Therapeutic Strategy For Alzheimer's Disease Research Articles

EBP1 potentiates amyloid β pathology by regulating γ-secretase.

The abnormal deposition of amyloid β (Aβ), produced by proteolytic cleavage events of amyloid precursor protein involving the protease γ-secretase and subsequent polymerization into amyloid plaques, plays a key role in the neuropathology of Alzheimer's disease (AD). Here we show that ErbB3 binding protein 1 (EBP1)/proliferation-associated 2G4 (PA2G4) interacts with presenilin, a catalytic subunit of γ-secretase, inhibiting Aβ production. Mice lacking forebrain Ebp1/Pa2g4 recapitulate the representative phenotypes of late-onset sporadic AD, displaying an age-dependent increase in Aβ deposition, amyloid plaques and cognitive dysfunction. In postmortem brains of patients with AD and 5x-FAD mice, we found that EBP1 is proteolytically cleaved by asparagine endopeptidase at N84 and N204 residues, compromising its inhibitory effect on γ-secretase, increasing Aβ aggregation and neurodegeneration. Accordingly, injection of AAV2-Ebp1 wild-type or an asparagine endopeptidase-uncleavable mutant into the brains of 5x-FAD mice decreased Aβ generation and alleviated the behavioral impairments. Thus, our study suggests that EBP1 acts as an inhibitor of γ-secretase on amyloid precursor protein cleavage and preservation of functional EBP1 could be a therapeutic strategy for AD.

Therapeutic potential of hydrogen-rich water in zebrafish model of Alzheimer's disease: targeting oxidative stress, inflammation, and the gut-brain axis.

Alzheimer's disease (AD) is a complex neurodegenerative disorder, with amyloid-beta (Aβ) aggregation playing a key role in its pathogenesis. Aβ-induced oxidative stress leads to neuronal damage, mitochondrial dysfunction, and apoptosis, making antioxidative strategies promising for AD treatment. This study investigates the effects of hydrogen-rich water (HRW) in a zebrafish AD model. Zebrafish were exposed to aluminum chloride to induce AD-like pathology and then treated with HRW using a nanobubble device. Behavioral assays, ELISA, Hematoxylin-eosin (H&E) staining, and reactive oxygen species (ROS) and neutrophil fluorescence labeling were employed to assess HRW's impact. Additionally, 16S rRNA sequencing analyzed HRW's effect on gut microbiota. HRW can significantly improve cognitive impairment and depression-like behavior in zebrafish AD model, reduce Aβ deposition (p < 0.0001), regulate liver Soluble epoxide hydrolase (sEH) levels (p < 0.05), reduce neuroinflammation, and reduce oxidative stress. Furthermore, HRW reduced the number of harmful bacteria linked to AD pathology by restoring the balance of microbiota in the gut. These findings suggest that HRW has potential as a therapeutic strategy for AD by targeting oxidative stress, inflammation, and gut-brain axis modulation.

Unsaturated Fatty Acids Are Decreased in Aβ Plaques in Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Aβ) plaques in the brain, contributing to neurodegeneration. This study investigates lipid alterations within these plaques using a novel, label-free, multimodal approach. Combining infrared (IR) imaging, machine learning, laser microdissection (LMD), and flow injection analysis mass spectrometry (FIA-MS), we provide the first comprehensive lipidomic analysis of chemically unaltered Aβ plaques in post-mortem human AD brain tissue. IR imaging revealed decreased lipid unsaturation within plaques, evidenced by a reduction in the alkene (=C-H) stretching vibration band. The high spatial resolution of IR imaging, coupled with machine learning-based plaque detection, enabled precise and label-free extraction of plaques via LMD. Subsequent FIA-MS analysis confirmed a significant increase in short-chain saturated lipids and a concomitant decrease in long-chain unsaturated lipids within plaques compared to the surrounding tissue. These findings highlight a substantial depletion of unsaturated fatty acids (UFAs) in Aβ plaques, suggesting a pivotal role for lipid dysregulation and oxidative stress in AD pathology. This study advances our understanding of the molecular landscape of Aβ plaques and underscores the potential of lipid-based therapeutic strategies in AD.

Multi-target-directed therapeutic strategies for Alzheimer's disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition.

Alzheimer's disease (AD) is the most prevalent neurodegenerative dementia, marked by progressive cognitive decline and memory impairment. Despite advances in therapeutic research, single-target-directed treatments often fall short in addressing the complex, multifactorial nature of AD. This arises from various pathological features, including amyloid-β (Aβ) aggregate deposition, metal ion dysregulation, oxidative stress, impaired neurotransmission, neuroinflammation, mitochondrial dysfunction, and neuronal cell death. This review illustrates their interrelationships, with a particular emphasis on the interplay among Aβ, metal ions, and AD-related enzymes, such as β-site amyloid precursor protein cleaving enzyme 1 (BACE1), matrix metalloproteinase 9 (MMP9), lysyl oxidase-like 2 (LOXL2), acetylcholinesterase (AChE), and monoamine oxidase B (MAOB). We further underscore the potential of therapeutic strategies that simultaneously inhibit Aβ aggregation and address other pathogenic mechanisms. These approaches offer a more comprehensive and effective method for combating AD, overcoming the limitations of conventional therapies.

Prospective use of miRNAs as biomarkers in the diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is the leading cause of dementia in the aging population. Pathogenic processes related to the accumulation of amyloid plaques (Aβ) and intracellular neurofibrillary tangles (NFTs) begin during the asymptomatic stage long before the onset of deterioration in cognitive functions and neurodegeneration, which makes rapid diagnosis and treatment difficult. Although biochemical diagnostic markers isolated from the body fluids of AD patients are currently used, scientists are engaged in research into molecular biomarkers that will significantly accelerate the diagnosis long before the first clinical symptoms appear. The research presented here focused on microRNAs (miRNAs), small, non-coding RNA molecules that are involved in the regulation of the post-transcriptional expression of many genes. A review of the literature revealed that miRNAs play an important role in regulating the expression of genes involved in the pathophysiological mechanisms of AD. Changes in the levels of miRNAs in a patient's body fluids can be used for rapid diagnosis. Original scientific articles published between 2014 and 2023 describing clinical and experimental studies on the role and expression levels of various miRNAs were selected from scientific databases such as PubMed, NCBI, Science Direct, and Google Scholar. The selected miRNAs were divided into 2 groups based on their expression level in AD: those with increased expression and those with decreased expression. A review of the latest scientific reports confirms that miRNAs may be a promising source of non-invasive and widely available biomarkers. Additionally, their modulation may prove to be an effective therapeutic strategy in AD.

The complex relationship between gut microbiota and Alzheimer's disease: A systematic review.

Alzheimer's disease (AD) is a progressive, degenerative disorder of the central nervous system. Despite extensive research conducted on this disorder, its precise pathogenesis remains unclear. In recent years, the microbiota-gut-brain axis has attracted considerable attention within the field of AD. The gut microbiota communicates bidirectionally with the central nervous system through the gut-brain axis, and alterations in its structure and function can influence the progression of AD. Consequently, regulating the gut microbiota to mitigate the progression of AD has emerged as a novel therapeutic approach. Currently, numerous studies concentrate on the intrinsic relationship between the microbiota-gut-brain axis and AD. In this paper, we summarize the multifaceted role of the gut microbiota in AD and present detailed therapeutic strategies targeting the gut microbiota, including the treatment of AD with Traditional Chinese Medicine (TCM), which has garnered increasing attention in recent years. Finally, we discuss potential therapeutic strategies for modulating the gut microbiota to alleviate the progression of AD, the current challenges in this area of research, and provide an outlook on future research directions in this field.

Recent advances in therapeutic strategies for Alzheimer's and Parkinson's disease using protein/peptide co‐modified polymer nanoparticles

Recent advances in therapeutic strategies for Alzheimer's and Parkinson's disease using protein/peptide co‐modified polymer nanoparticles

Vibrotactile stimulation at 40 Hz inhibits Aβ-induced changes in SH-SY5Y, BV2 cells, and pericytes

Alzheimer’s disease (AD) poses a major societal challenge, yet no definitive cure exists. Noninvasive brain stimulation methods, such as transcranial magnetic stimulation and transcranial direct current stimulation, have shown promise in alleviating cognitive symptoms associated with neurodegenerative disorders. This study investigated the effects of 40 Hz vibrotactile stimulation on AD-related cellular responses using SH-SY5Y neuroblastoma cells, primary human brain pericytes, and BV2 microglia. SH-SY5Y cells and brain pericytes treated with oligomeric beta-amyloid (Aβ) underwent 40 Hz vibrational stimulation for varying durations. Cell viability was determined via the CCK-8 assay, while intracellular calcium levels in pericytes were assessed. Protein expression was measured using western blotting, and gene expression was quantified via a real-time quantitative polymerase chain reaction. Detailed vibrational parameters were employed to ensure precise stimulation. Notably, 40 Hz vibrotactile stimulation improved cell viability in Aβ-exposed SH-SY5Y cells, reduced intracellular calcium ion (Ca2+) levels in Aβ-treated pericytes, activated autophagy, and mitigated tau hyperphosphorylation in SH-SY5Y cells. Additionally, it exhibited anti-neuroinflammatory properties in BV2 microglia. These findings highlight the potential of 40 Hz vibrotactile stimulation as a therapeutic strategy for AD.

Integrative analysis of single-nucleus RNA sequencing and Mendelian randomization to explore novel risk genes for Alzheimer's disease.

In this study, we aimed to delineate cellular heterogeneity in Alzheimer's disease (AD) and identify genetic markers contributing to its pathogenesis using integrative analysis of single-nucleus RNA sequencing (sn-RNA-Seq) and Mendelian randomization (MR). The dorsolateral prefrontal cortex sn-RNA-Seq dataset (GSE243292) was sourced from the Gene Expression Omnibus (GEO) database. Data preprocessing was conducted using the Seurat R software package, employing principal component analysis (PCA) and uniform manifold approximation and projection (UMAP) for cell clustering and annotation. MR analysis was used to identify instrumental variables from expression quantitative trait loci (eQTL) and GWAS data by applying inverse variance weighting (IVW), weighted median (WM) and MR-Egger methods. This was complemented by leave-one-out sensitivity analysis to validate the causal relationship on AD risk genes. We identified 23 distinct cell clusters, which were annotated into eight subgroups, including oligodendrocytes, oligodendrocyte precursors, astrocytes, macrophage cells, endothelial cells, glutamatergic neurons, neural stem cells, and neurons. Notably, the number of macrophages significantly increased in the AD group. Using genome-wide association study (GWAS) summaries and eQTL data, MR analysis identified causal relationships for 7 genes with significant impacts on AD risk. Among these genes, CACNA2D3, INPP5D, RBM47, and TBXAS1 were associated with a decreased risk of AD, whereas EPB41L2, MYO1F, and SSH2 were associated with an increased risk. A leave-one-out sensitivity analysis confirmed the robustness of these findings. Expression analysis revealed that these genes were variably expressed across different cell subgroups. Except for the CACNA2D3 gene, the other 6 genes showed increased expression levels in the macrophages, particularly EPB41L2 and SSH2. Our findings highlight the potential of specific genetic markers identified through integrative analysis of sn-RNA-Seq and MR in guiding the diagnosis and therapeutic strategies for Alzheimer's disease.

Altered immune response is associated with sex difference in vulnerability to Alzheimer's disease in human prefrontal cortex.

Alzheimer's disease (AD) is a neurodegenerative disorder with a higher risk incidence in females than in males, and there are also differences in AD pathophysiology between sexes. The role of sex in the pathogenesis of AD may be crucial, yet the cellular and molecular basis remains unclear. Here, we performed a comprehensive analysis using four public transcriptome datasets of AD patients and age-matched control individuals in prefrontal cortex, including bulk transcriptome (295 females and 402 males) and single-nucleus RNA sequencing (snRNA-seq) data (224 females and 219 males). We found that the transcriptomic profile in female control was similar to those in AD. To characterize the key features associated with both the pathogenesis of AD and sex difference, we identified a co-expressed gene module that positively correlated with AD, sex, and aging, and was also enriched with immune-associated pathways. Using snRNA-seq datasets, we found that microglia (MG), a resident immune cell in the brain, demonstrated substantial differences in several aspects between sexes, such as an elevated proportion of activated MG, altered transcriptomic profile and cell-cell interaction between MG and other brain cell types in female control. Additionally, genes upregulated in female MG, such as TLR2, MERTK, SPP1, SLA, ACSL1, and FKBP5, had high confidence to be identified as biomarkers to distinguish AD status, and these genes also interacted with some approved drugs for treatment of AD. These findings underscore the altered immune response in female is associated with sex difference in susceptibility to AD, and the necessity of considering sex factors when developing AD biomarkers and therapeutic strategies, providing a scientific basis for further in-depth studies on sex differences in AD.

Beyond Wolfram Syndrome 1: The WFS1 Gene's Role in Alzheimer's Disease and Sleep Disorders.

The WFS1 gene was first identified in Wolfram Syndrome 1 (WS1), a rare autosomal recessive genetic disorder characterized by severe and progressive neurodegenerative changes. WFS1's role in various cellular mechanisms, particularly in calcium homeostasis and the modulation of endoplasmic reticulum (ER) stress, suggests its potential involvement in the pathogenesis of Alzheimer's disease (AD) and sleep disorders. Because it is involved in maintaining ER balance, calcium signaling, and stress responses, WFS1 plays a multifaceted role in neuronal health. Numerous studies have shown that the absence or improper expression of WFS1 disrupts these cellular processes, leading to neurodegeneration and making neurons more vulnerable. In AD, WFS1 dysfunction is thought to contribute to the accumulation of amyloid-β (Aβ) plaques and tau tangles, thereby accelerating disease progression. Additionally, WFS1 plays an essential role in sleep regulation by influencing neuronal excitability and neurotransmitter release, which may explain the sleep disturbances frequently observed in neurodegenerative diseases. Due to its involvement in the pathological mechanisms of AD and sleep disorders, WFS1 is regarded as a potential early diagnostic marker for these diseases. Further research is required to fully elucidate WFS1's role in the cellular pathway, perhaps facilitating the development of new therapeutic strategies for Alzheimer's disease and sleep disorders.

Tyrosine modifications of insulin-degrading enzyme enable favorable control of substrate specificity for both Alzheimer’s disease and type-2 diabetes mellitus

Insulin-degrading enzyme (IDE) cleaves amyloid beta (Aβ), insulin, and other bioactive peptides. Because Aβ and insulin are closely related to Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM), respectively, IDE is a candidate drug target for treating both AD and T2DM. However, the activity of IDE has opposing effects, including decreasing AD risk by degrading Aβ and increasing T2DM risk by degrading insulin. The opposed substrate specificity is associated with the exo- and active sites containing Tyr314 and Tyr831 residues, the plausible modification targets for controlling substrate specificity. In this study, we used a tyrosine-specific modification regent, Cookson reagent (4-phenyl-1,2,4-triazoline-3,5-dione, PTAD), for IDE and examined the degradation activities on Aβ40 and insulin. Fifteen tyrosine residues, including Tyr314 and Tyr831, were modified by PTAD. After incubation with PTAD-modified IDE for 3 days, insulin remained intact, whereas Aβ40 was completely degraded. This favorable change of substrate specificity was also observed in the mixture of Aβ40 and insulin, suggesting that tyrosine modification of IDE might be a therapeutic strategy for AD and T2DM.

Targeting Epac2 and GluA3-containing AMPARs: a novel therapeutic strategy for Alzheimer’s disease

Targeting Epac2 and GluA3-containing AMPARs: a novel therapeutic strategy for Alzheimer’s disease

Positron Emission Tomography/Computed Tomography Imaging in Therapeutic Clinical Trials in Alzheimer's Disease: AnOverview of the Current State of the Artof Research.

The integration of positron emission tomography/computed tomography (PET/CT) has revolutionized the landscape of Alzheimer's disease (AD) research and therapeutic interventions. By combining structural and functional imaging, PET/CT provides a comprehensive understanding of disease pathology and response to treatment assessment. PET/CT, particularly with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG), facilitates the visualization of glucose metabolism in the brain, enabling early diagnosis, staging, and monitoring of neurodegenerative disease progression. The advent of amyloid and tau PET imaging has further propelled the field forward, offering invaluable tools for tracking pathological hallmarks, assessing treatment response, and predicting clinical outcomes. While some therapeutic interventions targeting amyloid plaque load showed promising results with the reduction of cerebral amyloid accumulation over time, others failed to demonstrate a significant impact of anti-amyloid agents for reducing the amyloid plaques burden in AD brains. Tau PET imaging has conversely fueled the advent of disease-modifying therapeutic strategies in AD by supporting the assessment of neurofibrillary tangles of tau pathology deposition over time. Looking ahead, PET imaging holds immense promise for studying additional targets such as neuroinflammation, cholinergic deficit, and synaptic dysfunction. Advances in radiotracer development, dedicated brain PET/CT scanners, and Artificial Intelligence-powered software are poised to enhance the quality, sensitivity, and diagnostic power of molecular neuroimaging. Consequently, PET/CT remains at the forefront of AD research, offering unparalleled opportunities for unravelling the complexities of the disease and advancing therapeutic interventions, although it is not yet enough alone to allow patients' recruitment in therapeutic clinical trials.

Network Pharmacology, Molecular Dynamics and In Vitro Assessments of Indigenous Herbal Formulations for Alzheimer’s Therapy

Alzheimer’s disease (AD) is an age-associated neurodegenerative condition marked by amyloid plaques, synaptic dysfunction, and neuronal loss. Besides conventional medical care, herbal therapies, both raw and refined, have attracted researchers for their potential therapeutic effects. As a proof-of-concept, our study combined HPLC-DAD analysis of bioactive constituents, network pharmacology, molecular dynamics (MD), molecular docking, post-MD analysis, and experimental verification to investigate the mechanisms of crude drug formulations as a therapeutic strategy for AD. We identified nine bioactive compounds targeting 188 proteins and 1171 AD-associated genes. Using a Venn diagram, we found 47 overlapping targets, forming “herb-compound-target (HCT)” interaction networks and a protein‒protein interaction (PPI) network. Simulations analyzed binding interactions among the three core targets and their compounds. MD assessed the stability of the best-ranked poses and beneficial compounds for each protein. Among the top 22 hub genes, AChE, BChE, and MAO, ranked 10, 14, and 34, respectively, were selected for further analysis. Two tetraherbal formulations, Form A and Form B, showed notable activity against AChE. Form A exhibited significant (p &lt; 0.0001) inhibitory activity (IC50 = 114.842 ± 2.084 µg/mL) compared to Form B (IC50 = 142.829 ± 4.258 µg/mL), though weaker than galantamine (IC50 = 27.950 ± 0.122 µg/mL). Form B had significant inhibitory effects on BChE (IC50 = 655.860 ± 32.812 µg/mL) compared to Form A (IC50 = 679.718 ± 20.656 µg/mL), but lower than galantamine (IC50 = 23.126 ± 0.683 µg/mL). Both forms protected against Fe2+-mediated brain injury by inhibiting MAO. Docking identified quercetin (−10.2 kcal/mol) and myricetin (−10.1 kcal/mol) for AChE; rutin (−10.6 kcal/mol) and quercetin (−9.7 kcal/mol) for BChE; and kaempferol (−9.1 kcal/mol) and quercetin (−8.9 kcal/mol) for MAO. These compounds were thermodynamically stable based on MD analysis. Collectively, the results offer a scientific rationale for the use of these specifically selected medicinal herbs as AD medications.

Glutamate Transporter 1 as a Novel Negative Regulator of Amyloid β.

Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting the GLT-1/PS1 interaction as a novel therapeutic strategy for AD.

Agonistes des récepteurs GLP-1 dans la maladie d’Alzheimer : Potentiel thérapeutique et mécanismes d’action

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by progressive cognitive decline and neuronal dysfunction. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for the treatment of type 2 diabetes, have demonstrated promising neuroprotective effects. This review aims to evaluate the effects and underlying mechanisms of GLP-1 RAs in the context of AD. A comprehensive search of databases yielded 622 articles, from which studies met the predefined inclusion criteria and were subjected to detailed analysis, 29 articles were deemed appropriate for analysis. The results indicate that GLP-1 RAs can significantly reduce amyloid-beta (Aβ) deposition and phosphorylated tau levels in the brains of AD patients. These neuroprotective effects are attributed to multiple synergistic mechanisms, including the enhancement of neuronal survival, reduction of oxidative stress, and attenuation of neuroinflammation. This review underscores the importance of further research to fully elucidate the mechanisms of GLP-1 RAs and their potential as a therapeutic strategy for AD.

Novel Therapeutic Strategies for Alzheimer's Disease

The molecular pathogenesis of Alzheimer's disease (AD) has been elucidated through the biochemical analysis of senile plaques, neurofibrillary tangles, and pathological features of the brains of patients with AD. Genetic analysis, initiated with familial AD investigation, has revealed that Aβ aggregation and accumulation are crucial processes in AD pathogenesis. The success of lecanemab against aggregated Aβ is the result of these efforts. Meanwhile, research on tau as a causative molecule in AD and various other tauopathies is advancing gradually. Furthermore, genetic analysis has revealed that the inflammatory response of glial cells modifies AD pathophysiology; a novel therapeutic strategy for inflammation control is thus currently under consideration. This article summarizes the latest discoveries related to these new therapeutic strategies for AD.

Acetylcholinesterase inhibitory phloroglucinols from tropic Rhodomyrtus tomentosa

Four previously undescribed phloroglucinols, including three pairs of enantiomers, (±)-rhodotomentodimer F, (±)-rhodotomentodimer G, and (±)-rhodotomentomonomer E, and one phloroglucinol-sesquiterpene meroterpenoid, rhodotomentodione E, together with one previously reported congener, (±)-rhodomyrtosone A, were obtained from the leaves of Rhodomyrtus tomentosa. The structures including absolute configurations of previously undescribed isolates were elucidated by extensive spectroscopic analysis (HRESIMS and NMR), ECD calculations, and single-crystal X-ray diffraction. (±)-Rhodotomentodimer F is a rare phloroglucinol derivative conjugated by a β-triketone moiety and an unprecedented resorcinol unit via the formation of a rare bis-furan ring system, whereas (±)-rhodotomentomonomer E shares a rearranged pentacyclic scaffold. Pharmacologically, (±)-rhodotomentomonomer E showed the strongest human acetylcholinesterase (hAChE) inhibitory effect with an IC50 value of 1.04 ± 0.05 μM. Molecular formula studies revealed that hydrogen bonds formed between hAChE residues Glu202, Ser203, Ala204, Gly121, Gly122, Tyr337, and His447 and (±)-rhodotomentomonomer E played crucial roles in its observed activity. These findings indicated that the leaves of Rhodomyrtus tomentosa can supply a rich source of hAChE inhibitors. These inhibitors might potentially be utilized in the therapeutic strategy for Alzheimer's disease, offering promising candidates for further research and development.

Androgen deprivation exacerbates AD pathology by promoting the loss of microglia in an age-dependent manner

AimsMicroglial cells are integral to the pathogenesis of Alzheimer's disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD. Methods and key findingsTo create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aβ) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aβ plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aβ1–42-induced apoptosis. SignificanceThese findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.