Molecular Neurodegeneration最新文献

{"title":"RAN translation as a dominant pathogenic axis in C9ORF72-associated ALS and FTD models.","authors":"Pegah Masrori, Defne Audrey Amado","doi":"10.1186/s13024-026-00959-9","DOIUrl":"10.1186/s13024-026-00959-9","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13465659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau extent outperforms tau load as a predictor of neurodegeneration in Alzheimer's disease.","authors":"Arthur C Macedo, Lydia Trudel, Seyyed Ali Hosseini, Joseph Therriault, Étienne Aumont, Gleb Bezgin, Nesrine Rahmouni, Jenna Stevenson, Cécile Tissot, Marcel S Woo, Stijn Servaes, Stuart Mitchell, Jaime Fernandez-Arias, Brandon Hall, Tevy Chan, Marina Pereira Gonçalves, Pamela C L Ferreira, João Pedro Ferrari-Souza, Bruna Bellaver, Firoza Z Lussier, Andréa L Benedet, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Dana L Tudorascu, Eduardo R Zimmer, Maxime Montembeault, Jean-Paul Soucy, Jesse Klostranec, Tharick A Pascoal, Paolo Vitali, Pedro Rosa-Neto","doi":"10.1186/s13024-026-00945-1","DOIUrl":"10.1186/s13024-026-00945-1","url":null,"abstract":"<p><strong>Background: </strong>In Alzheimer's disease (AD), tau pathology is more strongly linked to neurodegeneration than amyloid-β and better predicts brain atrophy. The spatial extent of tauopathy (SEOT) has shown promise as an earlier and more sensitive marker of AD severity than tau load, but how these complementary dimensions relate to neurodegeneration remains unclear. Here, we compared the in vivo associations of tau-PET extent versus load with cross-sectional and longitudinal neurodegeneration.</p><p><strong>Methods: </strong>We studied 367 participants across the healthy-aging to AD continuum (mean age 69.3 years; 61% female) from the TRIAD cohort who underwent [¹⁸F]MK-6240 tau-PET. Tau load was quantified as regional standardized uptake value ratio (SUVR), and SEOT as the proportion of abnormal voxels, within a temporal meta-region of interest (ROI) and a full-cortex ROI. Neurodegeneration markers included cortical thickness, hippocampal volume (HCV), medial temporal atrophy (MTA) visual ratings, plasma neurofilament light (NfL), and CSF total tau (t-tau). Cross-sectional associations were evaluated using multiple linear regression or covariate-adjusted Spearman correlations. We also compared local correlations of tau load and extent with cortical thickness across all cortical regions. Longitudinal predictive value for neurodegeneration was tested using linear mixed-effects models.</p><p><strong>Results: </strong>Cross-sectionally, all tau-PET metrics were significantly associated with neurodegeneration across imaging and fluid biomarkers. Full-cortex SEOT provided the best model fit for cortical thinning. SEOT outperformed tau load for associations with HCV and for predicting MTA, whereas SEOT and SUVR showed comparable associations with plasma NfL and CSF t-tau. Tau extent was equal or superior to tau load in its correlation with local cortical thickness across all cortical regions. Longitudinally, baseline full-cortex SEOT best predicted future cortical thinning, while temporal SEOT best predicted future hippocampal atrophy.</p><p><strong>Conclusions: </strong>Across cross-sectional and longitudinal analyses, tau extent provided superior predictive value for imaging-based neurodegeneration compared with tau load. By enabling a spatially unbiased, whole-brain assessment of tau burden that accommodates heterogeneous topographies, SEOT represents a promising complementary tau-PET metric for staging and tracking disease progression in AD.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13463738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148163815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.","authors":"LaShae Nicholson, Si Jie Tang, Tejaswini Karra, Habiba Abouelatta, Stephen M Strittmatter","doi":"10.1186/s13024-026-00946-0","DOIUrl":"10.1186/s13024-026-00946-0","url":null,"abstract":"<p><strong>Background: </strong>Metabolic dysfunction contributes to the risk and progression of Alzheimer's disease (AD), yet the cellular mechanisms linking impaired insulin signaling and systemic metabolic stress to brain dysfunction remain incompletely defined.</p><p><strong>Methods: </strong>We examined the impact of chronic high-fat, high-sugar (HFHS)-induced insulin resistance on metabolic parameters, spatial learning and memory, and in vivo glial activation and neuropathology in Alzheimer's disease knock-in mice expressing human mutant APP and wild-type (WT) tau. Single-nucleus RNA sequencing was performed to resolve cell-type-specific transcriptional responses.</p><p><strong>Results: </strong>HFHS-diet induced weight gain, hyperglycemia, and glucose intolerance in WT and AD knock-in mice as compared to control diet-fed mice. However, impaired spatial learning was observed only in AD knock-in mice on the HFHS diet, even though there was no greater amyloid-β deposition or tau phosphorylation than in control diet AD knock-in mice. Transcriptomic profiling revealed that HFHS-fed AD mice engaged a distinct glial program, which we termed the metabolic impairment in neurodegeneration (MinD) state, characterized by upregulation of genes involved in synaptic targeting and trans-synaptic signaling shared across microglia, astrocytes, and oligodendrocytes. In parallel, we identified selective induction of the transcription factor Meis2 in cortical Layer 2 inhibitory neurons, which exhibited HFHS-diet transcriptional remodeling enriched for pathways regulating vesicle release, synaptic organization, and membrane excitability. These coordinated glial and neuronal transcriptional changes were associated with reduced inhibitory synapse density in HFHS-fed AD mice.</p><p><strong>Conclusion: </strong>Diet-induced insulin resistance in AD knock-in mice is associated with coordinated glial and inhibitory neuron transcriptional remodeling and cognitive impairment, without alteration of the classical amyloid and tau pathology present in the AD mice fed a lean diet. These findings define cellular programs linking systemic insulin metabolic dysfunction to cortical circuity vulnerability in AD.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13459496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148157449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"3'UTR regulation of axon translation and optic nerve regeneration.","authors":"Minjuan Bian, Emma L Huie, Xin Xia, Michael Nahmou, Savana A Maxfield, Liang Li, Liang Liu, Ziming Luo, Christina Tsien, Katherine J Healzer, Heather V Chang, Kristina Russano, Jeffrey L Goldberg","doi":"10.1186/s13024-026-00952-2","DOIUrl":"10.1186/s13024-026-00952-2","url":null,"abstract":"<p><strong>Background: </strong>In the adult mammalian central nervous system (CNS), failure of axon regeneration limits recovery after traumatic injury or in neurodegenerative disease. Local protein translation has been implicated in the regulation of axon growth in highly compartmentalized neurons. 3' untranslated regions (3'UTRs) of mRNAs play critical roles in RNA localization and modification. Here we studied the regulation of 3'UTRs in growth cone and axon regeneration.</p><p><strong>Methods: </strong>Using fluorescence recovery after photobleaching (FRAP), we examined dynamic changes of mRNA 3'UTRs-related local translation in distal growth cones of primary neurons, initially comparing 3'UTRs from Gap43, normally localized to axons, and gamma-actin (Actg1), normally distributed to soma and axon. Local translation patterns in response to trophic factors and depolarization stimuli were analyzed, with or without translation inhibitor anisomycin. Adeno-associated viral vectors were used to express constitutively active Src with specific 3'UTRs after optic nerve injury in vivo. Axon growth and Src signaling were detected to identify function of 3'UTRs in axon regeneration. Statistical analysis was performed using one-way ANOVA or Kruskal-Wallis test, two-tailed unpaired t-test or Mann-Whitney test for data sets with different distributions.</p><p><strong>Results: </strong>We discovered different 3'UTRs led to differences in local translational regulation in growth cones in vitro, including in response to relevant signals such as brain-derived neurotrophic factor (BDNF), forskolin, ciliary neurotrophic factor (CNTF), depolarization and repolarization. In vivo, we found that addition of 3'UTRs from Gap43 or Actg1 to a construct expressing constitutively active Src, which normally regulates growth cone and axon elongation, increased Src mRNA and protein localization, and Src activity measured by phospho-FAK in the optic nerve and optic tract, and the 3'UTR of Gap43 promoted more long-distance axon regeneration after optic nerve injury.</p><p><strong>Conclusions: </strong>Together these data enhance our understanding of the complexity of 3'UTR-mediated regulation of local axon translation, and point to potential therapeutic avenues for growth cone-related protein expression and local translation via 3'UTR manipulation.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440112/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.","authors":"Dezhen Tu, Yuxiao Zheng, Pingping Ding, Miao Shen, Wangyang Tang, Bin Wei, Hongyan Wang","doi":"10.1186/s13024-026-00951-3","DOIUrl":"10.1186/s13024-026-00951-3","url":null,"abstract":"<p><p>Cholesterol metabolites are abundant in the central nervous system (CNS) that regulate cell membrane fluidity, signal transduction, and inter- and intracellular vesicular transport, as well as cell proliferation/cell death or migration. Brain cholesterol synthesis and metabolism are tightly coupled to the functional homeostasis of neurons, glial cells or microglia, and dysregulation of these processes has been strongly implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This review provides a comprehensive overview of how cholesterol synthesis, esterification, efflux, uptake, and oxidation affect the CNS function, highlighting the function of key enzymes or metabolites in distinct brain cell types during neurodegeneration. Based on single-cell/nucleus RNA sequencing data from the brains of AD, PD, and HD patients, we summarize cell-type-specific genes in cholesterol metabolism pathways, shedding new light to understand cellular heterogeneity. The role of cholesterol-derived neurosteroids in neurodegenerative diseases is also discussed. Furthermore, how cholesterol metabolites modulate the formation, aggregation, and degradation of amyloid-β (Aβ), α-synuclein and huntingtin, as well as Tau protein phosphorylation are outlined. Finally, future research directions are proposed that aim to understand neurodegenerative diseases with new angle.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13403443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148042998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Temporal single-cell atlas of full-length Huntington's disease mouse model defines stage-specific signatures of corticostriatal dysfunction.","authors":"Ashley B Robbins, Paul T Ranum, Icnelia Huerta-Ocampo, Michael Kuckyr, Beverly L Davidson","doi":"10.1186/s13024-026-00960-2","DOIUrl":"10.1186/s13024-026-00960-2","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Huntington's disease (HD) involves progressive corticostriatal dysfunction, yet the temporal dynamics and cell type-specific vulnerability patterns remain incompletely understood. While recent single-cell studies in rapidly progressing models have revealed early developmental and regional changes, temporal profiling distinguishing pathogenic mechanisms from normal aging in full-length HTT models remains lacking. Resolving stage-specific temporal dynamics across interconnected striatal and cortical neuronal populations over protracted time is essential for identifying drivers of cellular dysfunction.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A temporal single-nucleus transcriptomic atlas was generated from striatum and motor cortex from heterozygous zQ175 knock-in mice at early symptomatic (6 months) and late symptomatic (18 months) stages. This full-length huntingtin model enables staging of progressive circuit dysfunction alongside physiological aging. The high inherited CAG repeat length of the zQ175 model places cells beyond the somatic expansion threshold associated with transcriptional dysregulation and identity erosion in vulnerable human neuronal populations, yet prior to the de-repression crisis and cell loss observed at the most extreme expansions in HD, providing a tractable window into the progressive molecular pathogenic cascade. Genotype-dependent effects were modeled to distinguish cell type-specific signatures of disease mechanisms from age-related and compensatory changes. Integration of weighted gene co-expression and transcription factor regulatory networks with protein-protein interaction databases predicted candidate regulators of stage-specific programs. Findings were validated across human HD datasets and the rapidly progressive R6/2 mouse model.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Temporal gene and network analysis revealed diverging, converging and biphasic patterns of transcriptional changes, distinguishing progressive disease and neuronal identity loss from aging. 21 cell type-specific gene co-expression modules were validated in human HD and R6/2 mice datasets, revealing stage-specific shifts in cellular stress, proteostasis, and synaptic programs. Disease modules enriched for CAG repeat length-dependent genes resolved their temporal progression. Shared vulnerability across cortical and striatal projection neurons implicated epigenetic regulator Zswim6 and splicing factors Rbfox1 and Celf2 in corticostriatal dysfunction. Integrative network analysis identified Foxo1, Neurod2, and Npas2 as stage-specific transcriptional regulators. Cross-species validation established conserved gene regulatory modules in human HD, establishing generalizable cell type-specific gene modules of translational relevance.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;This temporally resolved atlas reveals stage-specific transcriptional dynamics of disease-relevant gene expression programs and physiological trajectories in vulnerable ne","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Decoding distinctive features of plasma extracellular vesicles in amyotrophic lateral sclerosis.","authors":"Laura Pasetto, Stefano Callegaro, Alessandro Corbelli, Fabio Fiordaliso, Deborah Ferrara, Laura Brunelli, Giovanna Sestito, Roberta Pastorelli, Elisa Bianchi, Marina Cretich, Marcella Chiari, Cristina Potrich, Cristina Moglia, Massimo Corbo, Gianni Sorarù, Christian Lunetta, Andrea Calvo, Adriano Chiò, Gabriele Mora, Maria Pennuto, Alessandro Quattrone, Francesco Rinaldi, Vito Giuseppe D'Agostino, Manuela Basso, Valentina Bonetto","doi":"10.1186/s13024-026-00955-z","DOIUrl":"10.1186/s13024-026-00955-z","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":17.5,"publicationDate":"2026-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148042996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurodegeneration as an evolutionary trade-off: a biological constraint-aware therapeutic perspective.","authors":"Seung Hyun Kim, Min-Young Noh, Matthew C Kiernan","doi":"10.1186/s13024-026-00958-w","DOIUrl":"10.1186/s13024-026-00958-w","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148016475","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo profiling of astrocyte secretome reveals brain-region specific regulatory networks in a mouse model of amyloid pathology.","authors":"Qiu Jiang, Jian-Ni Hu, Hao-Min Dong, Jia-Yan Xin, An-Yu Shi, Gui-Hua Zeng, Jie Liu, Yan-Jiang Wang","doi":"10.1186/s13024-026-00956-y","DOIUrl":"10.1186/s13024-026-00956-y","url":null,"abstract":"<p><p>Coordinated cell-to-cell communications is crucial for the proper functioning and maintenance of brain activities, and its disruption contributes to neurological disorders, including Alzheimer's disease (AD). Altered astrocyte-neuron communications have been implicated in AD progression, yet the underlying regulatory networks remain poorly understood. Given that secretory proteins mediate both local and long-range intercellular signaling, we constructed a spatiotemporal profile of the astrocyte-derived secretome using in vivo TurboID proximity labeling in mice of amyloid pathology. Early alterations in the entorhinal cortex secretome were identified and enriched in metabolic pathways, whereas changes in the hippocampus were observed later, correlating with neuronal and synaptic maintenance. These findings suggest that early remodeling of the astrocyte secretome in the entorhinal cortex may be involved in AD pathogenesis, while later changes in the hippocampus contribute to neurodegeneration and cognitive decline. This work provides a systematic map of the dynamic, region-specific remodeling of the astrocyte secretome in AD, identifying novel spatiotemporal vulnerabilities and potential therapeutic targets.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393950/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.","authors":"Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E Irmen, Nicholas J Constantino, Chanung Wang, Michael F Kanan, Marco Colonna, Shannon L Macauley, Jocelyn Y Cheng, Ken Hatanaka, Margaret Moline, Erik S Musiek","doi":"10.1186/s13024-026-00948-y","DOIUrl":"10.1186/s13024-026-00948-y","url":null,"abstract":"<p><strong>Background: </strong>Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.</p><p><strong>Methods: </strong>PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed by piezoelectric monitoring and EEG/EMG polysomnography. Amyloid pathology and microglial responses were quantified by immunohistochemistry, confocal microscopy, and single-cell RNA sequencing. Microglial depletion was induced with the CSF1R inhibitor PLX3397.</p><p><strong>Results: </strong>Lemborexant enhanced sleep quality with less active-phase sedation than doxepin. Both drugs reduced initial diffuse plaque deposition, but only lemborexant prevented fibrillar plaque accumulation in young mice and slowed plaque growth in older mice. Lemborexant increased peri-plaque microglial CD68 expression and enhanced Aβ phagocytosis in vivo. Single-cell transcriptomics revealed a shift toward activated, DAM-like microglial states with upregulation of phagocytic genes without broad inflammatory induction. Microglial depletion abolished lemborexant's anti-amyloid effects.</p><p><strong>Conclusions: </strong>Lemborexant mitigates amyloid pathology by augmenting microglial phagocytic function, positioning DORAs as promising therapeutics that couple sleep promotion with beneficial microglial modulation.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13214429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148006085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}