Mental State Examination (MMSE) preoperatively and postoperatively at 1, 2, 3, and 7 days. Serum APN and CSF levels of TNF-α, IL-1β, lactic acid, and pyruvic acid were measured. The occurrence of PND was recorded, and the patients were divided into a PND group and a non-PND group.

RESULTS: PND occurred in 16 patients (34.04%). The PND group had lower serum APN levels and higher cerebrospinal fluid (CSF) concentrations of TNF-α, IL-1β, and lactic acid compared to the non-PND group. CSF TNF-α and IL-1β levels were negatively correlated with serum APN concentration. These biomarkers are associated with PND occurrence and have high diagnostic value.

CONCLUSION: Decreases in serum APN and increases in TNF-α, IL-1β, and lactic acid in CSF may be involved in the pathophysiological process of PND in elderly patients after surgery.

RevDate: 2025-04-01

Xiong J, Chen X, Huang K, et al (2025)

Successful Guselkumab Treatment in a Patient with Comorbid Psoriasis and Amyotrophic Lateral Sclerosis: A Case Study and Literature Review.

Clinical, cosmetic and investigational dermatology, 18:735-741.

Psoriasis is genetically influenced and can be triggered by factors such as infections, stress, and lifestyle. Chronic plaque psoriasis, the most prevalent form, involves key roles for IL-17 and IL-23 in its pathogenesis. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons, resulting in muscle weakness and atrophy. Currently, there is no cure for ALS, and treatment is symptomatic, aimed at improving quality of life. The combination of psoriasis and ALS is relatively rare. Although biologic agents have shown remarkable efficacy in the treatment of chronic plaque psoriasis, we have not found any case reports regarding the use of biologic agents for treating psoriasis accompanied by ALS. Our study presents a patient with severe plaque psoriasis and ALS who exhibited a positive response to Guselkumab, without worsening of ALS symptoms, suggesting a promising therapeutic strategy. This could provide a treatment option for patients with psoriasis combined with ALS.We conducted a comprehensive review of the literature on the comorbidity of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and ALS, with plaque psoriasis. This review highlights the differential impact of treatment modalities. Specifically, we found that TNF-α inhibitors may have adverse effects in MS but could provide protective benefits in AD and PD. In ALS patients with psoriasis, IL-17A and IL-23 inhibitors, exemplified by Guselkumab, are suggested as a more suitable alternative due to their lower risk of worsening ALS symptoms.

RevDate: 2025-04-01

Chen Y, Touboul R, Chen Y, et al (2025)

Strategic delivery of omega-3 fatty acids for modulating inflammatory neurodegenerative diseases.

Frontiers in aging neuroscience, 17:1535094.

OBJECTIVES: Early-life inflammatory events like infections and injuries may predispose the brain to Alzheimer's disease (AD) by disrupting neurodevelopment and raising vulnerability. The association between early neuroinflammation and subsequent neurodegeneration leading to dementia remains unclear. We hypothesize that omega-3 (n-3) fatty acids (FA), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), positively regulate neuro-immune cells, preserving their cell membrane structure and metabolic homeostasis. Our study examined whether strategic delivery of n-3 FA via injectable n-3 triglycerides (TG) can influence microglial lipid metabolism to prevent or delay AD progression.

METHODS AND RESULTS: We characterized n-3 treatment effects on modulating lipid and metabolic homeostasis in microglia during the critical window of brain development. Our preliminary studies on determining the effects of early n-3 treatment on brain cell homeostasis indicate that perinatal bolus n-3 TG injections suppressed activation of gliosis-associated markers in young mice predisposed to AD (5xFAD) and yielded sustained regulatory effects on the expression of inflammatory molecules, such as interleukin-6 (Il6) and tumor necrosis factor-alpha (Tnfα), in adult brains. A significant increase in high-frequency ultrasonic vocalizations (USV) was observed in P6 5xFAD mice that received perinatal n-3 compared to vehicle control, implicating enhanced active communication patterns. Improvement in behavior deficits was observed in n-3-treated adult AD mice. Perinatal n-3 TG treatment modified brain lipid composition in young offspring, increasing key membrane lipid species, such as phospholipids (PL) and lysophospholipids (lysoPL). Pro-inflammatory sphingolipids associated with neurodegeneration, including lactosylceramide, were significantly lower in mice treated with n-3 than those in saline-treated AD mice.

CONCLUSION: Our study establishes a proof of principle for targeting brain immune cell metabolism with injectable n-3 TG to mitigate neuroinflammation in AD pathogenesis, paving the way for future research into early treatments for related central nervous system (CNS) disorders.

RevDate: 2025-04-01

Zammit MD, Price JC, Christian BT, et al (2025)

A head-to-head comparison of multiple amyloid PET radiotracers for Down syndrome clinical trials.

medRxiv : the preprint server for health sciences pii:2025.03.18.25324200.

Adults with Down syndrome carry high risk of developing Alzheimer's disease and efforts to include this population in clinical trials remain limited. A barrier to recruitment for anti-amyloid trials includes the availability of the same amyloid PET radiotracer to multiple treatment centers. 237 adults with Down syndrome from the Trial-Ready Cohort - Down syndrome and Alzheimer Biomarker Consortium - Down syndrome studies were imaged using T1-w MRI and using PET images of PiB, Florbetapir (FBP), NAV4694 (NAV) or Flutemetamol (FMM) to screen for amyloid plaque (Aβ) burden. PiB displayed the largest effect size to measure amyloid change while FBP had a small effect size. NAV and PiB, which are structurally similar compounds, displayed similar sensitivity to measure longitudinal amyloid increase. The estimated age at amyloid onset showed no significant difference between PiB, FBP, NAV or FMM. The findings suggest that different amyloid PET radiotracers provide consistent estimates of amyloid onset age for adults with Down syndrome. Multicenter studies of Alzheimer's disease therapeutics can utilize multiple amyloid PET radiotracers to facilitate recruitment, however, PiB and NAV displayed the greatest sensitivity to detect longitudinal change.

RevDate: 2025-04-01

Ma L, Wang J, Zhou R, et al (2025)

Traditional Chinese Medicine-derived formulations and extracts modulating the PI3K/AKT pathway in Alzheimer's disease.

Frontiers in pharmacology, 16:1528919.

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by memory decline, cognitive impairment, and behavioral abnormalities. Pathologically, AD is marked by neurofibrillary tangles caused by excessive phosphorylation of Tau protein and abnormal deposition of β-amyloid (Aβ) in the brain. The PI3K/AKT signaling pathway plays a crucial role in the development, survival, and metabolic regulation of the central nervous system, particularly in neuronal growth, differentiation, and apoptosis. However, this pathway is often inhibited in AD patients.In recent years, studies have shown that herbal formulations and extracts derived from Traditional Chinese Medicine (TCM) can regulate the PI3K/AKT signaling pathway, thereby improving AD pathological models. This study reviews fundamental research on both active metabolites and compound formulations from TCM for the treatment of AD, targeting the PI3K/AKT signaling pathway.Keywords include "Alzheimer's disease" "AD" "dementia" "PI3K" "AKT" "Traditional Chinese Medicine" "Chinese herbology" "Chinese medicine" and "TCM".The study is based on relevant literature published over the past 15 years, primarily sourced from electronic databases such as Web of Science, PubMed, CNKI, Wanfang, and VIP databases.The findings indicate that herbal formulations and extracts derived from TCM can mitigate AD pathology by regulating the PI3K/AKT signaling pathway, reducing Tau protein phosphorylation and Aβ deposition, inhibiting inflammatory responses and oxidative stress, and alleviating neuronal apoptosis. This study enhances our understanding of the anti-AD mechanisms of TCM through the PI3K/AKT pathway and offers new insights for the future.

RevDate: 2025-04-01

Laroche VT, Cavill R, Kouhsar M, et al (2025)

Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures.

bioRxiv : the preprint server for biology pii:2025.03.15.643144.

Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimer's disease contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances in molecular subtyping through proteomic and transcriptomic profiling reveal distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles. This insight underscores the need to expand molecular subtyping across new molecular layers, to identify novel drug targets for different patient subgroups. In this study, we analyzed genome-wide DNA methylation data from three independent postmortem brain cohorts (n = 831) to identify epigenetic subtypes of late-onset Alzheimer's disease. Unsupervised clustering approaches were employed to identify distinct DNA methylation patterns, with subsequent cross-cohort validation to ensure robustness and reproducibility. To explore the cell-type specificity of the identified epigenomic subtypes, we characterized their methylation signatures utilizing DNA methylation profiles derived from purified brain cells. Transcriptomic data from bulk and single-cell RNA sequencing were integrated to examine the functional impact of epigenetic subtypes on gene expression profiles. Finally, we performed statistical analyses to investigate associations between these DNA methylation-defined subtypes and clinical or neuropathological features, aiming to elucidate their biological significance and clinical implications. We identified two distinct epigenomic subtypes of late-onset Alzheimer's disease, each defined by reproducible DNA methylation patterns across three cohorts. Both subtypes exhibit cell-type-specific DNA methylation profiles. Subtype 1 and subtype 2 show significant microglial methylation enrichment, with odds ratios (OR) of 1.6 and 1.3, respectively. The minimal overlap between them suggests distinct microglial states. Additionally, subtype 2 displays strong neuronal (OR = 1.6) and oligodendrocyte (OR = 3.6) enrichment. Bulk transcriptomic analyses further highlighted divergent biological mechanisms underpinning these subtypes, with subtype 1 enriched for immune-related processes, and subtype 2 characterized predominantly by neuronal and synaptic functional pathways. Single-cell transcriptional profiling of microglia revealed subtype-specific inflammatory states: subtype 1 represented a state of chronic innate immune hyperactivation with impaired resolution, while subtype 2 exhibited a more dynamic inflammatory profile balancing pro-inflammatory signaling with reparative and regulatory mechanisms. This study highlights the molecular heterogeneity of late-onset Alzheimer's disease by identifying two epigenetic subtypes with distinct cell-type-specific DNA methylation patterns. Their alignment with previously defined molecular classifications underscores their relevance in disease pathogenesis. By linking these subtypes to inflammatory microglial activity, our findings provide a foundation for future precision medicine approaches in Alzheimer's research and treatment.

RevDate: 2025-04-01

Cruchaga C, Heo G, Thomas A, et al (2025)

Large-scale Plasma Proteomic Profiling Unveils Novel Diagnostic Biomarkers and Pathways for Alzheimer's Disease.

Research square pii:rs.3.rs-5167552.

Alzheimer disease (AD) is a complex neurodegenerative disorder. Proteomic studies have been instrumental in identifying AD-related proteins present in the brain, cerebrospinal fluid, and plasma. This study comprehensively examined 6,905 plasma proteins in more than 3,300 well-characterized individuals to identify new proteins, pathways, and predictive model for AD. With three-stage analysis (discovery, replication, and meta-analysis) we identified 416 proteins (294 novel) associated with clinical AD status and the findings were further validated in two external datasets including more than 7,000 samples and seven previous studies. Pathway analysis revealed that these proteins were involved in endothelial and blood hemostatic (ACHE, SMOC1, SMOC2, VEGFA, VEGFB, SPARC), capturing blood brain barrier (BBB) disruption due to disease. Other pathways were capturing known processes implicated in AD, such as lipid dysregulation (APOE, BIN1, CLU, SMPD1, PLA2G12A, CTSF) or immune response (C5, CFB, DEFA5, FBXL4), which includes proteins known to be part of the causal pathway indicating that some of the identified proteins and pathways are involved in disease pathogenesis. An enrichment of brain and neural pathways (axonal guidance signaling or myelination signaling) indicates that, in fact, blood proteomics capture brain- and disease-related changes, which can lead to the identification of novel biomarkers and predictive models. Machine learning model was employed to identify a set of seven proteins that were highly predictive of both clinical AD (AUC > 0.72) and biomarker-defined AD status (AUC > 0.88), that were replicated in multiple external cohorts as well as with orthogonal platforms. These extensive findings underscore the potential of using plasma proteins as biomarkers for early detection and monitoring of AD, as well as potentially guiding treatment decisions.

RevDate: 2025-04-01

Lin AL, Aware C, Neher C, et al (2025)

Rapamycin enhances neurovascular, peripheral metabolic, and immune function in cognitively normal, middle-aged APOE4 Carriers: genotype-dependent effects compared to non-carriers.

Research square pii:rs.3.rs-6214340.

Rapamycin, known for its anti-aging properties, shows promise as a preventive strategy for Alzheimer's disease (AD) in APOE4 carriers-the highest-risk group for late-onset AD. Here we show that a 4-week open-label trial of low-dose Rapamycin (Sirolimus; 1 mg/day) significantly improved cerebral blood flow (CBF) relative to baseline in cognitively normal APOE4 carriers (E4(+)) aged 45-65. It also reduced inflammatory cytokines, enhanced lipid metabolism, increased short-chain fatty acids (SCFA) and enriched gut microbiome composition linked to SCFA production. Conversely, non-carriers (E4(-)) displayed stable baseline-to-post-treatment CBF and SCFA and demonstrated different treatment-related patterns of metabolic and anti-inflammatory effects than E4(+). Serum amyloid A and tau remained unchanged for both groups. These findings suggest Rapamycin may counter early vascular and metabolic deficits in E4(+) individuals, with genotype-specific effects. By bridging anti-aging research and AD prevention, this study highlights a novel, safe, and precision-based approach to mitigating AD risk in APOE4 carriers.

RevDate: 2025-04-01
CmpDate: 2025-04-01

Feng G, Lan X, Qin S, et al (2025)

Advances in Research on Exosomal miRNAs in Central Nervous System Diseases.

ASN neuro, 17(1):2465546.

Neurological diseases present a wide range of conditions, intricate diagnosis and treatment processes, and complex prognostic considerations. Therefore, research focusing on the diagnosis and treatment of these diseases is crucial. Exosomal miRNAs are small RNA molecules enclosed in membrane vesicles, released by cells and known to play roles in the development of various neurological disorders. They also serve as specific biomarkers for these conditions. Drawing on extensive research on exosomal miRNAs in diseases like stroke, Alzheimer's, epilepsy, Parkinson's, and neuroregeneration, this paper provides a comprehensive review of the relationship between exosomal miRNAs and neurological diseases. We strive to offer current and detailed theoretical understandings to help with the diagnosis and treatment of these disorders.

RevDate: 2025-04-01
CmpDate: 2025-04-01

Yan YJ, Lin R, Luo YT, et al (2025)

Impact of combined art-based intervention on functional connectivity of multiple brain networks in older adults along the cognitive continuum: result from a parallel randomised controlled trial.

BMC psychiatry, 25(1):307.

BACKGROUND: Combined art-based interventions (CAIs) are considered effective treatment options for older adults along the cognitive continuum; however, the neural mechanisms underlying associated changes in neurocognitive performance remain unclear. Thus, we aimed to investigate the impact of a CAI programme in older adults along the cognitive continuum and to understand its mechanism.

METHODS: This parallel-arm randomised controlled trial was conducted between April 2021 and January 2023. Participants were randomised in a 1:1 ratio to either intervention group (IG) or waitlist control group (WG). The IG underwent a 16-week CAI programme. Neuropsychological assessments and magnetic resonance imaging were conducted before and after the intervention.

RESULTS: After the intervention, the IG showed greater improvement in general cognitive function, language, and memory than the WG. Significant differences were observed in the functional connectivity (FC) values in the temporal and cerebellar anterior lobes, fusiform, inferior occipital, and lingual gyri, and perirhinal and visual cortices between the groups. Further analyses showed that FC values were reduced in these regions in the IG. In addition, changes in FC values were positively correlated with those in neuropsychological test scores in the IG.

CONCLUSIONS: Our study suggests that the CAI programme can effectively improve general cognitive function, language, and memory in older adults along the cognitive continuum. These improvements may be changed due to decreases in FC in key brain regions, deepening the understanding of the neurocentral mechanisms that act as a tool for improving cognitive function.

TRIAL REGISTRATION: This trial was registered at ChiCTR.org. Identifier: ChiCTR2100044959, 03/04/2021.

RevDate: 2025-03-31

Bogdanovic N, Smailovic U, V Jelic (2025)

Alzheimer mimicry: LATE and PART.

Journal of neural transmission (Vienna, Austria : 1996) [Epub ahead of print].

Alzheimer's disease (AD) is the main cause of dementia and accounts for 60% of dementia syndromes in people older than 75 years. The correct classification of AD and non-AD cases is mandatory to study disease mechanisms or new treatment possibilities. A typical clinical picture of AD consists of a progressive cognitive decline, with primary memory impairment. Structural, functional, and molecular brain imaging, along with CSF biomarkers of amyloid pathology, neurodegeneration, and the presence of a vulnerability-associated APOE genotype, support the diagnosis of AD. Use of biomarkers have led to the identification of individuals with mild cognitive impairment who are amyloid-negative addressing a conceptually separate clinical entity named suspected non-Alzheimer disease pathophysiology (SNAP). Clinical presentation and progression of SNAP can mimic AD which makes the final diagnosis and possible treatment uncertain in up to 30% of cases in clinical centers that are not using biomarkers. These non-AD pathologies are common with advancing age both in cognitively impaired and clinically normal elderly people and include Argyrophilic Grain Disease (ARG), Tangle Predominant Dementia and TDP-43 proteinopathy. The terms Primary age-related tauopathy (PART) and Limbic-dominant TDP-43 age-related encephalopathy (LATE) have been proposed as the most common and useful biological and emerging clinical construct to describe this phenomenon in > 80 years old individuals. Current evidence underlines the limitations of existing diagnostic tools, which remain inadequate for fully capturing the complexities of these conditions. Addressing these diagnostic ambiguities is crucial for assigning accurate diagnoses, reducing frequent misdiagnoses of AD, and implementing appropriate therapeutic strategies for elderly patients with mild cognitive impairment and dementia.

RevDate: 2025-03-31
CmpDate: 2025-04-01

Bassal R, Rivkin-Natan M, Rabinovich A, et al (2025)

APOE4 impairs autophagy and Aβ clearance by microglial cells.

Inflammation research : official journal of the European Histamine Research Society ... [et al.], 74(1):61.

Alzheimer's disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.

RevDate: 2025-03-31

Horie K, Salvadó G, Koppisetti RK, et al (2025)

Plasma MTBR-tau243 biomarker identifies tau tangle pathology in Alzheimer's disease.

Nature medicine [Epub ahead of print].

Insoluble tau aggregates within neurofibrillary tangles are a defining neuropathological feature of Alzheimer's disease (AD) and closely correlate with clinical symptoms. Although tau pathology can be assessed using tau positron emission tomography, a more accessible biomarker is needed for diagnosis, prognosis and tracking treatment effects. Here we present a new plasma tau species, the endogenously cleaved, microtubule-binding region containing residue 243 (eMTBR-tau243), which specifically reflects tau tangle pathology. Across the AD spectrum in three different cohorts (n = 108, 55 and 739), plasma eMTBR-tau243 levels were significantly elevated at the mild cognitive impairment stage and increased further in dementia. Plasma eMTBR-tau243 showed strong associations with tau positron emission tomography binding (β = 0.72, R[2] = 0.56) and cognitive performance (β = 0.60, R[2] = 0.40), outperforming other plasma tau (%p-tau217 and %p-tau205) biomarkers. These results suggest that plasma eMTBR-tau243 may be useful for estimating the tauopathy load in AD, thereby improving the diagnostic evaluation of AD in clinical practice and monitoring the efficacy of tau-targeted therapies in clinical trials.

RevDate: 2025-03-31

Shah FA, Qadir H, Khan JZ, et al (2025)

A review: From old drugs to new solutions: The role of repositioning in alzheimer's disease treatment.

Neuroscience pii:S0306-4522(25)00266-0 [Epub ahead of print].

Drug repositioning or drug reprofiling, involves identifying novel indications for approved and previously abandoned drugs in the treatment of other diseases. The traditional drug discovery process is tedious, time-consuming, risky, and challenging. Fortunately, the inception of the drug repositioning concept has expedited the process by using compounds with established safety profiles in humans, and thereby significantly reducing costs. Alzheimer's disease (AD) is a severe neurological disorder characterized by progressive degeneration of the brain with limited and less effective therapeutic interventions. Researchers have attempted to identify potential treatment of AD from existing drug however, the success of drug repositioning strategy in AD remains uncertain. This article briefly discusses the importance and effectiveness of drug repositioning strategies, the major obstacles in the development of drugs for Alzheimer's disease (AD), approaches to address these challenges, and the role of machine learning in identifying early markers of AD for improved management.

RevDate: 2025-04-01

Yang X, Yao K, Zhang M, et al (2025)

New insight into the role of altered brain cholesterol metabolism in the pathogenesis of AD: A unifying cholesterol hypothesis and new therapeutic approach for AD.

Brain research bulletin, 224:111321 pii:S0361-9230(25)00133-9 [Epub ahead of print].

The dysregulation of cholesterol metabolism homeostasis has been universally suggested in the aeotiology of Alzheimer's disease (AD). Initially, studies indicate that alteration of serum cholesterol level might contribute to AD. However, because blood-brain barrier impedes entry of plasma cholesterol, brain cells are not directly influenced by plasma cholesterol. Furthermore, mounting evidences suggest a link between alteration of brain cholesterol metabolism and AD. Interestingly, Amyloid-β proteins (Aβ) can markedly inhibit cellular cholesterol biosynthesis and lower cellular cholesterol content in cultured cells. And Aβ overproduction/overload induces a significant decrease of brain cellular cholesterol content in familial AD (FAD) animals. Importantly, mutations or polymorphisms of genes related to brain cholesterol transportation, such as ApoE4, ATP binding cassette (ABC) transporters, low-density lipoprotein receptor (LDLR) family and Niemann-Pick C disease 1 or 2 (NPC1/2), obviously lead to decreased brain cholesterol transport, resulting in brain cellular cholesterol loss, which could be tightly associated with AD pathological impairments. Additionally, accumulating data show that there are reduction of brain cholesterol biosynthesis and/or disorder of brain cholesterol trafficking in a variety of sporadic AD (SAD) animals and patients. Collectively, compelling evidences indicate that FAD and SAD could share one common and overlapping neurochemical mechanism: brain neuronal/cellular cholesterol deficiency. Therefore, accumulated evidences strongly support a novel hypothesis that deficiency of brain cholesterol contributes to the onset and progression of AD. This review highlights the pivotal role of brain cholesterol deficiency in the pathogenesis of AD. The hypothesis offers valuable insights for the future development of AD treatment.

RevDate: 2025-03-31

Tonegawa-Kuji R, Hou Y, Hu B, et al (2025)

Efficacy and safety of passive immunotherapies targeting amyloid beta in Alzheimer's disease: A systematic review and meta-analysis.

PLoS medicine, 22(3):e1004568 pii:PMEDICINE-D-24-02295 [Epub ahead of print].

BACKGROUND: While recently U.S. FDA-approved anti-amyloid beta (anti-Aβ) monoclonal antibodies (mAbs) offer new treatment approaches for patients suffering from Alzheimer's disease (AD), these medications also carry potential safety concerns and uncertainty about their efficacy for improving cognitive function. This study presents an updated meta-analysis of cognitive outcomes and side effects of anti-Aβ mAbs from phase III randomized controlled trials (RCTs) in patients with sporadic AD.

METHODS AND FINDINGS: Phase III randomized, placebo-controlled blinded trial evaluating the efficacy and safety of anti-Aβ mAbs in patients with AD were identified through a search in clinical trials.gov, PubMed and Embase on January 14th, 2024. The retrieved studies were further screened from January 15th, 2024, to February 14th, 2024. We included studies that had been published in any language. Quality of trials was assessed using the Jadad score and publication bias was assessed using Egger's test and Funnel plot. Primary outcomes were mean changes from baseline to post-treatment in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB) and AD Assessment Scale-Cognitive Subscale (ADAS-Cog) scores, and secondary outcomes were adverse events including amyloid-related imaging abnormalities with edema (ARIA-E), and ARIA with hemorrhage (ARIA-H). Random-effects meta-analysis and meta-regression analyses were conducted. The literature search identified 13 phase III RCTs, which included 18,826 patients with mild cognitive impairment or dementia due to AD. Compared with placebo, treatment with mAbs significantly improved cognitive performance on CDR-SB (mean difference -0.25, 95% confidence interval [CI] [-0.38, -0.11]) and ADAS-Cog (standardized mean difference -0.09, 95% CI [-0.12, -0.06]), in which a negative change indicates improvement for both scores. Meta-regression analysis suggested that trials enrolling patients with early-stage AD were associated with better efficacy. Elevated risk of ARIA-E (risk ratio [RR] 9.79, 95% CI [5.32,18.01]), ARIA-H (RR 1.94, 95% CI [1.47,2.57]), and headaches (RR 1.21, 95% CI [1.10,1.32]) were noted. Statistical heterogeneity was relatively high for ARIA-E and ARIA-H, leading to wide confidence intervals and considerable variability in effect sizes, though meta-regression was conducted to address this. Furthermore, differences in trial designs introduce limitations in cross-trial comparisons.

CONCLUSIONS: Anti-Aβ mAb therapy slows cognitive decline, but with small effect sizes, and raises potential concerns about ARIA and headaches.

RevDate: 2025-03-31

Wadan AS, Shaaban AH, El-Sadek MZ, et al (2025)

Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.

Naunyn-Schmiedeberg's archives of pharmacology [Epub ahead of print].

Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.

RevDate: 2025-03-31

Fotovat L, Wang K, F Chiappelli (2024)

Integrating MICRORNA941 and T cell subset research into public health strategies for managing inflammaging in elderly and immune-compromised patients.

Bioinformation, 20(11):1529-1531.

As of 2022, the Centers for Disease Control and Prevention (CDC) reported that the average life expectancy for both sexes in the United States is 77.5 years. While new advances in health have increased life expectancy, aging comes with complications that impact the development of diseases like cancer, senile dementia (non-Alzheimer), diabetes and Parkinson's. Through aging, the body's immune system declines, a process recognized as immunosenescence and which contributes to inflammaging, a state of chronic, though non-productive, inflammation that progresses with advancing age in the absence of overt infection and that contributes to the onset and progression of a spectrum of age-related pathologies. MicroRNAs are small forms of RNA that control gene expression by binding to messenger RNA (mRNA) in the cell cytoplasm. In particular, microRNA-941 (miR-941) has been found to play a critical role in the regulation of differentiation of cell populations, certain T cell subsets responsible for maintaining efficient immune surveillance in normal subjects, immune compromised individuals as well as the elderly. We propose that concerted research designed to define and characterize interventions targeting the regulatory effects of miRNA-941 specifically on T-cell subsets will benefit treatment of infectious (e.g., CoViD-19, H5N1 infection) and chronic illnesses (e.g., diabetes II, diabetes III, Long Covid [i.e., Post-Acute Covid-19 Syndrome, PACS], autoimmune disease), which are most common among the aging and the immune compromised population. It is possible and even probable that active research in this specific area will proffer new horizons for finding cures, aid in disease management and improved accessibility and affordability of public health services.

RevDate: 2025-03-31

Liu X, Zhou B, Chen Y, et al (2025)

Design and synthesis of 2-phenyl-1H-benzo[d]imidazole derivatives as 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.

RSC medicinal chemistry pii:d4md00861h [Epub ahead of print].

It has been reported that 17β-HSD10 plays a key role in Alzheimer's disease. Here, a total of 44 2-phenyl-1H-benzo[d]imidazole derivatives were designed and synthesized as novel 17β-HSD10 inhibitors based on rational design and SAR studies. Among them, compound 33 (N-(4-(1,4,6-trimethyl-1H-benzo[d] imidazol-2-yl)phenyl)cyclohexanecarboxamide) showed high inhibitory efficacy (17β-HSD10 IC50 = 1.65 ± 0.55 μM) and low toxicity (HepaRG IC50 >100 μM). The Morris water maze experiment revealed that compound 33 could alleviate cognitive impairment induced by scopolamine in mice. This study facilitates the further development of more potent 17β-HSD10 inhibitors for the treatment of Alzheimer's disease.

RevDate: 2025-03-31

Hoang MT, Zenker A, Saha S, et al (2025)

Economic evaluations of strategies targeting pre-diagnosis dementia populations: Protocol for a systematic review.

HRB open research, 8:11.

INTRODUCTION: Dementia remains incurable, and treatment trials are typically conducted after the symptoms manifest, potentially too late in the disease process to alter its course. Early identification and intervention during the pre-diagnosis phase offer the potential to introduce more cost-effective strategies and enhance quality of life. This review aims to scrutinise emerging evidence and present a comprehensive summary of cost-effectiveness estimates of all strategies targeting the pre-diagnosis dementia population.

METHOD AND ANALYSIS: A systematic search will be conducted across six electronic databases. All articles will be assessed against pre-defined eligibility criteria through title and abstract screening, and full-text screening phases. Data from the included articles will be extracted using a standardized template. A newly established framework based on the CHEERS 2022 checklist will be applied to assess the reporting quality of the included articles. The entire review process, from screening to data extraction and quality assessment, will be a dual process conducted by two reviewers. Disagreements will be resolved by a third senior reviewer. The extracted data will be synthesised and presented in tables and figures.

CONCLUSION: This systematic review will present evidence of cost-effectiveness, along with the strengths and limitations of the existing literature. These findings aim to identify existing gaps, thereby informing and guiding the design of future studies in this domain.

ETHICS AND DISSEMINATION: Since this is a systematic review protocol, ethical approval is not required. The results will be published in a peer-reviewed journal, with both raw and summarised data shared through the journal or other open platforms.

PROSPERO - CRD42024521521.

RevDate: 2025-03-31

Cordeiro GA, Faria JA, Pavan L, et al (2025)

Evaluation of the neuroprotective potential of benzylidene digoxin 15 against oxidative stress in a neuroinflammation models induced by lipopolysaccharide and on neuronal differentiation of hippocampal neural precursor cells.

Frontiers in pharmacology, 16:1537720 pii:1537720.

Neuroinflammation, often driven by the overproduction of reactive oxygen species (ROS), plays a crucial role in the pathogenesis of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. The susceptibility of the brain to oxidative stress is attributed to its high metabolic activity and limited antioxidant defense. This study aimed to evaluate the neuroprotective potential of Benzylidene Digoxin 15 (BD-15) following treatment and pretreatment in a lipopolysaccharide (LPS)-induced neuroinflammation model. Additionally, we examined whether BD-15 enhances the generation of neurons from neural progenitor cells (NPCs).Male Wistar rats were used for acute treatment studies and divided into four groups: control (saline), BD-15 (100 μg/kg), LPS (250 μg/kg), and LPS + BD-15 (250 μg/kg + 100 μg/kg). Swiss albino mice were used for chronic pretreatment studies and divided into the following groups: control (saline), BD-15 (0.56 mg/kg), LPS (1 mg/kg), and LPS + BD-15 (1 mg/kg + 0.56 mg/kg). Behavioral changes were assessed using the open field test, and brain tissues were analyzed for oxidative stress markers, including malondialdehyde (MDA), reduced glutathione (GSH), protein carbonylation, catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST). To assess neurogenesis, primary NPC cultures derived from the hippocampus of newborn Wistar rats were used, which led to reduced locomotor activity and increased oxidative stress, particularly in the cortex, as indicated by elevated MDA levels and reduced GSH levels. BD-15 treatment reversed these effects, notably by restoring GSH levels and reducing protein carbonylation in the cerebellum. Chronic BD-15 treatment in Swiss mice improved oxidative stress markers including MDA, SOD, CAT, and GST. Furthermore, BD-15 exhibits neuroprotective properties by alleviating oxidative stress and motor dysfunction, suggesting its potential as a therapeutic agent for neuroinflammatory disorders. However, BD-15 did not affect NPC cell proliferation, indicating that this cardiotonic steroid did not alter the cell cycle of these progenitor cells.

RevDate: 2025-03-31

Chen X, Lv Z, Xie G, et al (2025)

Unleashing the potential: 40 Hz multisensory stimulation therapy for cognitive impairment.

Journal of central nervous system disease, 17:11795735251328029 pii:10.1177_11795735251328029.

Cognitive impairment encompasses a spectrum of disorders marked by acquired deficits in cognitive function, potentially leading to diminished daily functioning and work capacity, often accompanied by psychiatric and behavioral disturbances. Alzheimer's disease (AD) and Post-stroke cognitive impairment (PSCI) are significant causes of cognitive decline. With the global population getting older, AD and PSCI are becoming major health concerns, underscoring the critical necessity for successful treatment options. In recent years, various non-invasive biophysical stimulation techniques, including ultrasound, light, electric, and magnetic stimulation, have been developed for the treatment of central nervous system diseases. Preliminary clinical studies have demonstrated the feasibility and safety of these techniques. This review discuss the impact of 40 Hz multisensory stimulation on cerebral function, behavioral outcomes, and disease progression in both animal models and individuals exhibiting cognitive deficits, such as AD and PSCI. Furthermore, it summarizes the potential neural pathways involved in this therapeutic modality by synthesizing evidence from a variety of studies within the field. Subsequently, it evaluates the existing constraints of this technique and underscores the potential advantages of 40 Hz multisensory stimulation therapy for individuals with cognitive deficits, with the goal of enhancing the management and care of AD and PSCI.

RevDate: 2025-03-31

Han X, Gong S, Gong J, et al (2025)

Structural and metabolic topological alterations associated with butylphthalide treatment in mild cognitive impairment: Data from a randomized, double-blind, placebo-controlled trial.

Psychiatry and clinical neurosciences [Epub ahead of print].

AIMS: Effective intervention for mild cognitive impairment (MCI) is key for preventing dementia. As a neuroprotective agent, butylphthalide has the potential to treat MCI due to Alzheimer disease (AD). However, the pharmacological mechanism of butylphthalide from the brain network perspective is not clear. Therefore, we aimed to investigate the multimodal brain network changes associated with butylphthalide treatment in MCI due to AD.

METHODS: A total of 270 patients with MCI due to AD received either butylphthalide or placebo at a ratio of 1:1 for 1 year. Effective treatment was defined as a decrease in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) > 2.5. Brain networks were constructed using T1-magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. A support vector machine was applied to develop predictive models.

RESULTS: Both treatment (drug vs. placebo)-time interactions and efficacy (effective vs. ineffective)-time interactions were detected on some overlapping structural network metrics. Simple effects analyses revealed a significantly increased global efficiency in the structural network under both treatment and effective treatment of butylphthalide. Among the overlapping metrics, an increased degree centrality of left paracentral lobule was significantly related to poorer cognitive improvement. The predictive model based on baseline multimodal network metrics exhibited high accuracy (88.93%) of predicting butylphthalide's efficacy.

CONCLUSION: Butylphthalide may restore abnormal organization in structural networks of patients with MCI due to AD, and baseline network metrics could be predictive markers for therapeutic efficacy of butylphthalide.

CLINICAL TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (Registration Number: ChiCTR1800018362, Registration Date: 2018-09-13).

RevDate: 2025-03-31

Lu J, Yu P, Wang Y, et al (2025)

Rational Design of the First Dual Agonist at Trace Amine-Associated Receptor 1 and 5-HT2C Receptors Based on Binding Pocket Similarity for the Treatment of Schizophrenia and Alzheimer's Disease-Related Psychosis.

Journal of medicinal chemistry [Epub ahead of print].

The clinical-stage agonists for trace amine-associated receptor 1 (TAAR1) show insufficient clinical efficacy, requiring the design of new compounds beyond the TAAR1 receptor alone. Here, we provide evidence for the feasibility of designing TAAR1/5-HT2CR dual agonists based on structural basis of these two targets and similarities of their agonists. Three series of novel agonists were discovered, leading to a potent compound named 21b. 21b exhibits submicromolar potency on both TAAR1 and 5-HT2CR targets with high specificity confirmed by site-directed mutagenesis. Preclinical proof-of-concept studies showed that 21b was highly efficacious against the positive and negative symptoms of schizophrenia in mice models. 21b also alleviated cognitive deficits and psychoactive symptoms in Alzheimer's disease (AD) model mice. Four week repeated dosing of 21b is exceptionally well tolerated in rats and beagle dogs without hyperglycemia commonly seen with antipsychotics. Thus, the favorable druggability of compound 21b warrants further clinical development for the treatment of schizophrenia and AD-related psychosis.

RevDate: 2025-03-30

Wang MT, Hu ZC, Xiang Y, et al (2025)

Fingolimod ameliorates amyloid deposition and neurodegeneration in APP/PS1 mouse model of Alzheimer's disease.

The journal of prevention of Alzheimer's disease pii:S2274-5807(25)00075-5 [Epub ahead of print].

INTRODUCTION: The immune system plays a critical role in regulating amyloid-beta (Aβ) metabolism in Alzheimer's Disease (AD). Both T and B lymphocytes are involved in the pathogenesis of AD. The sphingosine-1-phosphate (S1P) receptor modulator fingolimod used in the treatment of multiple sclerosis, can promote lymphocyte homing, potentially reducing the infiltration of peripheral lymphocytes into the brain.

METHODS: In this study, 8-month-old APP/PS1 mice were orally administered fingolimod at a dose of 1 mg/kg/day or saline as a control for 2 months. After treatment, the mice were subjected to behavioral tests, pathological examinations, and biochemical analyses to evaluate behavioral deficits and AD-type pathologies.

RESULTS: Fingolimod inhibits the infiltration of peripheral lymphocytes into the brain and reduces neuroinflammation. Fingolimod enhances cognitive function and alleviates brain Aβ deposition. Additionally, fingolimod treatment mitigates other AD-related pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration. Proteomic analysis further confirms the therapeutic effects of fingolimod in AD, reflected by the downregulation of proteins involved in multiple AD-associated pathways.

DISCUSSION: This study illustrates that fingolimod effectively ameliorates multiple pathological features of AD, highlighting its potential as a promising therapeutic candidate for the disease.

RevDate: 2025-03-30

Kshirsagar S, Alvir RV, Pradeepkiran JA, et al (2025)

Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.

Mitochondrion pii:S1567-7249(25)00033-9 [Epub ahead of print].

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.

RevDate: 2025-03-30

Wang W, Liu Z, Cheng H, et al (2025)

Cerium-doped carbon dots as dual-target agents against Alzheimer's β-amyloid fibrillogenesis and reactive oxygen species.

Colloids and surfaces. B, Biointerfaces, 252:114655 pii:S0927-7765(25)00162-6 [Epub ahead of print].

Both fibrillogenesis of amyloid β-protein (Aβ) and elevated levels of reactive oxygen species (ROS) contribute to the pathogenesis of Alzheimer's disease (AD). Beyond Aβ aggregation inhibition, the complexity necessitates the development of comprehensive therapeutic interventions for halting AD progression. Herein, a dual-target agent capable of Aβ aggregation inhibition and ROS scavenging was synthesized by doping cerium into carbon dots (Ce CDs). Ce CDs with a high Ce (III)/Ce (IV) ratio of 0.67 can scavenge various ROS, including superoxide anion radicals, hydroxyl radicals, hydrogen peroxide, and Aβ40-induced ROS, thus mitigating cellular oxidative damage and rescuing cell viability. Additionally, Ce CDs present potent inhibition on Aβ40 on-pathway fibrillization, disrupting the formation of highly ordered β-sheet structures and increasing cell viability from 50.2 % to 91.9 %. It is validated that the electrostatic interactions between Ce CDs and Aβ40 are primarily responsible for preventing the conformational transition of Aβ40 monomers. In vivo experiments with the transgenic Caenorhabditis elegans strain further validate the bifunctionality of Ce CDs in suppression of Aβ fibrillogenesis and attenuation of oxidative stress, thereby demonstrating the potential of combination therapy for AD. This finding highlights the important role of electrostatic interactions between Aβ and inhibitors in regulating Aβ aggregation, and provides new insights into the development of multifunctional agents for AD treatment.

RevDate: 2025-03-29

Kshirsagar S, Reddy AP, PH Reddy (2025)

Beneficial effects of mitophagy enhancers on amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer's disease.

Mitochondrion pii:S1567-7249(25)00035-2 [Epub ahead of print].

The purpose of our study is to investigate the beneficial effects of mitophagy enhancers against mutant amyloid precursor protein (APP) and amyloid beta (Aβ) induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Research spanning over two decades highlights the critical role of mitochondrial dysfunction and synaptic damage in the pathogenesis of both early-onset and late-onset AD. Emerging evidence suggests impaired clearance of damaged mitochondria is an early pathological event in AD, positioning mitophagy enhancers as potential therapeutic candidates. This study determined the optimal doses of four mitophagy enhancers-Urolithin A (UA), actinonin, tomatidine, and nicotinamide riboside (NR)-using immortalized mouse hippocampal (HT22) neurons. HT22 cells were transfected with mutant APP (mAPP) cDNA and treated with the enhancers. The effects were assessed by evaluating mRNA and protein expression levels of genes involved in mitochondrial dynamics, biogenesis, mitophagy, and synaptic function, alongside cell survival and mitochondrial respiration. Mitochondrial morphology was also examined in treated and untreated mAPP-HT22 cells. Results showed that mAPP-HT22 cells exhibited increased mitochondrial fission, reduced fusion, downregulated synaptic and mitophagy-related genes, diminished cell survival, impaired mitochondrial respiration, and excessively fragmented, shortened mitochondria. Treatment with mitophagy enhancers reversed these deficits, restoring mitochondrial and synaptic health. Enhanced cell survival, upregulation of mitochondrial fusion, synaptic, and mitophagy genes, improved mitochondrial structure, and reduced fragmentation were observed. Notably, UA demonstrated the most robust mitigating effects. These findings underscore the therapeutic potential of mitophagy enhancers, particularly UA, as promising candidates to treat mitochondrial and synaptic dysfunctions in AD.

RevDate: 2025-03-29
CmpDate: 2025-03-29

Odu P, Odu VK, Oyebanjo OT, et al (2024)

Cognitive And Neuroprotective Effects of Vernonia amygdalina in scopolamine-induced Memory impaired Rats.

Nigerian journal of physiological sciences : official publication of the Physiological Society of Nigeria, 39(2):233-240.

Cognitive impairment is largely associated with functional and structural loss in the brain of Alzheimer's disease (AD) models, and scopolamine has been successfully used to mimic these deficits in rodents. The cost and side effects of drugs presently used for the treatment of AD-related cognitive impairment have prompted research into alternative products, especially natural ones with high antioxidant capacity, since oxidative stress is a major pathophysiology associated with AD. The current study evaluated the cognitive and neuroprotective effects of Vernonia amygdalina (VA) on scopolamine-induced cognitive impairment in rats. Thirty-five male rats, randomly divided into seven groups (n = 5), were used. Group 1 served as the control and received distilled water. Groups 2 and 3 received Vernonia amygdalina, VA (50 and 100 mg/kg, respectively) per orally (p.o.). Group 4 received 1 mg/kg scopolamine SC (i.p.). Groups 5, 6, and 7 received pretreatment with either VA 50 mg/kg, VA 100 mg/kg, or Donepezil, DP (1 mg/kg), and then in combination with SC (1 mg/kg). The animals were subjected to memory tasks using the Morris water maze (MWM) and novel object recognition tasks (NORT) and sacrificed on day 14, after which their brains were isolated for biochemical and histological studies. The study showed that during MWM and NORT, spatial and non-spatial recognition memories, which were respectively impaired in the SC group compared to the control group, were reversed in the VA pretreatment groups. Scopolamine injection caused significant decreases in superoxide dismutase and catalase levels and an increase in malonaldehyde (MDA) levels in group 4 compared with the control group. Pretreatments with either VA or DP, however, caused a significant increase in the SOD and catalase levels and a decrease in the MDA level compared with the SC group. Histological studies revealed that VA was more potent in protecting the brain against SC-induced neurodegeneration and morphological alterations in the hippocampus and prefrontal cortex. Findings of this study suggest that VA attenuates scopolamine-induced cognitive deficits via inhibition of oxidative stress and neuronal degeneration and enhancement of cognition in the brains of rats.

RevDate: 2025-03-29

Donaghy PC, Hasoon J, Hamilton CA, et al (2025)

Plasma Biomarkers and Disease Prognosis in Mild Cognitive Impairment with Lewy Bodies.

Movement disorders : official journal of the Movement Disorder Society [Epub ahead of print].

BACKGROUND: Little is known about the prognostic value of plasma biomarkers in mild cognitive impairment with Lewy bodies (MCI-LB).

OBJECTIVES: To investigate the association of four plasma biomarkers with disease progression in MCI.

METHODS: Plasma amyloid-beta (Aβ)42/40, glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 181 (pTau181) were measured at baseline in a longitudinal MCI cohort (n = 131).

RESULTS: Baseline plasma NfL was associated with increased risk of dementia/death in the entire cohort. In MCI-LB, baseline plasma NfL, GFAP, and pTau181 were associated with increased risk of dementia/death and increased cognitive decline measured by the Addenbrooke's Cognitive Examination-Revised.

CONCLUSIONS: pTau181, GFAP, and NfL are associated with more rapid disease progression in MCI-LB and, with further validation, could be useful to support prognosis and stratification for clinical practice and treatment trials. Further work, including clinicopathological studies, is needed to understand the biological correlates of these markers in MCI-LB. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

RevDate: 2025-03-31
CmpDate: 2025-03-29

Jahng GH, Lee MB, OI Kwon (2025)

Gadolinium based contrast agent induced electrical conductivity heterogeneity analysis in the brain of Alzheimer's disease.

Scientific reports, 15(1):10832.

Magnetic resonance imaging (MRI) often uses gadolinium-based contrast agents (GBCAs) to improve the characterization of imaging contrast, owing to their strong paramagnetic properties. Magnetic resonance electrical properties tomography (MREPT) visualizes the conductivity distribution of biological tissues at the Larmor frequency using the [Formula: see text] field phase signal. In this paper, we investigate the effect of GBCA on brain conductivity. To compare the differences of reconstructed noisy conductivity maps before and after the GBCA injection, we propose a method to remove the background low-frequency noise artifact based on an elliptic partial differential equation. By analyzing the relationship between electrical conductivity and magnetic permeability, the objective of this study is to develop a cost-effective and accessible initial screening imaging tool for diagnosing and monitoring the treatment of Alzheimer's disease (AD) pathophysiology. To investigate vascular damage in AD, we define a conductivity heterogeneity volume fraction (CHVF) caused by GBCA leakage. Using CHVF, we develop three indices to characterize mild cognitive impairment (MCI) and AD. To verify the proposed method, we studied a total of 42 participants, including 14 individuals diagnosed with AD, 18 participants with MCI, and 10 cognitively normal (CN) participants. Finally, we designed a radar chart informed by the CHVF analysis, to exhibit the pertinent parameters for MCI and AD patients, facilitating the evaluation and ongoing monitoring of each patient's diagnosis and treatment regimen.

RevDate: 2025-03-28

Rabinovici GD, Selkoe DJ, Schindler SE, et al (2025)

Donanemab: Appropriate use recommendations.

The journal of prevention of Alzheimer's disease pii:S2274-5807(25)00094-9 [Epub ahead of print].

Donanemab (Kisunla®), an IgG1 monoclonal antibody targeting N-terminal pyroglutamate-modified forms of amyloid-β, is approved in the United States for treatment of early symptomatic Alzheimer's disease (AD). Appropriate Use Recommendations (AUR) were developed to guide the implementation of donanemab in real-world practice, prioritizing safety considerations and opportunity for effectiveness. The AUR were developed by the AD and Related Disorders Therapeutic Workgroup by consensus, integrating available data and expert opinion. Appropriate candidates for donanemab treatment include persons with mild cognitive impairment or mild dementia due to AD (Clinical Stages 3-4, MMSE 20-30) who have biomarker confirmation of AD pathology by PET or CSF. Tau PET is not required for eligibility. Apolipoprotein E (APOE) genotyping should be performed prior to treatment to inform an individual's risk of developing Amyloid-Related Imaging Abnormalities (ARIA). Pre-treatment MRI should be obtained no more than 12 months prior to treatment. Patients with findings of >4 cerebral microbleeds, cortical superficial siderosis or a major vascular contribution to cognitive impairment should be excluded from treatment. The decision to initiate therapy should be grounded in a shared decision-making process that emphasizes the patient's values and goals of care. Donanemab is administered as a monthly intravenous infusion. Surveillance MRIs to evaluate for ARIA should be performed prior to the 2nd, 3rd, 4th and 7th infusions, prior to the 12th dose in higher risk individuals, and at any time ARIA is suspected clinically. Clinicians may consider discontinuing treatment if amyloid clearance is demonstrated by amyloid PET, typically obtained 12-18 months after initiating treatment.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Chen Y, Cheng H, Tao H, et al (2025)

Dual-mode sensing platform based on an iodide ion synergistic covalent triazine frameworks (CTFs) for point-of-care testing (POCT) of acetylcholinesterase.

Analytica chimica acta, 1350:343836.

Acetylcholinesterase (AChE) plays a critical role in maintaining nervous system homeostasis and coordinating essential biological reactions. AChE is an important biomarker for early diagnosis and treatment, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). Therefore, developing efficient and immediate sensing platforms for AChE detection is crucial for advancing early diagnostic tools. In this study, we developed a dual-mode colorimetric/photothermal sensing platform based on iodide ion-synergized covalent porphyrin-triazine backbone nanozymes (Zn-CTF/I) to detect AChE with high sensitivity and reliability. The synergistic interaction between iodide ions and zinc atoms effectively modulated the electronic structure of the catalytic active site, significantly enhancing the peroxidase-like (POD-like) activity of Zn-CTF/I. This enhancement led to a 10-fold reduction in the AChE detection limit compared to controls, with a minimum detection limit of 0.003 U L[-1], outperforming other reported assays. The integration of temperature-based photothermal signals with colorimetric detection improved the platform's accuracy and reliability. The system also demonstrated excellent recovery performance in detecting AChE in complex serum samples. The proposed dual-mode sensing platform provides a sensitive, reliable, and robust tool for AChE detection, with promising applications in early diagnosis and treatment monitoring of neurodegenerative diseases.

RevDate: 2025-03-28

Wang Y, Lei X, Zhao D, et al (2025)

Revealing the effective components and mechanism of Zhimu-Huangbai herb-pair in the treatment of Alzheimer's disease.

Journal of ethnopharmacology pii:S0378-8741(25)00383-6 [Epub ahead of print].

The Zhimu-Huangbai herb-pair (ZB) is one of the most widely accepted prescriptions for treating Alzheimer's disease (AD) in traditional Chinese medicine. However, the effective components and mechanism of ZB for treating AD have not been fully understood.

AIM OF THE STUDY: This study aims to reveal the active components of ZB in the treatment of AD through serum pharmacochemistry, identify the potential targets and pathways of ZB in treating AD through metabolomics, and subsequently verify its mechanism through in vivo experiments.

MATERIALS AND METHODS: The components of ZB in both blood and cerebrospinal fluid were determined by using UPLC-Q-TOF-MS. The efficacy of ZB was assessed in a mouse model of AD induced by D-galactose. Metabolomics methods were used for screening and identification of differential metabolites and enrichment analysis of metabolic pathways. The enzyme-linked immunosorbent assay (ELISA) was used to detect the activities of enzyme complexes I-IV, as well as the levels of ATP and ROS in hippocampal mitochondria of mice. Additionally, the expression of key genes and proteins in the signaling pathway was examined by utilizing immunohistochemistry, real-time quantitative PCR, and Western blot.

RESULTS: A total of 27 prototype components were identified from the serum of rats given ZB, of which 8 components were simultaneously detected in the cerebrospinal fluid. A total of 20 different metabolites were identified from mouse plasma using a metabolomics technique. The enrichment analysis results revealed that the pathway of ZB treatment for AD mainly involves glycerophospholipid metabolism, arachidonic acid metabolism, and unsaturated fatty acid biosynthesis. In vivo experiments have shown that ZB can improve the energy metabolism of the brain and increase the production of ATP by improving mitochondrial dysfunction. In addition, ZB could promote the release of brain-derived neurotrophic factor (BDNF), increase the density of postsynaptic density protein (PSD95), and enhance the expression of synaptophysin (SYN).

CONCLUSION: Our study demonstrates that ZB can improve mitochondrial and synaptic function in AD mice induced by D-gal, providing experimental support for the clinical application and drug development for the prevention and treatment of AD.

RevDate: 2025-03-28

Hida M, Yasuda K, Toyokawa M, et al (2025)

Amyloidogenic and non-amyloidogenic pathways of amyloid precursor protein processing in oligodendrocytes.

Brain research pii:S0006-8993(25)00160-X [Epub ahead of print].

Excessive accumulation of toxic amyloid-β (Aβ) species in the brain is a major pathological process triggering neurodegeneration in Alzheimer's disease (AD). Recent studies indicate that both neurons and glial cells, including oligodendrocyte lineages (OLs), contribute to brain homeostasis and affect AD pathology; however, the roles of oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLGs) in AD remain to be fully elucidated. This study examined Aβ production and related protein expression in primary cultured OLs. Primary cultured OLs produced Aβ40 and Aβ42 and expressed amyloid precursor protein (APP), β-secretase (BACE1) and γ-secretase (PS1) as well as α-secretase (ADAM10). OLGs express APP770 in addition to APP695. Treatment with a γ-secretase inhibitor reduced Aβ40 and Aβ42 production levels derived from OPCs/OLGs and suppressed OPC differentiation. Additionally, conditioned media from OLGs improved neuronal cell viability under oxidative stress and contained higher levels of sAPPα compared to OPCs. The neuroprotective effect of OLG was diminished by a sAPPα inhibitor, suggesting that OLG-derived sAPPα protects neurons under oxidative stress. These findings revealed that OLs produce pathogenic Aβ40/42 via the amyloidogenic pathway and secrete neuroprotective sAPPα via the non-amyloidogenic pathway. Elucidating the pathological shift from beneficial non-amyloidogenic to harmful amyloidogenic processes in OLs during AD onset and progression would provide crucial insights into novel therapeutic approaches.

RevDate: 2025-03-28

Costa ML, Casanova-Martinez D, Chen H, et al (2025)

Implications of the glymphatic system in the pathogenesis of normal pressure hydrocephalus: an illustrated scoping review.

Journal of neurosurgery [Epub ahead of print].

Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the clinical triad of cognitive impairment, gait disturbances, and urinary incontinence, coupled with ventricular enlargement on brain imaging. The pathophysiology of iNPH remains complex, with varied patient responses to CSF diversion and a generally progressive nature of the disease. This scoping review aimed to provide an overview of the glymphatic system (GS) and its role in the development of iNPH. The review highlights the crucial function of the GS in maintaining brain homeostasis by clearing waste products from the interstitial space. Dysfunction in this system leads to impaired CSF clearance, resulting in the accumulation of neurotoxic substances that contribute to the symptoms of iNPH. Additionally, potential shared pathophysiological pathways between iNPH and other conditions affecting the GS such as aging, diabetes mellitus, hypertension, and sleep disorders are discussed. The findings suggest that GS dysfunction is a key factor in iNPH pathogenesis and may also be linked to the disease's poor responsiveness to shunt treatment. By enhancing understanding of these mechanisms, there is potential to develop targeted therapies aimed at restoring glymphatic function, thereby improving outcomes for patients with iNPH.

RevDate: 2025-03-28

Norata D, Capone F, Motolese F, et al (2025)

1953-2023. Seventy Years of the Nerve Growth Factor: A Potential Novel Treatment in Neurological Diseases?.

Aging and disease pii:AD.2024.0573 [Epub ahead of print].

Rita Levi-Montalcini's 1953 discovery of nerve growth factor (NGF) in mouse sarcoma tumors marked a groundbreaking moment in neuroscience. NGF, a key signaling molecule, became the first identified neurotrophic factor, influencing the growth, differentiation, and survival of neurons in both peripheral and central nervous systems. NGF and related neurotrophic factors hold therapeutic potential for various neurological disorders, such as Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, amyotrophic lateral sclerosis, spinal cord injuries, neuropathies, traumatic brain injuries, and stroke. However, despite promising in vitro studies and animal models findings, NGF efficacy in patients remains unproven. Indeed, its use as a therapeutic agent faces challenges in delivery and clinical translation. This review delves into these challenges, exploring ongoing research on refined delivery methods, dosages, and safety profiles. Innovative strategies, including molecular mimicking, combination therapies, gene therapy, and coupling with neuromodulation techniques like transcranial magnetic stimulation and vagal nerve stimulation, are discussed. Incorporating nerve growth factor (NGF) into a comprehensive strategy may prove beneficial, particularly in non-neurodegenerative conditions such as stroke, trauma, and neuropathies. In these instances, NGF holds promise for promoting tissue regeneration and repair. Challenges persist in addressing the complexity of neurodegenerative pathologies for a combined therapeutic approach.

RevDate: 2025-03-31
CmpDate: 2025-03-31

Loupy KM, Dawud LM, Zambrano CA, et al (2025)

Effects of Oral Administration of the Probiotic Lactobacillus rhamnosus GG on the Proteomic Profiles of Cerebrospinal Fluid and Immunoregulatory Signaling in the Hippocampus of Adult Male Rats.

Neuroimmunomodulation, 32(1):94-109.

INTRODUCTION: The microbiome-gut-brain axis, by modulating bidirectional immune, metabolic, and neural signaling pathways in the host, has emerged as a target for the prevention and treatment of psychiatric and neurological disorders. Oral administration of the probiotic bacterium Lactobacillus rhamnosus GG (LGG; ATCC 53103) exhibits anti-inflammatory effects, although the precise mechanisms by which LGG benefits host physiology and behavior are not known. The goal of this study was to explore the general effects of LGG on the cerebrospinal fluid (CSF) proteome and a biological signature of anti-inflammatory signaling in the central nervous system (CNS) of undisturbed, adult male rats.

METHODS: Liquid chromatography-tandem mass spectrometry-based proteomics were conducted using CSF samples collected after 21 days of oral treatment with live LGG (3.34 × 107 colony-forming units (CFU)/mL in the drinking water (resulting in an estimated delivery of ∼1.17 × 109 CFU/day/rat) or water vehicle. Gene enrichment analysis (using DAVID, v. 6.8) and protein-protein interactions (using STRING, v. 11) were used to explore physiological network changes in CSF. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR) was performed to assess gene expression changes of anti-inflammatory cytokines in the hippocampus. Genes associated with anti-inflammatory signaling that were analyzed included Il10, Tgfb1, Il4, and IL-4-responsive genes, Cd200, Cd200r1, and Mrc1 (Cd206).

RESULTS: Oral LGG administration altered the abundance of CSF proteins, increasing the abundance of five proteins (cochlin, NPTXR, reelin, Sez6l, and VPS13C) and decreasing the abundance of two proteins (CPQ, IGFBP-7) in the CSF. Simultaneously, LGG increased the expression of Il10 mRNA, encoding the anti-inflammatory cytokine interleukin 10, in the hippocampus.

CONCLUSION: Oral LGG altered the abundance of CSF proteins associated with extracellular scaffolding, synaptic plasticity, and glutamatergic signaling. These data are consistent with the hypothesis that oral administration of LGG improves memory and cognition, and promotes a physiological resilience to neurodegenerative disease, by increasing glutamatergic signaling and promoting an anti-inflammatory environment in the brain.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Dantas LP, Carneiro de Vasconcelos E, da Silva Cunha C, et al (2025)

Protective effects of alpha-lipoic acid on memory deficit induced by repeated doses of solifenacin in mice: the role of nitro-oxidative stress.

Metabolic brain disease, 40(4):165.

Solifenacin (Sol) is one of the most used antimuscarinics for the treatment of bladder dysfunction and there are no conclusive studies on its effects on learning and memory after long-term use. Since substances with antioxidant action, such as alpha-lipoic acid (ALA), have shown protective action in memory deficit and Alzheimer's disease, we decided to study the effects of Sol alone or associated with ALA in behavioral tests of memory and its relation to nitro-oxidative stress in different brain areas. Mice received saline or Sol p.o. for 14 or 28 days. ALA groups received: (a) saline + ALA, (b) Sol for 14 days and Sol + ALA from the 15th to the 28th days and, (c) Sol + ALA for 28 days. Behavioral tests were performed and oxidative changes (lipid peroxidation) and nitrite in the prefrontal cortex (PFC), hippocampus (HC) and striatum (ST) were also determined. Sol produced memory alterations in the mice, reducing the step-down latency and the recognition index in the novel object recognition test. Sol also increased lipid peroxidation in PFC, HC and ST and nitrite levels in the HC. On the other hand, ALA associated with Sol was able to restrict the effects caused by Sol alone, both in relation to nitro-oxidative parameters and in relation to behavioral tests. Taken together, our data suggest that ALA can be administered as an adjunctive drug in patients requiring prolonged use of Sol to mitigate these adverse central nervous system effects. However, clinical studies need to be performed to corroborate preclinical research.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Awad SM, Attia YA, ElSayed H, et al (2025)

Efficacy of curcumin-selenium nanoemulsion in alleviating oxidative damage induced by aluminum chloride in a rat model of Alzheimer's disease.

Journal of molecular histology, 56(2):122.

Alzheimer's disease (AD) is a common neurological disorder primarily affecting older adults. A hallmark of this condition is the generation of reactive oxygen species (ROS), leading to increased oxidative stress and cellular damage. Treatment with a curcumin-selenium nanoemulsion has been shown to enhance behavioural performance and mitigate degenerative changes induced by aluminium chloride (AlCl3). This nanoemulsion also reduced the activity of acetylcholinesterase (AChE) and lowered levels of key proteins, including Aβ, p53, tau, nuclear factor erythroid 2-related factor 2 (Nrf2), and tumour necrosis factor-alpha (TNF-α). Additionally, it significantly decreased nitric oxide (NO) levels in the brain while enhancing the activity of catalase (CAT) and superoxide dismutase (SOD). The study highlights the antioxidant and anti-inflammatory properties of the curcumin-selenium nanoemulsion, suggesting its potential as a therapeutic option for alleviating AD induced by AlCl3. These results are further supported by improvements in the histological structure of the cortex and hippocampus, as well as enhanced immunohistochmical assessment of glial fibrillary acidic protein (GFAP). Cur- Se-nanoemulsion, the current drug delivery technology, may lower the amount of amyloid-β in AD rat brain and considerably ameliorate the memory deficit that improve therapy efficacy in AD lesions.

RevDate: 2025-03-28

Issa EHB, Alghazo EM, Gharaibeh R, et al (2025)

Therapeutic potential and challenges of mesenchymal stem cells in neurological disorders: A concise analysis.

Journal of neuropathology and experimental neurology pii:8097959 [Epub ahead of print].

Neurological diseases comprise a wide array of conditions affecting both the central and peripheral nervous systems. Neurodegenerative diseases encompass a group of debilitating and often fatal neurological disorders for which effective treatments are currently lacking. Stem cells are recognized for their remarkable capacity for proliferation, multilineage differentiation, and self-renewal. The transplantation of stem cells represents a significant advancement in therapeutic strategies for neurological disorders, with applications in both preclinical and clinical settings. Mesenchymal stem cells (MSCs), in particular, have garnered substantial interest due to their unique properties, making them a highly sought-after source of therapeutic cells. Although the efficacy of MSCs in treating neurological disorders is well documented, further research is needed to elucidate the underlying mechanisms and to assess their in vivo applications more comprehensively. This article summarizes current research on the use of MSCs in the treatment of various neurological disorders, including Parkinson disease, stroke, multiple sclerosis, and Alzheimer disease.

RevDate: 2025-03-28

Yadav M, VP Singh (2025)

A review on benzoselenazoles: synthetic methodologies and potential biological applications.

Organic & biomolecular chemistry [Epub ahead of print].

Among the various heterocyclic organoselenium compounds, a new class of benzoselenazoles has received great attention due to their chemical properties and biological applications. The ever-growing interest in the five-membered benzoselenazole heterocycles amongst chemists has made commendable impact. These heterocycles are a prominent class of organic molecules that have emerged as potential therapeutic agents for the treatment of a wide range of diseases. Substantial progress has been made in elucidating the complex chemical properties of these heterocycles. Moreover, they have garnered significant importance in a wide range of biological applications. However, despite their biological activities, research on benzoselenazoles remains relatively limited, emphasising the need for further exploration in this area. Hence, considering the importance of benzoselenazoles, this comprehensive review compiles various synthetic procedures, highlighting the recent advances in their synthesis that have been disclosed in the literature. This review would offer chemists an array of information that will assist them in the development of more affordable and effective synthesis processes for benzoselenazoles. Therefore, it is believed that this review would provide relevant context on these achievements and will inspire synthetic organic chemists to use these effective technologies of such heterocycles for the future treatment of diseases caused by oxidative stress. The biological and pharmacological properties of these organoselenium heterocycles, which include their antioxidant, antitumor, and antibacterial activities and their application in Alzheimer's disease treatment and as pancreatic lipase inhibitors, are thoroughly summarized. Finally, this review provides some perspectives on the challenges and future directions in the development of benzoselenazoles as heterocyclic organoselenium compounds.

RevDate: 2025-03-28

Zhai Y, Lu K, Yuan Y, et al (2025)

Semaglutide improves cognitive function and neuroinflammation in APP/PS1 transgenic mice by activating AMPK and inhibiting TLR4/NF-κB pathway.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.

RevDate: 2025-03-28

Bartolini E, Di Crosta A, La Malva P, et al (2025)

Gamma oscillation modulation for cognitive impairment: A systematic review.

Journal of Alzheimer's disease : JAD [Epub ahead of print].

BackgroundGamma oscillation modulation has emerged as a potential non-invasive treatment to counteract cognitive impairment in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Non-invasive brain stimulation techniques like transcranial alternating current stimulation (tACS), gamma sensory stimulation (GSS), and transcranial magnetic stimulation (TMS) show promise in supporting specific cognitive functions.ObjectiveTo review and evaluate the efficacy of gamma oscillation modulation techniques in benefiting cognitive functions among individuals with AD and MCI.MethodsA systematic review was conducted, analyzing studies from 2015 to 2023 across databases such as PubMed, Web of Science, and Scopus. Inclusion criteria focused on studies involving tACS, GSS, or TMS applied to older adults with MCI or AD. A total of 438 articles were screened, of which 10 met the eligibility criteria.ResultsFindings suggest that gamma tACS, especially targeting the precuneus and dorsolateral prefrontal cortex, benefits episodic memory and cognitive performance. GSS also showed potential in supporting memory and attention, while TMS exhibited inconsistent but promising results when applied to the angular gyrus. However, heterogeneity in study designs and small sample sizes limit the generalizability of these outcomes.ConclusionsGamma oscillation modulation offers potential cognitive benefits for patients with AD and MCI, particularly in memory support. Further studies with larger samples and well-designed protocols are needed to confirm its therapeutic efficacy and optimize intervention parameters.

RevDate: 2025-03-28

Grant KL, SN Long (2025)

Extended release huperzine for the treatment of idiopathic epilepsy in dogs - a Case Report.

Frontiers in veterinary science, 12:1518379.

Huperzine is a naturally occurring alkaloid derived from the Chinese clubmoss Huperzia serrata. It is a potent acetylcholinesterase inhibitor, among other properties, and has demonstrated protection against induced seizures in a mouse model of Dravet's syndrome as well as nerve-agent induced seizures and is being explored as a novel anticonvulsant in a human clinical trial for focal impaired awareness seizures. It is also being explored as a treatment for Alzheimer's, via neuroprotective effects and an ability to ameliorate neuroinflammation. Here we present a case series of 6 dogs with idiopathic epilepsy treated with huperzine to investigate this potential novel anticonvulsant. Despite a 50% drop out rate over the course of the study due to various causes including unexplained death, humane euthanasia and systemic disease, huperzine was generally well tolerated and showed some positive effects on demeanor. This study highlights the need for more research to investigate its efficacy as a novel antiepileptic medication in dogs.

RevDate: 2025-03-28

Roy SM, Acquarone E, Argyrousi EK, et al (2025)

Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction.

Alzheimer's & dementia (New York, N. Y.), 11(1):e70073.

INTRODUCTION: Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT2b receptor (5-HT2bR) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT2bR inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT2bR inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.

METHODS: Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT2bR activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT2bR agonist activity.

RESULTS: MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT2bR activity and β-arrestin-1 recruitment.

DISCUSSION: Selective inhibition of 5-HT2bR activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.

HIGHLIGHTS: A new highly selective 5-HT2bR antagonist, MW073, is described and used as a reference standard.MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes.Risperidone is a dose dependent inhibitor of 5-HT2bR activity and arrestin recruitment.

RevDate: 2025-03-28

Hermans AMM, Bakker E, Starokozhko V, et al (2025)

Biomarkers for neurodegenerative diseases in regulatory decision-making by the European Medicines Agency.

Alzheimer's & dementia (New York, N. Y.), 11(1):e70072.

INTRODUCTION: Biomarkers (BMs) are valuable tools to facilitate early diagnosis of (subtypes of) diseases, improve patient selection and stratification, and detect therapeutic effects or safety concerns. This study explores the extent to which BMs are utilized in the development of treatments for neurodegenerative diseases (NDDs), as well as topics of discussion regarding BMs in regulatory advice- and decision-making processes and sharing of BM-related data.

METHODS: The European Medicines Agency's marketing authorization application (MAA), qualification (QA/QO), and scientific advice (SA) procedures regarding NDDs were screened, and those that mention BMs were analyzed. Data were extracted on the intended disease, BM type, and context of use proposed by applicants. BMs were categorized based on both nature and function.

RESULTS: In total, 105 procedures that discussed BMs were analyzed, 57 SAs (January 2020 to December 2022), 19 QAs/QOs (January 2008 to December 2023), and 29 MAAs (January 1995 to December 2023). The majority involved Alzheimer's disease (AD; n = 30), Parkinson's disease (PD; n = 9), and multiple sclerosis (MS; n = 33). Imaging BMs were the most common type of BMs discussed, and most BMs were used as pharmacodynamic/response measures. The acceptance and role of BMs differed between AD, PD, MS, and other NDDs. In regulatory procedures for AD, for example, diagnostic BMs guiding patient selection were commonly discussed, whereas in MAAs for MS, imaging BMs (particularly lesions) were generally accepted as supportive/secondary endpoints.

DISCUSSION: Despite the established role of certain BMs, mainly imaging BMs for MS, there remains a major need for more precise and reliable BMs to improve diagnostic accuracy and treatment monitoring for NDDs. To implement novel BMs and facilitate development of new treatments and to eventually improve clinical practice, robust evidence bases showcasing biological plausibility or clear clinical benefits are essential. Collaboration and data-sharing among stakeholders is vital in generating this evidence and enhancing the understanding and management of NDDs.

HIGHLIGHTS: The European Medicines Agency's marketing authorization applications and qualification and scientific advice procedures.One hundred five procedures were analyzed regarding neurodegenerative diseases that discuss biomarkers.We found that acceptance and role of biomarkers differ per disease.Biological plausibility/clinical benefits are essential for biomarker implementation.

RevDate: 2025-03-28

Nawaz A, Sadiq A, Bashir N, et al (2025)

Synthetic Derivates of Progesterone Ameliorate Scopolamine-Induced Cognitive Deficits in Animal Models: Antioxidant, Enzyme Inhibitory, Molecular Docking and Behavioral Correlates.

Current neuropharmacology pii:CN-EPUB-147413 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a neurological disorder characterized by cognitive decline and behavioral turbulence and is anticipated to badly affect the patient's quality of life. Previous studies revealed the neuroprotective effects of progesterone, so this study aimed to appraise the neuroprotective potentials of new derivatives of progesterone (AN-1 to AN-5).

METHODS: Subsequent to compound synthesis and structure elucidation, the in-vitro antioxidant (DPPH), acetylcholinesterase (AChE), butyrylcholinesterase (BChE) inhibitory and molecular docking studies were performed following standard procedures. The most potent compound was subjected to more detailed behavioral studies, including Y-Maze, Elevated Plus Maze (EPM), and open field tests in scopolamine-induced amnesic animals.

RESULTS: In the DPPH assay, the AN-1 compound at 1000 μg/ml concentration exhibited 83.37 ± 2.03% inhibition of DPPH free radicals and an IC50 value of 24.81 μg/ml. Likewise, the compound AN-1 demonstrated 88.94 ± 1.20% inhibition against AChE and 86.78 ± 1.24% inhibition against BChE enzymes at 1000 μg/ml with IC50 values of 24.51 and 18.79 μg/ml, correspondingly. In behavioral studies, compound AN-1 demonstrated a significant decline in cognitive impairments and improved working memory as well as locomotor activities of the amnesic animals. Molecular docking studies also demonstrated that the compound AN-1 has promising inhibitory potentials against AChE and BChE enzymes by binding to their active sites. The binding energies of AN-1 with both enzymes were -7.6 Kcal/mol for AChE and -8.1 Kcal/mol for BChE.

CONCLUSION: Based on our findings, it is concluded that the derivatives of progesterone exhibit neuroprotective potential, and further research is needed to extend their neuroprotective role in the treatment of AD.

RevDate: 2025-03-28

Verwaerde P, O Defert (2025)

AZP2006 (Ezeprogind[®]): a Promising New Drug Candidate in the Battle Against Neurodegenerative Diseases.

ChemMedChem [Epub ahead of print].

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disorder characterized by abnormal tau protein accumulation. This perspective article explores AZP2006 (INN: Ezeprogind), a novel small molecule targeting the Progranulin (PGRN) and Prosaposin (PSAP) axis to enhance lysosomal health in PSP treatment. AZP2006 stabilizes the PGRN-PSAP complex, improving lysosomal function and reducing tau pathology. Preclinical studies in tauopathy models demonstrated AZP2006's ability to decrease tau hyperphosphorylation, enhance neuronal survival, mitigate neuroinflammation and promote synaptogenesis. Clinical trials have shown AZP2006 to be well-tolerated in healthy volunteers and PSP patients. A Phase 2a study met its primary endpoints, as it provided valuable safety data and even encouraged further investigation of its efficacy in a larger clinical study. An upcoming Phase 2b/3 trial aims to assess long-term safety and efficacy in a larger PSP cohort. AZP2006's mechanism of action strongly suggests potential applications in other tauopathies, including Alzheimer's and Parkinson's diseases. By addressing lysosomal dysfunction and tau pathology, AZP2006 represents a promising disease-modifying approach for PSP and other neurodegenerative disorders.

RevDate: 2025-03-28

Muksimova S, Umirzakova S, Baltayev J, et al (2025)

Multi-Modal Fusion and Longitudinal Analysis for Alzheimer's Disease Classification Using Deep Learning.

Diagnostics (Basel, Switzerland), 15(6): pii:diagnostics15060717.

Background: Addressing the complex diagnostic challenges of Alzheimer's disease (AD), this study introduces FusionNet, a groundbreaking framework designed to enhance AD classification through the integration of multi-modal and longitudinal imaging data. Methods: FusionNet synthesizes inputs from Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET), and Computed Tomography (CT) scans, harnessing advanced machine learning strategies such as generative adversarial networks (GANs) for robust data augmentation, lightweight neural architectures for efficient computation, and deep metric learning for precise feature extraction. The model uniquely combines cross-sectional and temporal data, significantly enhancing diagnostic accuracy and enabling the early detection and ongoing monitoring of AD. The FusionNet architecture incorporates specialized feature extraction pathways for each imaging modality, a fusion layer to integrate diverse data sources effectively, and attention mechanisms to focus on salient diagnostic features. Results: Demonstrating superior performance, FusionNet achieves an accuracy of 94%, with precision and recall rates of 92% and 93%, respectively. Conclusions: These results underscore its potential as a highly reliable diagnostic tool for AD, facilitating early intervention and tailored treatment strategies. FusionNet's innovative approach not only improves diagnostic precision but also offers new insights into the progression of Alzheimer's disease, supporting personalized patient care and advancing our understanding of this debilitating condition.

RevDate: 2025-03-28

Chen Y, Xiao D, X Li (2025)

Lactylation and Central Nervous System Diseases.

Brain sciences, 15(3): pii:brainsci15030294.

As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer's disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.

RevDate: 2025-03-28

Singh AA, Katiyar S, M Song (2025)

Phytochemicals Targeting BDNF Signaling for Treating Neurological Disorders.

Brain sciences, 15(3): pii:brainsci15030252.

Neurological disorders are defined by a deterioration or disruption of the nervous system's structure and function. These diseases, which include multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and schizophrenia, are caused by intricate pathological processes that include excitotoxicity, neuroinflammation, oxidative stress, genetic mutations, and compromised neurotrophic signaling. Although current pharmaceutical treatments relieve symptoms, their long-term efficacy is limited due to adverse side effects and weak neuroprotective properties. However, when combined with other neuroprotective drugs or adjunct therapy, they may offer additional benefits and improve treatment outcomes. Phytochemicals have emerged as attractive therapeutic agents due to their ability to regulate essential neurotrophic pathways, especially the brain-derived neurotrophic factor (BDNF) signaling cascade. BDNF is an important target for neurodegenerative disease (ND) treatment since it regulates neuronal survival, synaptic plasticity, neurogenesis, and neuroprotection. This review emphasizes the molecular pathways through which various phytochemicals-such as flavonoids, terpenoids, alkaloids, and phenolic compounds-stimulate BDNF expression and modulate its downstream signaling pathways, including GSK-3β, MAPK/ERK, PI3K/Akt/mTOR, CREB, and Wnt/β-catenin. This paper also highlights how phytochemical combinations may interact to enhance BDNF activity, offering new therapeutic options for ND treatment. Despite their potential for neuroprotection, phytochemicals face challenges related to pharmacokinetics, blood-brain barrier (BBB) permeability, and absorption, highlighting the need for further research into combination therapies and improved formulations. Clinical assessment and mechanistic understanding of BDNF-targeted phytotherapy should be the main goals of future studies. The therapeutic efficacy of natural compounds in regulating neurotrophic signaling is highlighted in this review, providing a viable approach to the prevention and treatment of NDs.

RevDate: 2025-03-28

Ortiz GG, González-Usigli H, Nava-Escobar ER, et al (2025)

Primary Progressive Aphasias: Diagnosis and Treatment.

Brain sciences, 15(3): pii:brainsci15030245.

Background and Objective: Primary Progressive Aphasias (PPAs) are rare neurodegenerative disorders classified within frontotemporal lobar degeneration (FTLD) and typically manifest between 45 and 70 years of age. In Mexico-and many other countries-reliable epidemiological data are lacking; however, estimates suggest that PPA accounts for 0.5-2.5% of neurodegenerative disease cases in Memory Clinics, with an incidence of approximately 1 per 100,000 and an average survival of 8 years. This review aims to provide clinicians with an overview of PPA's epidemiology, clinical features, and classification, thereby enhancing understanding of its subtypes and distinguishing characteristics from other aphasic conditions, such as vascular aphasia. Methods: This narrative review was conducted through a literature search using databases such as PubMed and Scopus. Relevant studies addressing the epidemiology, clinical presentation, and classification of PPA were identified, selected, and synthesized to offer a broad, clinically oriented overview of the condition. This approach was chosen to inform clinical practice and highlight the need for further targeted investigations, such as future systematic reviews focusing on specific aspects like therapeutic strategies. Key Contents and Findings: (a) Epidemiology: PPA is estimated to affect 0.5-2.5% of patients with neurodegenerative diseases in Memory Clinics, with an incidence of roughly 1 per 100,000. Average survival time is around 8 years (ranging from 3 to 17 years), with a generally balanced gender ratio, though some studies indicate a predominance of men. A positive family history is observed in 20-40% of cases, with about 10% following an autosomal dominant inheritance pattern. (b) Clinical Characteristics and Classification: PPA is marked by a gradual decline in language abilities, differentiating it from vascular aphasias. Subtypes include non-fluent forms (non-fluent progressive aphasia [nfPPA] and logopenic progressive aphasia [lPPA]), fluent forms (progressive fluent aphasia [PFA] and semantic dementia [SD]), and mixed forms (progressive mixed aphasia [PMA]). The neurodegenerative process in PPA extends beyond vascular boundaries, often resulting in presentations that deviate from classical Broca's and Wernicke's aphasias. Common symptoms include difficulties in word finding and naming, sometimes mistaken for memory loss, and, in the case of semantic dementia, personality changes that may go unnoticed by the patient. Conclusions: PPA is a heterogeneous and complex group of neurodegenerative disorders with significant clinical variability and a profound impact on patients and their families. While current epidemiological data are limited, this review emphasizes the need for further research to better delineate disease progression and refine diagnostic and therapeutic approaches. Future systematic reviews will be essential to address specific aspects of PPA, such as treatment strategies, to further improve patient care.

RevDate: 2025-03-28

Weidauer S, E Hattingen (2025)

Cerebral Amyloid Angiopathy: Clinical Presentation, Sequelae and Neuroimaging Features-An Update.

Biomedicines, 13(3): pii:biomedicines13030603.

The prevalence of cerebral amyloid angiopathy (CAA) has been shown to increase with age, with rates reported to be around 50-60% in individuals over 80 years old who have cognitive impairment. The disease often presents as spontaneous lobar intracerebral hemorrhage (ICH), which carries a high risk of recurrence, along with transient focal neurologic episodes (TFNE) and progressive cognitive decline, potentially leading to Alzheimer's disease (AD). In addition to ICH, neuroradiologic findings of CAA include cortical and subcortical microbleeds (MB), cortical subarachnoid hemorrhage (cSAH) and cortical superficial siderosis (cSS). Non-hemorrhagic pathologies include dilated perivascular spaces in the centrum semiovale and multiple hyperintense lesions on T2-weighted magnetic resonance imaging (MRI). A definitive diagnosis of CAA still requires histological confirmation. The Boston criteria allow for the diagnosis of a probable or possible CAA by considering specific neurological and MRI findings. The recent version, 2.0, which includes additional non-hemorrhagic MRI findings, increases sensitivity while maintaining the same specificity. The characteristic MRI findings of autoantibody-related CAA-related inflammation (CAA-ri) are similar to the so-called "amyloid related imaging abnormalities" (ARIA) observed with amyloid antibody therapies, presenting in two variants: (a) vasogenic edema and leptomeningeal effusions (ARIA-E) and (b) hemorrhagic lesions (ARIA-H). Clinical and MRI findings enable the diagnosis of a probable or possible CAA-ri, with biopsy remaining the gold standard for confirmation. In contrast to spontaneous CAA-ri, only about 20% of patients treated with monoclonal antibodies who show proven ARIA on MRI also experience clinical symptoms, including headache, confusion, other psychopathological abnormalities, visual disturbances, nausea and vomiting. Recent findings indicate that treatment should be continued in cases of mild ARIA, with ongoing MRI and clinical monitoring. This review offers a concise update on CAA and its associated consequences.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Poniah P, Abdul Rashed A, Abdul Jalil J, et al (2025)

Clinical Significance of Early-Onset Alzheimer's Mutations in Asian and Western Populations: A Scoping Review.

Genes, 16(3): pii:genes16030345.

BACKGROUND/OBJECTIVES: Background: Early-onset Alzheimer's disease (EOAD) is primarily inherited in an autosomal dominant pattern, with mutations in the APP, PSEN1, and PSEN2 genes being central contributors. Diagnosing Alzheimer's poses challenges due to the coexistence of various co-pathologies, and treatment options remain limited for most patients, apart from familial cases linked to specific genetic mutations. While significant research on Alzheimer's genetics has been conducted in both Asian and Caucasian populations, the specific mutations and their clinical impacts in EOAD are still inadequately explored. This review aims to provide a detailed analysis of commonly reported genetic mutations and associated clinical features in EOAD patients from Asian and Western populations.

METHODS: Following the PRISMA-ScR guidelines, a systematic database search was conducted for studies published between 2016 and 2023. After screening 491 records, 36 studies from Asian cohorts and 40 from Western cohorts met the inclusion criteria.

RESULTS: The analysis revealed 127 unique mutations in the Asian population and 190 in the Western population. About 16.7% of Asian and 21.9% of Western studies covered both familial and sporadic AD, with consistent patterns across groups. Some mutations were shared between the populations and displayed similar clinical features, while others were population-specific.

CONCLUSIONS: These findings underscore the considerable variability in EOAD mutations and phenotypes, emphasizing the importance of genetic testing in younger patients to enhance diagnostic accuracy and guide treatment strategies effectively.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Simonyan K, Darbinyan L, Hambardzumyan L, et al (2025)

Teucrium Polium ameliorates amyloid β-induced brain network disorders in rats: electrophysiological and behavioral studies.

BMC complementary medicine and therapies, 25(1):116.

Synaptic failure in specific cholinergic networks in rat brains has been implicated in amyloid β-induced neurodegeneration. Teucrium polium is a promising candidate for drug development against Alzheimer's disease (AD) and similar disorders. However, the protective effect of Teucrium polium against amyloid β-induced impairment of short-term synaptic plasticity is still poorly understood. In this study, we used in vivo extracellular single-unit recordings to investigate the preventive efficacy of Teucrium polium on Aβ(25-35)-induced aberrant neuronal activity in the hippocampus and basolateral amygdala of rats, in response to high-frequency stimulation of the cholinergic nucleus basalis magnocellularis (NBM). After 12 weeks of intracerebroventricular administration of Aβ(25-35), alterations such as decreased excitatory responses and increased inhibitory synaptic activity were observed in the NBM-hippocampus and NBM-basolateral amygdala cholinergic circuits. Treatment with Teucrium polium improved the balance of excitatory and inhibitory responses by modulating synaptic transmission strength and restoring short-term plasticity. Acute injection of a therapeutic dose of Teucrium temporarily inhibited spiking activity in single NBM neurons. Open field tests revealed that amyloid-injected rats displayed anxiety and reduced exploratory drive. Treatment with Teucrium polium improved these behaviors, reducing anxiety and increasing exploration. Teucrium polium mitigated amyloid β-induced alterations in cholinergic circuits by enhancing the adaptive capacity of short-term synaptic plasticity. These findings suggest that Teucrium polium could serve as a preventive strategy to delay the progression of cholinergic neurodegeneration.

RevDate: 2025-03-28
CmpDate: 2025-03-28

Liu J, Yan M, Chen L, et al (2025)

Construction and evaluation of a diagnostic model for Alzheimer's disease based on mitophagy-related genes.

Scientific reports, 15(1):10632.

Alzheimer's disease (AD) is the most common cause of dementia. Mitophagy fulfills crucial functions in neurodegenerative disorders and neuronal survival but the relationship between mitophagy and AD is unclear. Mitophagy correlation scores between AD samples and control samples were calculated using single-sample GSEA (ssGSEA) based on two datasets from gene expression omnibus (GEO) database. Mitophagy-related genes (MRGs) and differentially expressed genes (DEGs) in AD screened by WGCNA and "limma" package were intersected to take common genes. These overlapping genes were further compressed and used for diagnostic modeling by adopting the recursive feature elimination (RFE) and LASSO analysis. The reliability of the diagnostic model was verified based on the receiver operating characteristic (ROC) curve. Then, a transcription factor (TF)-mRNA regulatory network of these key genes was established. Lastly, ssGSEA was employed to examine the relationship between the identified genes and cellular pathways and immune cell infiltration. AD samples had notably lower mitophagy correlation scores than control samples. A total of 12 MRGs in the module with the greatest mitophagy connection with AD patients were identified. Functional enrichment analysis revealed that the DEGs were significantly enriched in synaptic function-related pathways. Based on GSE122063, a diagnostic prediction model was created and validated using two mitophagy-related genes (YWHAZ and NDE1), showing an area under ROC curve (AUC) greater than 0.7. This confirmed that the diagnostic model had a high predictive value. The TF-mRNA network showed that four TFs, namely, FOXC1, FOXL1, HOXA5 and GATA2, were regulated by both YWHAZ and NDE1 genes. Immune infiltration analysis revealed that NDE1 promoted the infiltration of most immune cells, while YWHAZ mainly inhibited the infiltration of most immune cells. The current findings improved our understanding of mitophagy in AD, contributing to future research and treatment development in AD.

RevDate: 2025-03-27

Lee SK, Han M, Park S, et al (2025)

Association of Physical Activity with Dementia Risk in Cancer Survivors: A Korean Nationwide Cohort Study.

Cancer research and treatment pii:crt.2024.901 [Epub ahead of print].

PURPOSE: This study aimed to investigate the impact of physical activity on dementia risk among cancer survivors in South Korea.

MATERIALS AND METHODS: This retrospective, population-based cohort study included 344,152 cancer survivors identified from the National Health Insurance Service database in South Korea. The mean follow-up time was 5.81 years. Different levels of physical activity post-cancer diagnosis, ranging from inactive to highly active, were assessed. The primary outcome was the incidence of overall dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Secondary outcomes included dementia risk stratified by cancer type and treatment (chemotherapy and radiation).

RESULTS: Of the total participants, 24,363 (7.08%) developed dementia. The risk of overall dementia decreased sequentially across the exercise groups compared to the inactive group: insufficiently active (adjusted HR, 0.89; 95% CI, 0.86-0.92), active (adjusted HR, 0.85; 95% CI, 0.83-0.88), and highly active (adjusted HR, 0.79; 95% CI, 0.76-0.82). This inverse relationship between exercise and dementia risk was statistically significant across various cancer types and was consistent regardless of age, comorbidities, and whether or not excluding the first 1, 2 years.

CONCLUSION: Among cancer survivors in South Korea, increased physical activity post-diagnosis was associated with a significantly lower risk of dementia. These findings underscore the importance of promoting physical activity in cancer survivors for cognitive health.

RevDate: 2025-03-27

Li C, Gao Z, Chen X, et al (2025)

Ensemble network using oblique coronal MRI for Alzheimer's disease diagnosis.

NeuroImage pii:S1053-8119(25)00153-3 [Epub ahead of print].

Alzheimer's disease (AD) is a primary degenerative brain disorder commonly found in the elderly, Mild cognitive impairment (MCI) can be considered a transitional stage from normal aging to Alzheimer's disease. Therefore, distinguishing between normal aging and disease-induced neurofunctional impairments is crucial in clinical treatment. Although deep learning methods have been widely applied in Alzheimer's diagnosis, the varying data formats used by different methods limited their clinical applicability. In this study, based on the ADNI dataset and previous clinical diagnostic experience, we propose a method using oblique coronal MRI to assist in diagnosis. We developed an algorithm to extract oblique coronal slices from 3D MRI data and used these slices to train classification networks. To achieve subject-wise classification based on 2D slices, rather than image-wise classification, we employed ensemble learning methods. This approach fused classification results from different modality images or different positions of the same modality images, constructing a more reliable ensemble classification model. The experiments introduced various decision fusion and feature fusion schemes, demonstrating the potential of oblique coronal MRI slices in assisting diagnosis. Notably, the weighted voting from decision fusion strategy trained on oblique coronal slices achieved accuracy rates of 97.5% for CN vs. AD, 100% for CN vs. MCI, and 94.83% for MCI vs. AD across the three classification tasks.

RevDate: 2025-03-27

Sharma V, Reang J, Yadav V, et al (2025)

Discovery of 6-amino pyridine clubbed heterocycles as potent dual GSK-3β/CK-1δ inhibitors for the treatment of Alzheimer's disease.

Bioorganic chemistry, 159:108409 pii:S0045-2068(25)00289-5 [Epub ahead of print].

Alzheimer's disease (AD) is a progressive and chronic neurodegenerative disorder progression through various kinases. Glycogen synthase kinase 3β (GSK-3β) and Casein Kinase-1δ (CK-1δ) have gained a lot of attention for its role in tau pathology. Utilizing a multitarget strategy, a series of 6-amino pyridine derivatives were developed as promising dual GSK-3β/CK-1δ inhibitors for the treatment of AD. This study involved the design, synthesis, and evaluation of novel 6-amino pyridine derivatives as dual GSK-3β/CK-1δ inhibitors exhibiting excellent biological activities. The in-vitro results indicated that most of compounds displayed promising activity against GSK-3β/CK-1δ. Among the tested compounds, 8d exhibited strong inhibitory activity against GSK-3β and CK-1δ, with IC50 values of 0.77 ± 0.01 μM and 0.57 ± 0.12 μM, respectively. Notably, compound 8d significantly reduced tau hyperphosphorylated aggregates while demonstrating safety in SH-SY5Y neuroblastoma cell lines. ADME prediction results indicated that compound 8d adhered to Lipinski's rule of five and exhibited potential to permeate the blood-brain barrier (BBB). Molecular docking analysis revealed that this compound fits well within the ATP binding site, forming hydrogen bonds between its 6-amino pyridine ring with key amino acids, including Asp133 and Val135 in the hinge region of GSK-3β, as well as Leu85 of CK-1δ. These findings indicate that 6-amino pyridine derivatives have the potential to be effective dual-target candidates for AD.

RevDate: 2025-03-27

Zhao W, Liu Z, Wu J, et al (2025)

Potential targets of microglia in the treatment of neurodegenerative diseases: mechanism and therapeutic implications.

Neural regeneration research pii:01300535-990000000-00748 [Epub ahead of print].

For diverse neurodegenerative disorders, microglial cells are activated. Furthermore, dysfunctional and hyperactivated microglia initiate mitochondrial autophagy, oxidative stress, and pathological protein accumulation, ending with neuroinflammation that exacerbates damage to dopaminergic neurons and contributes significantly to the pathology of neurodegenerative disorder. Microglial overactivation is closely associated with the secretion of pro-inflammatory cytokines, the phagocytosis of injured neurons, and the modulation of neurotoxic environments. This review summarizes the role of microglia neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, cortical degeneration, Lewy body dementia, and Huntington's disease. It also discusses novel forms of cell death such as ferroptosis, cuproptosis, disulfidptosis, and parthanatos (poly(adenosine diphosphate ribose) polymerase 1-dependent cell death), as well as the impact of regulatory factors related to microglial inflammation on microglial activation and neuroinflammation. The aim is to identify potential targets for microglial cell therapy in neurodegenerative diseases.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Ruthirakuhan M, Guan DX, Mortby M, et al (2025)

Updates and future perspectives on neuropsychiatric symptoms in Alzheimer's disease.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(3):e70079.

Neuropsychiatric symptoms (NPS) are common throughout the Alzheimer's disease (AD) continuum and profoundly affect patients, caregivers, and health-care systems. This review synthesizes key research presented in the 2022 and 2023 Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment Neuropsychiatric Syndromes-Professional Interest Area (NPS-PIA) Year-In-Reviews, emphasizing six critical areas: (1) diversity and disparities, (2) diagnostic frameworks, (3) neurobiology of NPS, (4) NPS as a disease marker, (5) the impact of COVID-19, and (6) interventions. NPS accelerates AD progression, increases functional decline, diminishes quality of life, and heightens caregiver burden and institutionalization rates. Current treatments primarily rely on psychotropics, which offer limited efficacy and raise safety concerns. This review aims to inform clinicians and researchers about recent NPS advancements while identifying gaps for future studies to improve outcomes for individuals with AD. HIGHLIGHTS: Research in Alzheimer's disease-related neuropsychiatric symptoms has rapidly increased, indicating heightened interest. Key areas include: diversity, diagnostics, markers, COVID-19 impact, and treatments. A road map for future studies, based on the key areas of research, is provided. This road map includes considerations to improve study applicability and validity.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Hazan J, Liu KY, Isaacs JD, et al (2025)

Cut-points and gray zones: The challenges of integrating Alzheimer's disease plasma biomarkers into clinical practice.

Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(3):e70113.

Plasma biomarkers for Alzheimer's disease (AD), such as plasma phosphorylated (p)-tau217, offer a more accessible means of testing for the presence of AD pathology compared to cerebrospinal fluid (CSF) or positron emission tomography (PET) methods. They can support diagnostic assessment and determine patient eligibility for treatment with amyloid beta-lowering drugs in community settings where access to CSF examination and amyloid-PET are limited. However, there are important challenges associated with interpreting and integrating plasma biomarker results in clinical practice. This article explores different approaches to interpreting plasma biomarker results in secondary care, important potential sources of uncertainty, and considerations for their clinical application. HIGHLIGHTS: Plasma biomarkers such as phosphorylated tau-217 (p-tau217) offer a promising, accessible alternative to cerebrospinal fluid (CSF) and positron emission tomography (PET) for detecting Alzheimer's disease pathology, especially in settings with limited diagnostic resources. Clinical integration of plasma biomarker testing presents challenges, particularly in interpreting results. This includes uncertainties around intermediate results and their role in patient management. Clear frameworks and guidelines are essential to optimize the use of plasma biomarkers, supported by further research and education to ensure effective application in clinical practice.

RevDate: 2025-03-28

Han L (2025)

AD-Diff: enhancing Alzheimer's disease prediction accuracy through multimodal fusion.

Frontiers in computational neuroscience, 19:1484540.

Early prediction of Alzheimer's disease (AD) is crucial to improving patient quality of life and treatment outcomes. However, current predictive methods face challenges such as insufficient multimodal information integration and the high cost of PET image acquisition, which limit their effectiveness in practical applications. To address these issues, this paper proposes an innovative model, AD-Diff. This model significantly improves AD prediction accuracy by integrating PET images generated through a diffusion process with cognitive scale data and other modalities. Specifically, the AD-Diff model consists of two core components: the ADdiffusion module and the multimodal Mamba Classifier. The ADdiffusion module uses a 3D diffusion process to generate high-quality PET images, which are then fused with MRI images and tabular data to provide input for the Multimodal Mamba Classifier. Experimental results on the OASIS and ADNI datasets demonstrate that the AD-Diff model performs exceptionally well in both long-term and short-term AD prediction tasks, significantly improving prediction accuracy and reliability. These results highlight the significant advantages of the AD-Diff model in handling complex medical image data and multimodal information, providing an effective tool for the early diagnosis and personalized treatment of Alzheimer's disease.

RevDate: 2025-03-28

Wang W, Ye J, Wei Y, et al (2025)

Clinical characteristics of schizophrenia, depression, and Alzheimer's diseases among older adults: a retrospective study of 271 consecutive admissions.

Frontiers in psychiatry, 16:1486626.

OBJECTIVE: This study aims to identify the clinical characteristics of schizophrenia, depression, and AD among older adults.

METHODS: General information of patients was collected, including diagnosis, age, gender, level of education, marital status, drinking behavior, smoking behavior, course of mental disorder, type of admission, history of modified electroconvulsive therapy (MECT) and hospitalization period. The Brief Psychiatric Rating Scale (BPRS), Geriatric Depression Scale (GDS), Generalized Anxiety Disorder 7-Item Scale (GAD-7), Insight and Treatment Attitudes Questionnaire (ITAQ), and Mini-Mental State Examination (MMSE) were employed to evaluate the participants' mental status. The Functional Activities Questionnaire (FAQ), Social Support Rating Scale (SSRS), Barthel ADL Index, Standardized Swallowing Assessment (SSA), and Mini-Nutritional Assessment (MNA) were applied to measure social and daily living function. The Nurses' Global Assessment of Suicide Risk (NGASR) and The Brøset Violence Checklist (BVC) were used to assess the patients' risk of suicide.

RESULTS: Totally 271 participants were recruited, the numbers of participants with schizophrenia, depression, and Alzheimer's diseases (AD), were 81 (29.9%), 85 (31.4%), and 105 (38.7%), respectively. One-way ANOVA was used to compare the variance of the crude score results among three groups of subjects. The results showed that patients with depression had the highest GDS total score, followed by patients with AD, and patients with schizophrenia had the lowest score (P < 0.001). The total scores of GAD-7 and ITAQ in patients with depression were higher than those in patients with AD and schizophrenia (P < 0.001). The total score of MMSE in patients with schizophrenia and depression was higher than that in patients with AD (P < 0.001). The incidence of circulatory system diseases in patients with depression and AD was higher than that in patients with schizophrenia (P < 0.05). The incidence of respiratory system diseases in patients with AD was highest, followed by patients with schizophrenia, and patients with depression had the lowest incidence (P < 0.05). The incidence of nervous system diseases in patients with AD was highest, followed by patients with depression, and patients with schizophrenia had the lowest incidence (P < 0.05). The total scores of FAQ and SSA in patients with AD were higher than those in patients with schizophrenia and depression (P < 0.001), while patients with depression had statistically lower SSRS scores than patients with schizophrenia and patients with AD (P < 0.05). Furthermore, patients with AD had lower Barthel ADL Index scores and water-swallowing test (P < 0.001). MNA scores of patients with schizophrenia were higher than those of patients with depression and AD, with statistical significance (P < 0.05). The NGASR scores of patients with depression were higher than those of patients with schizophrenia and AD, which was statistically significant (P < 0.001). Patients with AD had the highest BVC total score, followed by that of patients with schizophrenia and patients with depression had lowest score, and the difference was statistically significant (P < 0.05).

CONCLUSIONS: Patients with geriatric psychosis may experience abnormalities in various aspects that influenced daily living, including disorders of thinking, cognition, emotion, and behavior. Patients with schizophrenia have cognitive impairment. Cognitive training and medication are important. Patients with depression were considered to be at a greater risk for suicide compared to those with schizophrenia and AD. Active clinical measures must be adopted to improve patients' depressive symptoms, change their suicidal attitudes, and enhance their self-confidence. Patients with AD were prone to respiratory and neurological diseases. Treatment of respiratory infections and hypoxia and other respiratory diseases would be necessary, and cognitive function training should be conducted. In addition, regarding to high risk of swallowing disorders and malnutrition, swallowing function training should be carried out to ensure food intake and prevent malnutrition. Driven by psychiatric symptoms, violent behavior was prevalent, thus effective communication and de-escalation techniques are needed. Although the symptoms of these three diseases are different, timely professional intervention and support from family members are urgently needed.

RevDate: 2025-03-27

Évora A, Garcia G, Rubi A, et al (2025)

Exosomes enriched with miR-124-3p show therapeutic potential in a new microfluidic triculture model that recapitulates neuron-glia crosstalk in Alzheimer's disease.

Frontiers in pharmacology, 16:1474012.

BACKGROUND: Alzheimer's disease (AD), a complex neurodegenerative disease associated with ageing, is the leading cause of dementia. Few people with early AD are eligible for the novel Food and Drug Administration (FDA)-approved drug treatments. Accordingly, new tools and early diagnosis markers are required to predict subtypes, individual stages, and the most suitable personalized treatment. We previously demonstrated that the regulation of microRNA (miR)-124 is crucial for proper neuronal function and microglia reshaping in human AD cell models.

OBJECTIVE: The aim of this study was to develop an efficient miR-124-3p-loaded exosome strategy and validate its therapeutic potential in using a multi-compartment microfluidic device of neuron-glia that recapitulates age-AD pathological features.

METHODS AND RESULTS: Using cortical microglia from mouse pups, separated from glial mixed cultures and maintained for 2 days in vitro (stressed microglia), we tested the effects of SH-SY5Y-derived exosomes loaded with miR-124-3p mimic either by their direct transfection with Exo-Fect™ (ET124) or by their isolation from the secretome of miR-124 transfected cells (CT124). ET124 revealed better delivery effciency and higher potent effects in improving the stressed microglia status than CT124. Tricultures of human SH-SY5Y neuroblastoma cells (SH-WT) were established in the presence of the human microglia cell line (HMC3) and immortalized human astrocytes (IM-HA) in tricompartmentalized microfluidic devices. Replacement of SH-WT cells with those transfected with APP695 (SH-SWE) in the tricultures and addition of low doses of hydrogen peroxide were used to simulate late-onset AD. The system mimicked AD-associated neurodegeneration and neuroinflammation processes. Notably, ET124 exhibited neuroprotective properties across the three cell types in the AD model by preventing neuronal apoptosis and neurite deficits, redirecting microglial profiles towards a steady state, and attenuating the inflammatory and miRNA fingerprints associated with astrocyte reactivity.

CONCLUSION: To the best of our knowledge, this is the first study supporting the neuro- and immunoprotective properties of miR-124-engineered exosomes in a microfluidic triculture platform, recapitulating age-related susceptibility to AD. Our system offers potential to develop personalized medicines in AD patient subtypes.

RevDate: 2025-03-27

Zeng R, Yang B, Wu F, et al (2025)

Early prediction of Alzheimer's disease using artificial intelligence and cortical features on T1WI sequences.

Frontiers in neurology, 16:1552940.

BACKGROUND: Accurately predicting the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD) is a challenging task, which is crucial for helping develop personalized treatment plans to improve prognosis.

PURPOSE: To develop new technology for the early prediction of AD using artificial intelligence and cortical features on MRI.

METHODS: A total of 162 MCI patients were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. By using a 3D-MPRAGE sequence, T1W images for each patient were acquired. All patients were randomly divided into a training set (n = 112) and a validation set (n = 50) at a ratio of 7:3. Morphological features of the cerebral cortex were extracted with FreeSurfer software. Network features were extracted from gray matter with the GRETNA toolbox. The network, morphology, network-clinical, morphology-clinical, morphology-network and morphology-network-clinical models were developed by multivariate Cox proportional hazard model. The performance of each model was assessed by the concordance index (C-index).

RESULTS: In the training group, the C-indexes of the network, morphology, network-clinical, morphology-clinical, morphology-network and morphology-network-clinical models were 0.834, 0.926, 0.915, 0.949, 0.928, and 0.951, respectively. The C-indexes of those models in the validation group were 0.765, 0.784, 0.849, 0.877, 0.884, and 0.880, respectively. The morphology-network-clinical model performed the best. A multi-predictor nomogram with high accuracy for individual AD prediction (C-index = 0.951) was established.

CONCLUSION: The early occurrence of AD could be accurately predicted using our morphology-network-clinical model and the multi-predictor nomogram. This could help doctors make early and personalized treatment decisions in clinical practice, which showed important clinical significance.

RevDate: 2025-03-27

Zhang H, Ya J, Sun M, et al (2025)

Inhibition of the cGAS-STING pathway via an endogenous copper ion-responsive covalent organic framework nanozyme for Alzheimer's disease treatment.

Chemical science [Epub ahead of print].

Inhibition of cGAS-STING overactivation has recently emerged as a promising strategy to counteract Alzheimer's disease (AD). However, current cGAS-STING inhibitors as immunosuppressants suffer from instability, non-specific targeting, and innate immune disruption. Here, an endogenous AD brain copper ion-responsive covalent organic framework (COF)-based nanozyme (denoted as TP@PB-COF@NADH) has been designed for targeted inhibition of the cGAS-STING pathway for AD treatment. The effective trapping of excess brain endogenous copper ions by TP@PB-COF@NADH not only inhibits the Cu[2+]-induced harmful reactive oxygen species (ROS) production which is one of the mediators of cGAS-STING activation, but also activates the nanozyme activity of TP@PB-COF@NADH. Furthermore, the well-prepared nanozyme catalytically generates NAD[+] and consumes hydrogen peroxide (H2O2) through second near-infrared (NIR-II) enhanced nicotinamide adenine dinucleotide (NADH) peroxidase (NPX)-like activity, realizing the efficient inhibition of the cGAS-STING pathway and associated neuroinflammation. Moreover, replenishing NAD[+] levels efficiently restores mitochondrial function and ATP supply. In vivo studies demonstrate that TP@PB-COF@NADH with NIR-II irradiation significantly improves cognitive function in 3× Tg-AD mice, with a reduction in amyloid-β (Aβ) plaque, neuroinflammation and neuronal damage. Collectively, this work presents a promising approach for AD treatment by using an AD brain harmful excess endogenous copper ion-responsive and efficient nanozyme.

RevDate: 2025-03-27

Pradeep S, Sai Chakith MR, Sindhushree SR, et al (2025)

Exploring shared therapeutic targets for Alzheimer's disease and glioblastoma using network pharmacology and protein-protein interaction approach.

Frontiers in chemistry, 13:1549186.

BACKGROUND: Alzheimer's disease (AD) and glioblastoma (GBM) are complex neurological disorders with distinct pathologies but overlapping molecular mechanisms, including neuroinflammation, oxidative stress, and dysregulated signaling pathways. Despite significant advancements in research, effective therapies targeting both conditions remain elusive. Identifying shared molecular targets and potential therapeutic agents could offer novel treatment strategies for these disorders.

METHODOLOGY: The study employs an integrative network pharmacology approach to explore the therapeutic potential of bioactive compounds from Eclipta alba, a medicinal herb known for its neuroprotective and anti-inflammatory properties. A systematic methodology was adopted, starting with network pharmacology analysis using STRING and DisGeNET databases, which identified 617 common genes associated with AD and GBM. Among these, key hub genes-TP53, STAT3, AKT1, and IL6-were prioritized using Cytoscape for network visualization and analysis.

RESULTS: Molecular docking studies were conducted using PyRx software to assess the binding interactions of 26 phytochemicals from Eclipta alba against the identified target genes. Luteolin exhibited the highest binding affinity to IL6 (-7.8 kcal/mol), forming stable hydrogen bonds and hydrophobic interactions. To further validate this interaction, molecular dynamics simulations (MDS) were performed using GROMACS, confirming the stability of the Luteolin-IL6 complex. Additionally, MM-PBSA binding energy calculations using AmberTools (-145.44 kJ/mol) provided further evidence of a strong and stable interaction. Pharmacokinetic and toxicity evaluations, conducted using SwissADME and pkCSM, highlighted luteolin's favorable drug-like properties, including good bioavailability and low toxicity. These findings suggest that luteolin may serve as a promising multi-target therapeutic agent for AD and GBM by modulating key pathological pathways.

CONCLUSION: The present study provides a strong computational foundation for further in vitro and in vivo validation. The results highlight the potential of luteolin in developing dual-target treatment strategies for neurodegenerative and oncological disorders, offering new avenues for therapeutic advancements.

RevDate: 2025-03-27

Lithgow BJ, Saha C, Dastgheib Z, et al (2025)

Surface Versus Penetrative rTMS Stimulation May Be More Effective for AD Patients with Cerebrovascular Disease.

Neuroscience insights, 20:26331055251328355.

Repetitive Transcranial Magnetic Stimulation (rTMS) has been applied as an investigational therapy for Alzheimer's Disease (AD). The recent largest (N = 135) double-blind study with 6 months post-treatment follow-up investigating rTMS efficacy as a treatment for AD found about 72% of participants in each group of active and sham were positively responsive to rTMS (using Magstim AirFilm active and sham coils). Since the used sham coil produced about 25.3% of the peak active stimulus, it was hypothesized it could evoke a measurable response in AD patients. This study looks at the details of the above study's sham responses to determine why and how such a response might occur and how cerebrovascular symptomatology may have impacted that response. In the above-mentioned study, 90 and 45 patients were randomly assigned to active and sham groups, respectively. Those with modified Hachinski Ischemic Scores (HIS) below and above 2 were labeled AD2 and ADcvd2, respectively. Analysis of the primary outcome measure ADAS-Cog score change from baseline to post-treatment and follow-ups showed the ADcvd2 in the sham group had a significantly (p = .034) greater improvement or less decline at post-treatment and follow-up sessions compared to the ADcvd2 in the active group. Additionally, the improvement of the ADcvd2 sham compared to those in the active group persisted longer. Also, there was a significant (p = .036) improvement for AD2 individuals in the active compared to AD2 sham stimulation group at 2-months post-treatment. Overall, the sham rTMS stimulus did evoke a measurable response which was more effective for ADcvd2 in sham than ADcvd2 in active support of a vascular mechanism likely linked to the shallower sham stimulus penetration.

RevDate: 2025-03-27

Alanazi MM, Albaker AB, Alzaagi LA, et al (2025)

Oxytocin Protects PC12 Cells Against β-Amyloid-Induced Cell Injury.

Pharmaceuticals (Basel, Switzerland), 18(3): pii:ph18030390.

Background/Objectives: Neurodegenerative diseases, particularly Alzheimer's disease (AD), are characterized by progressive cognitive decline and non-cognitive symptoms that significantly affect health and quality of life. Beta-amyloid (Aβ) protein accumulation is a key factor in AD pathology, leading to neuronal damage. Oxytocin (OXT), a neuropeptide with neuroprotective potential, has garnered interest owing to its ability to mitigate neurotoxicity. We hypothesized that oxytocin could protect PC12 cells from Aβ-induced cytotoxicity through antioxidant effects and modulation of apoptotic pathways (i.e., mitochondrial and MAPK pathways). In this study, we aim to assess oxytocin's protective effects on cell viability, oxidative stress, mitochondrial function, and apoptotic signaling. Methods: PC12 cells were treated with Aβ25-35 and pre-treated with varying oxytocin concentrations to assess cell viability, reactive oxygen species (ROS) generation, and mitochondrial membrane potential. Western blotting was performed to analyze the effects on mitochondrial apoptosis and MAPK pathways. Results: Oxytocin treatment significantly improved cell viability in a dose-dependent manner and reduced Aβ-induced oxidative stress and mitochondrial dysfunction. Oxytocin-treated groups exhibited decreased ROS levels, increased mitochondrial membrane potential, and modulation of apoptosis-related proteins. Oxytocin upregulated phosphorylated ERK1/2 and Bcl-2 while downregulating BAX and caspase-3, reducing the BAX/Bcl-2 ratio. Conclusions: Oxytocin effectively protects PC12 cells from Aβ-induced neurotoxicity, highlighting its potential as a therapeutic agent for AD. Further research is needed to clarify oxytocin's mechanisms and clinical implications in AD treatment.

RevDate: 2025-03-27

Pérez Aguilar RDC, Rodríguez Salgado T, Cruz-Miranda OL, et al (2025)

Huperzine A Production and Acetylcholinesterase Inhibition by Phlegmariurus taxifolius Cell Suspension Culture: A Comparative Study in Flasks and an Airlift Bioreactor.

Pharmaceuticals (Basel, Switzerland), 18(3): pii:ph18030383.

Background: The callus cultures from the fronds of the lycophyte Phlegmariurus taxifolius produce the huperzine A (HupA) alkaloid, which is used in Alzheimer's disease treatment. This study aimed to establish the growth kinetics and HupA production by the newly HupS21 cell line grown in 250 mL flasks and in a 2 L airlift bioreactor. Methods: Batch-type kinetics were carried out for 60 days in 250 mL flasks and for 20 days in a 2 L airlift bioreactor. Measurements of dry weight (DW), specific growth rate (μ), doubling time (dt), pH, carbohydrate consumption, and HupA quantification were performed. The acetylcholinesterase (AChE) inhibitory assay of the HupS21 alkaloidal extract was determined. Results: The 250 mL flasks kinetic reached a maximum cell growth of 8.17 g/L DW, with a μ of 0.045 day[-1] and a dt of 15.40 days. The maximum HupA production was of 2.03 μg/g DW at day 45. In the 2 L airlift reactor, a maximum growth of 16.70 g/L DW, a μ of 0.062 day[-1], a dt of 11.20 days, and HupA production of 2.48 μg/g DW at day 15 were obtained. The alkaloidal extract from the HupS21 cell line at 100 μg/mL showed an AChE inhibitory activity of 85.6 ± 1.27%. Conclusions: The airlift reactor outperformed the flask cultures in maximum cell growth, specific growth rate, doubling time, and HupA production. To our knowledge, this research is the first report on the establishment of suspension cell cultures of P. taxifolius in shaken flasks and in an airlift bioreactor, providing a foundation for scaling up HupA production for pharmaceutical use.

RevDate: 2025-03-27

Tsimpili H, G Zoidis (2025)

A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.

Pharmaceuticals (Basel, Switzerland), 18(3): pii:ph18030369.

The cholinergic pathways in the central nervous system (CNS) play a pivotal role in different cognitive functions of the brain, such as memory and learning. This review takes a dive into the pharmacological side of this important part of CNS function, taking into consideration muscarinic receptors and cholinesterase enzymes. Targeting a specific subtype of five primary muscarinic receptor subtypes (M1-M5) through agonism or antagonism may benefit patients; thus, there is a great pharmaceutical research interest. Inhibition of AChE and BChE, orthosteric or allosteric, or partial agonism of M1 mAChR are correlated with Alzheimer's disease (AD) symptoms improvement. Agonism or antagonism on different muscarinic receptor subunits may lessen schizophrenia symptoms (especially positive allosteric modulation of M4 mAChR). Selective antagonism of M4 mAChR is a promising treatment for Parkinson's disease and dystonia, and the adverse effects are limited compared to inhibition of all five mAChR. Additionally, selective M5 antagonism plays a role in drug independence behavior. M3 mAChR overexpression is associated with malignancies, and M3R antagonists seem to have a therapeutic potential in cancer, while M1R and M2R inhibition leads to reduction of neoangiogenesis. Depending on the type of cancer, agonism of mAChR may promote cancer cell proliferation (as M3R agonism does) or protection against further tumor development (M1R agonism). Thus, there is an intense need to discover new potent compounds with specific action on muscarinic receptor subtypes. Chemical structures, chemical modification of function groups aiming at action enhancement, reduction of adverse effects, and optimization of Drug Metabolism and Pharmacokinetics (DMPK) will be further discussed, as well as protein-ligand docking.

RevDate: 2025-03-27

Zou Y, Zhang J, Chen L, et al (2025)

Targeting Neuroinflammation in Central Nervous System Diseases by Oral Delivery of Lipid Nanoparticles.

Pharmaceutics, 17(3): pii:pharmaceutics17030388.

Neuroinflammation within the central nervous system (CNS) is a primary characteristic of CNS diseases, such as Parkinson's disease, Alzheimer's disease (AD), amyotrophic lateral sclerosis, and mental disorders. The excessive activation of immune cells results in the massive release of pro-inflammatory cytokines, which subsequently induce neuronal death and accelerate the progression of neurodegeneration. Therefore, mitigating excessive neuroinflammation has emerged as a promising strategy for the treatment of CNS diseases. Despite advancements in drug discovery and the development of novel therapeutics, the effective delivery of these agents to the CNS remains a serious challenge due to the restrictive nature of the blood-brain barrier (BBB). This underscores the need to develop a novel drug delivery system. Recent studies have identified oral lipid nanoparticles (LNPs) as a promising approach to efficiently deliver drugs across the BBB and treat neurological diseases. This review aims to comprehensively summarize the recent advancements in the development of LNPs designed for the controlled delivery and therapeutic modulation of CNS diseases through oral administration. Furthermore, this review addresses the mechanisms by which these LNPs overcome biological barriers and evaluate their clinical implications and therapeutic efficacy in the context of oral drug delivery systems. Specifically, it focuses on LNP formulations that facilitate oral administration, exploring their potential to enhance bioavailability, improve targeting precision, and alleviate or manage the symptoms associated with a range of CNS diseases.

RevDate: 2025-03-27

Tew VK, Barathan M, Nordin F, et al (2025)

Emerging Role of Mesenchymal Stromal Cell and Exosome Therapies in Treating Cognitive Impairment.

Pharmaceutics, 17(3): pii:pharmaceutics17030284.

Cognitive aging, characterized by the gradual decline in cognitive functions such as memory, attention, and problem-solving, significantly impacts daily life. This decline is often accelerated by neurodegenerative diseases, particularly Alzheimer's Disease (AD) and Parkinson's Disease (PD). AD is marked by the accumulation of amyloid-beta plaques and tau tangles, whereas PD involves the degeneration of dopaminergic neurons. Both conditions lead to severe cognitive impairment, greatly diminishing the quality of life for affected individuals. Recent advancements in regenerative medicine have highlighted mesenchymal stromal cells (MSCs) and their derived exosomes as promising therapeutic options. MSCs possess regenerative, neuroprotective, and immunomodulatory properties, which can promote neurogenesis, reduce inflammation, and support neuronal health. Exosomes, nanosized vesicles derived from MSCs, provide an efficient means for delivering bioactive molecules across the blood-brain barrier, targeting the underlying pathologies of AD and PD. While these therapies hold great promise, challenges such as variability in MSC sources, optimal dosing, and effective delivery methods need to be addressed for clinical application. The development of robust protocols, along with rigorous clinical trials, is crucial for validating the safety and efficacy of MSC and exosome therapies. Future research should focus on overcoming these barriers, optimizing treatment strategies, and exploring the integration of MSC and exosome therapies with lifestyle interventions. By addressing these challenges, MSC- and exosome-based therapies could offer transformative solutions for improving outcomes and enhancing the quality of life for individuals affected by cognitive aging and neurodegenerative diseases.

RevDate: 2025-03-27

Lei K, Zhou L, Dan M, et al (2025)

Trojan Horse Delivery Strategies of Natural Medicine Monomers: Challenges and Limitations in Improving Brain Targeting.

Pharmaceutics, 17(3): pii:pharmaceutics17030280.

Central nervous system (CNS) diseases, such as brain tumors, Alzheimer's disease, and Parkinson's disease, significantly impact patients' quality of life and impose substantial economic burdens on society. The blood-brain barrier (BBB) limits the effective delivery of most therapeutic drugs, especially natural products, despite their potential therapeutic effects. The Trojan Horse strategy, using nanotechnology to disguise drugs as "cargo", enables them to bypass the BBB, enhancing targeting and therapeutic efficacy. This review explores the applications of natural products in the treatment of CNS diseases, discusses the challenges posed by the BBB, and analyzes the advantages and limitations of the Trojan Horse strategy. Despite the existing technical challenges, future research is expected to enhance the application of natural drugs in CNS treatment by integrating nanotechnology, improving delivery mechanisms, and optimizing targeting characteristics.

RevDate: 2025-03-27

Sundararaman L, Gouda D, Kumar A, et al (2025)

Glucagon-like Peptide-1 Receptor Agonists: Exciting Avenues Beyond Weight Loss.

Journal of clinical medicine, 14(6): pii:jcm14061978.

The last two decades have proffered many remarkable choices in managing type 1 and type 2 diabetes mellitus. Leading the list are glucagon-like peptide-1 receptor agonists (GLP1RAs), the first of which, exenatide, was approved by the FDA in 2005. Two other major classes of drugs have also entered the market: dipeptidyl peptidase-4 (DPP-4) inhibitors, commonly known as gliptins and approved in 2006, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, with the first approval occurring in 2013. These drugs have revolutionized the treatment of diabetes. Additionally, on the horizon, the once-weekly basal insulin analog insulin icodec and the once-weekly combination of insulin icodec and semaglutide are expected to be available in the future. Beyond glycemic control, GLP1RAs have exhibited benefits in conditions associated with diabetes, including hypertension, dyslipidemia, non-alcoholic steatohepatitis, as well as in neurodegenerative diseases such as Alzheimer's disease. Additionally, emerging research suggests potential roles in certain types of cancer, infertility, and associative learning. Major cardiovascular events seem to be lower in patients on GLP1RAs. While some evidence is robust, other findings remain tenuous. It is important that clinicians are familiar with current research in order to provide optimal evidence-based care to patients. In the not-too-distant future, there may be a case to prescribe these drugs for benefits outside diabetes.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Palacino F, Manganotti P, A Benussi (2025)

Targeting Neural Oscillations for Cognitive Enhancement in Alzheimer's Disease.

Medicina (Kaunas, Lithuania), 61(3): pii:medicina61030547.

Alzheimer's disease (AD), the most prevalent form of dementia, is marked by progressive cognitive decline, affecting memory, language, orientation, and behavior. Pathological hallmarks include extracellular amyloid plaques and intracellular tau tangles, which disrupt synaptic function and connectivity. Neural oscillations, the rhythmic synchronization of neuronal activity across frequency bands, are integral to cognitive processes but become dysregulated in AD, contributing to network dysfunction and memory impairments. Targeting these oscillations has emerged as a promising therapeutic strategy. Preclinical studies have demonstrated that specific frequency modulations can restore oscillatory balance, improve synaptic plasticity, and reduce amyloid and tau pathology. In animal models, interventions, such as gamma entrainment using sensory stimulation and transcranial alternating current stimulation (tACS), have shown efficacy in enhancing memory function and modulating neuroinflammatory responses. Clinical trials have reported promising cognitive improvements with repetitive transcranial magnetic stimulation (rTMS) and deep brain stimulation (DBS), particularly when targeting key hubs in memory-related networks, such as the default mode network (DMN) and frontal-parietal network. Moreover, gamma-tACS has been linked to increased cholinergic activity and enhanced network connectivity, which are correlated with improved cognitive outcomes in AD patients. Despite these advancements, challenges remain in optimizing stimulation parameters, individualizing treatment protocols, and understanding long-term effects. Emerging approaches, including transcranial pulse stimulation (TPS) and closed-loop adaptive neuromodulation, hold promise for refining therapeutic strategies. Integrating neuromodulation with pharmacological and lifestyle interventions may maximize cognitive benefits. Continued interdisciplinary efforts are essential to refine these approaches and translate them into clinical practice, advancing the potential for neural oscillation-based therapies in AD.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Singh AA, Khan F, M Song (2025)

Biofilm-Associated Amyloid Proteins Linked with the Progression of Neurodegenerative Diseases.

International journal of molecular sciences, 26(6): pii:ijms26062695.

Biofilm-associated amyloid proteins have emerged as significant contributors to the progression of neurodegenerative diseases, representing a complex intersection of microorganisms and human health. The cross-beta sheet structure characteristic of amyloids produced by gut-colonizing bacteria remains intact, crucial for the resilience of biofilms. These amyloids exacerbate neurodegenerative disorders such as Alzheimer's and Parkinson's by cross-seeding human amyloidogenic proteins like amyloid-beta and α-synuclein, accelerating their misfolding and aggregation. Despite molecular chaperones and heat shock proteins maintaining protein homeostasis, bacterial amyloids can overwhelm them, worsening neuronal damage. Genetic variations in chaperone genes further influence amyloidogenesis and neurodegeneration. Persistent bacterial infections and inflammation compromise the blood-brain barrier, allowing inflammatory molecules and amyloids to enter the brain, perpetuating the cycle of neurodegeneration. The gut-brain axis underscores the impact of dysbiosis and gut microbiota on brain function, potentially contributing to neurodegeneration. The enhancement of biofilm resilience and antibiotic resistance by functional amyloid fibrils complicates the treatment landscape. The interplay among chaperone systems, microbial amyloids, and neurodegenerative diseases underscores the urgent need for advanced treatment strategies targeting these pathways to attenuate disease progression. Understanding the processes that relate biofilm-associated amyloids to the onset of neurological disorders is critical for diagnosing and developing novel treatment strategies.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Muramoto S, Shimizu S, Shirakawa S, et al (2025)

Noradrenaline Synergistically Enhances Porphyromonas gingivalis LPS and OMV-Induced Interleukin-1β Production in BV-2 Microglia Through Differential Mechanisms.

International journal of molecular sciences, 26(6): pii:ijms26062660.

Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer's disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1β (IL-1β) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30-1000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1β up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 μg/mL) and OMVs (150 μg of protein/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the β2 adrenergic receptor (Aβ2R)-mediated pathway. NF-κB, which is activated by the Pg LPS/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1β production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-κB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-κB p65 to the IκB site, resulting in the synergistic augmentation of the IL-1β promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9/p52/RelB-mediated pathway. The Aβ2R/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1β in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1β in response to Pg LPS and OMVs through distinct mechanisms.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Fang X, Border JJ, Zhang H, et al (2025)

A Soluble Epoxide Hydrolase Inhibitor Improves Cerebrovascular Dysfunction, Neuroinflammation, Amyloid Burden, and Cognitive Impairments in the hAPP/PS1 TgF344-AD Rat Model of Alzheimer's Disease.

International journal of molecular sciences, 26(6): pii:ijms26062433.

Alzheimer's disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We recently reported that SNPs in soluble epoxide hydrolase (sEH) are linked to AD in human genetic studies and that long-term administration of an sEH inhibitor attenuated cerebral vascular and cognitive dysfunction in a rat model of AD. However, the mechanisms linking changes in cerebral vascular function and neuroprotective actions of sEH inhibitors in AD remain to be determined. This study investigated the effects of administration of an sEH inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood-brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP/PS1 TgF344-AD rat model of AD. We observed predominant β-amyloid accumulation in the brains of 9-10-month-old AD rats and that TPPU treatment for three months reduced amyloid burden. The functional hyperemic response to whisker stimulation was attenuated in AD rats, and TPPU normalized the response. The sEH inhibitor, TPPU, mitigated capillary rarefaction, BBB leakage, and activation of astrocytes and microglia in AD rats. TPPU increased the expression of pre- and post-synaptic proteins and reduced loss of hippocampal neurons and cognitive impairments in the AD rats, which was confirmed in a transcriptome and GO analysis. These results suggest that sEH inhibitors could be a novel therapeutic strategy for AD.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Wang K, Adjeroh DA, Fang W, et al (2025)

Comparison of Deep Learning and Traditional Machine Learning Models for Predicting Mild Cognitive Impairment Using Plasma Proteomic Biomarkers.

International journal of molecular sciences, 26(6): pii:ijms26062428.

Mild cognitive impairment (MCI) is a clinical condition characterized by a decline in cognitive ability and progression of cognitive impairment. It is often considered a transitional stage between normal aging and Alzheimer's disease (AD). This study aimed to compare deep learning (DL) and traditional machine learning (ML) methods in predicting MCI using plasma proteomic biomarkers. A total of 239 adults were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort along with a pool of 146 plasma proteomic biomarkers. We evaluated seven traditional ML models (support vector machines (SVMs), logistic regression (LR), naïve Bayes (NB), random forest (RF), k-nearest neighbor (KNN), gradient boosting machine (GBM), and extreme gradient boosting (XGBoost)) and six variations of a deep neural network (DNN) model-the DL model in the H2O package. Least Absolute Shrinkage and Selection Operator (LASSO) selected 35 proteomic biomarkers from the pool. Based on grid search, the DNN model with an activation function of "Rectifier With Dropout" with 2 layers and 32 of 35 selected proteomic biomarkers revealed the best model with the highest accuracy of 0.995 and an F1 Score of 0.996, while among seven traditional ML methods, XGBoost was the best with an accuracy of 0.986 and an F1 Score of 0.985. Several biomarkers were correlated with the APOE-ε4 genotype, polygenic hazard score (PHS), and three clinical cerebrospinal fluid biomarkers (Aβ42, tTau, and pTau). Bioinformatics analysis using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) revealed several molecular functions and pathways associated with the selected biomarkers, including cytokine-cytokine receptor interaction, cholesterol metabolism, and regulation of lipid localization. The results showed that the DL model may represent a promising tool in the prediction of MCI. These plasma proteomic biomarkers may help with early diagnosis, prognostic risk stratification, and early treatment interventions for individuals at risk for MCI.

RevDate: 2025-03-27
CmpDate: 2025-03-27

Pilotto A, Carini M, Bresciani R, et al (2025)

Next Generation Sequencing Analysis in Patients Affected by Parkinson's Disease and Correlation Between Genotype and Phenotype in Selected Clinical Cases.

International journal of molecular sciences, 26(6): pii:ijms26062397.

Parkinson's Disease (PD) is the most frequent movement disorder and is second only to Alzheimer's Disease as the most frequent neurodegenerative pathology. Early onset Parkinson's disease (EOPD) is less common and may be characterized by genetic predisposition. NGS testing might be useful in the diagnostic assessment of these patients. A panel of eight genes (SNCA, PRKN, PINK1, DJ1, LRRK2, FBXO7, GBA1 and HFE) was validated and used as a diagnostic tool. A total of 38 in sequence EOPD patients of the Parkinson's Disease Unit of our Hospital Institution were tested. In addition, the number of the hexanucleotide repeats of the C9ORF72 gene and the frequency of main HFE mutations were evaluated. Six patients were carriers of likely pathogenic mutations in heterozygosity in the analyzed genes, one of them presented mutations in association and another had a complex genetic background. Their clinical symptoms were correlated with their genotypes. In the cohort of patients, only the p.Cys282Tyr of HFE was significantly decreased in the dominant model and allele contrast comparison. Only one patient with one allele of C9ORF72 containing 10 repeats was identified and clinically described. The clinical signs of sporadic and monogenic PD are often very similar; for this reason, it is fundamental to correlate genotypes and phenotypes, as we tried to describe here, to better classify PD patients with the aim to deepen our knowledge in the molecular mechanisms involved and collaborate in reaching a personalized management and treatment.

RevDate: 2025-03-27

Azarfar K, Decourt B, Sanchez Camacho B, et al (2025)

Cholesterol-modifying strategies for alzheimer disease: promise or fallacy?.

Expert review of neurotherapeutics [Epub ahead of print].

INTRODUCTION: As the world population ages, Alzheimer disease (AD) prevalence increases. However, understanding of AD etiology continues to evolve, and the pathophysiological processes involved are only partially elucidated. One compound suspected to play a role in the development and progression of AD is cholesterol. Several lines of evidence support this connection, yet it remains unclear whether cholesterol-modifying strategies have potential applications in the clinical management of AD.

AREAS COVERED: A deep literature search using PubMed was performed to prepare this narrative review. The literature search, performed in early 2024, was inclusive of literature from 1990 to 2024. After providing an overview of cholesterol metabolism, this study summarizes key preclinical studies that have investigated cholesterol-modifying therapies in laboratory models of AD. It also summarizes past and current clinical trials testing specific targets modulated by anti-cholesterol therapies in AD patients.

EXPERT OPINION: Based on current epidemiological and mechanistic studies, cholesterol likely plays a role in AD etiology. The use of cholesterol-modifying therapies could be a promising treatment approach if administered at presymptomatic to early AD phases, but it is unlikely to be efficient in mild, moderate, and late AD stages. Several recommendations are provided for hypercholesterolemia management in AD patients.

RevDate: 2025-03-27

Kalokhe VM, Simran S, Ahmad A, et al (2025)

Unveiling Gaps and Demographic Influences in Alzheimer's Therapy: A Data-Centric Study of FDA-Approved Late-Phase Clinical Trials.

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology [Epub ahead of print].

BACKGROUND: Alzheimer's disease is more prevalent in women than in men. In this study, the author examined the U.S. Food and Drug Administration (FDA) completed phase 4 clinical trials associated with Alzheimer's. The research aims to evaluate the women's participation-to-prevalence ratio (PPR) for Alzheimer's disease.

METHOD: Using the FDA's publicly available clinical trial database, 45 Phase 4 Alzheimer's trials from 2003 to 2019 were assessed. Further, the total PPR and yearly PPR value are calculated by dividing the percentage of women in clinical trials by the total percentage of women affected by Alzheimer's disease. The PPR value equal to 1 showcases the balanced participation of females in the Phase 4 clinical trial and the diseased affected population.

RESULT: Out of 45 trials, 41 were completed and four were terminated. The gender data was unavailable for three trials. In 38 clinical trials associated with Alzheimer's disease, 4502 participants were enrolled. Among 4502, 2604 (57.84%) were found to be female and 1898 (42.15%) were male. The PPR for women was 0.80, reflecting an adequate representation of women participants in late-phase clinical trials. The yearly PPR reduction has been seen in female participants.

CONCLUSION: In the year-based PPR, the range was from 0.72-1.0. In the initial year, the range was 1, which was reduced to 0.72 in 2007. In total, 38 completed clinical trials, 18 trials used placebo treatment, and the gender ratio in placebo was adequate. More transparency is essential in gender concerning SAE in publicly available databases.

RevDate: 2025-03-26

Koyama G, Nakano M, Takata T, et al (2025)

Reversible dementia due to hyperthyroidism: Cognitive impairment, delusions, and agitation resolved with antithyroid treatment.

RevDate: 2025-03-26

Yu T, Wei Z, Wang J, et al (2025)

Ginkgo biloba Extract GBE50 ameliorates cerebrovascular dysfunction and cognitive impairment in a mouse model of Alzheimer's disease.

Phytomedicine : international journal of phytotherapy and phytopharmacology, 141:156646 pii:S0944-7113(25)00286-7 [Epub ahead of print].

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder in which neurovascular unit (NVU) dysfunction plays a critical role. GBE50, a refined extract of Ginkgo biloba containing over 50 % total flavonoids and terpene lactones, is widely used in the clinical prevention and treatment of cardiovascular and cerebrovascular diseases due to its anti-platelet aggregation, anti-inflammatory, and antioxidant properties. However, its specific effects on NVU integrity and cerebrovascular function in AD remain unclear.

PURPOSE: This study aims to investigate the therapeutic effects of GBE50 on NVU integrity and cognitive impairment in an AD mouse model.

METHODS: APP/PS1 transgenic mice were treated with GBE50 via intragastric administration for 10 weeks. Cognitive performance was assessed through behavioral tests, while the structural and functional integrity of the NVU was evaluated using immunofluorescence, laser speckle imaging, and in vivo multi-photon imaging. Furthermore, target prediction and transcriptomic analyses were conducted to uncover potential molecular mechanisms and identify specific targets of GBE50.

RESULTS: GBE50 treatment significantly alleviated cognitive deficits in APP/PS1 mice. It enhanced cerebrovascular structure and function by increasing vessel density, diameter, and branching, leading to improved cerebral blood flow (CBF). GBE50 also restored NVU components such as endothelial cells, astrocytes, and pericytes, promoted parenchyma and perivascular Aβ clearance, and reduced neuroinflammation. Bioinformatics and transcriptomic analyses revealed that GBE50 exerted its effects by regulating pathways related to vascular repair, neuroprotection, and Aβ clearance.

CONCLUSION: The findings demonstrate that GBE50 improves cognitive dysfunction in AD by restoring NVU integrity and cerebrovascular function through multi-target mechanisms. This study highlights the potential of GBE50 as a promising therapeutic approach for AD and other neurodegenerative diseases involved in cerebrovascular dysfunction.

RevDate: 2025-03-26

Walsh AE, JR Lukens (2025)

Harnessing microglia-based cell therapies for the treatment of neurodegenerative diseases.

Current opinion in immunology, 94:102552 pii:S0952-7915(25)00028-7 [Epub ahead of print].

Given the growing evidence linking microglia to the onset and progression of various neurodegenerative diseases, these brain-resident macrophages have emerged as a promising cell type for targeted therapeutic interventions. This review highlights recent studies that utilized innovative, microglia-focused strategies for the treatment of diverse neurodegenerative disorders including lysosomal storage disorders, granulin frontotemporal dementia, and Alzheimer's disease. Cutting-edge therapeutic strategies range from replacing faulty microglia with peripheral macrophage precursors or induced human pluripotent stem cell-derived microglia to engineering microglia that target toxic aggregates or deliver remediating payloads. We also examine the potential limitations as well as the clinical benefits of these strategies.

RevDate: 2025-03-26
CmpDate: 2025-03-26

Sillapakong P, Wakabayashi T, K Suzuki (2025)

Naturido alleviates amyloid β1-42-induced adverse effects in a transgenic Caenorhabditis elegans model of Alzheimer's disease.

PloS one, 20(3):e0320636 pii:PONE-D-24-54123.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily associated with aging. While the amyloid hypothesis is not the only explanation for AD pathogenesis, it is widely recognized that the accumulation of amyloid β (Aβ) protein triggers pathological changes in the brains of patients. In a previous study, we showed that Naturido, a cyclic peptide derived from the medicinal fungus (Isaria japonica) grown on domestic silkworms (Bombyx mori), could reverse several age-related deficits in senescence-accelerated mice. In this study, we explored the potential of Naturido to reduce Aβ-related toxicity in transgenic Caenorhabditis elegans models of AD, where human Aβ1-42 protein is overexpressed in neurons. Our results demonstrated that Naturido administration alleviated various phenotypes, including Aβ-induced impairment in associative learning, serotonin hypersensitivity, and locomotion in the transgenic C. elegans. These findings suggest the potential of Naturido as a candidate molecule for the prevention and/or treatment of AD.

RevDate: 2025-03-26
CmpDate: 2025-03-26

Liu H, Zhou J, WW Yang (2025)

Etomidate ameliorates Alzheimer-like neuropathology and cognitive impairment in APP/PS1 mice.

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 76(1):.

To investigate the effect and mechanism of etomidate on attenuating Alzheimer-like neuropathology and cognitive impairment in mice with Alzheimer's disease (AD). AD was modeled in vivo using amyloid precursor protein/presenilin 1 (APP/PS1) mice. After etomidate treatment, behavioral experiments and histopathological observation of hippocampus were performed. Hippocampal Aβ deposition was detected using immunofluorescence. AD was modeled in vitro using a HT22 cells which are an immortalized cell line derived from primary mouse hippocampal neurons induced by Aβ1-42. Cell viability, apoptosis rate and LDH release were detected after etomidate intervention. Synaptic proteins were detected by mmunofluorescence or Western blot, and neurotransmitters and inflammatory factors were detected by ELISA. Etomidate improved the memory ability, novel object cognition ability, and spatial learning of APP/PS1 mice. The improvement of cognitive function and memory ability may be due to the recovery effect of etomidate on hippocampal pathological changes in APP/PS1 mice, including reducing Aβ deposition, neuron and synaptic loss. Etomidate also regulated neuroinflammation and the release of neurotransmitters GABA and 5-HT in APP/PS1 mice. Etomidate effectively reversed Aβ1-42-induced hippocampal neuronal damage, which was reflected in the improvement of cell viability and the inhibition of cytotoxicity, apoptosis and pro-inflammatory factors. Etomidate reversed the inhibition of the expression of synaptophysin (SYP) and postsynaptic density protein-95 (PSD-95) induced by Aβ1-42 in vitro. After etomidate intervention, the expression of serotonin 1A receptor (5HT1A) and gamma-aminobutyric acid type A receptor subunit alpha1 (GABRA1) in Aβ1-42-injured HT22 cells were up-regulated, and free calcium ion was increased. In conclusion, etomidate ameliorates Alzheimer-like neuropathology and cognitive impairment in APP/PS1 mice, indicating that etomidate may be a potentially useful drug for the treatment of AD.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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