GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE312nnn/GSE312840/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE312840GEOGSEfalseDual Orexin Receptor Antagonism with Lemborexant Enhances Microglial Clearance of β-Amyloid in MiceBackground: Sleep regulates brain amyloid-beta (Aβ) levels, and disruption of sleep is a risk factor for Alzheimer’s Disease (AD) and can exacerbate amyloid pathology. The orexin/hypocretin system, a key sleep-wake regulator, represents an emerging therapeutic target in AD, though the effects of FDA-approved dual orexin receptor antagonist drugs (DORAs) on amyloid pathology are unknown. Here, we assessed and compared the effects of lemborexant (LEM), an FDA-approved DORA, and doxepin, an anti-histaminergic sleep drug, on amyloid pathology and glial responses in the APP/PS1 mouse model of AD. Methods: APP/PS1 mice were treated with lemborexant (10 or 30mg/kg daily) or doxepin (35mg/kg daily) for 3 months, starting just before the onset of amyloid plaque accumulation, or for 1 month after plaque pathology was established. Sleep was measured using a piezoelectric system, and amyloid pathology and glial responses were quantified by immunohistochemistry and confocal microscopy, as well as single cell RNAseq of isolated microglia. Amyloid plaques were labeled with methoxy-X04 to monitor plaque growth, and microglial plaque phagocytosis was assessed by flow cytometry. Microglial elimination was performed using the CSF1r inhibitor PLX3397. Results: Despite equivalent total sleep enhancement, LEM more effectively prevented formation of and slowed growth of both fibrillar and diffuse Aβ plaques. LEM enhanced peri-plaque microglial activation and enhanced microglial amyloid phagocytosis in vivo. Single-cell microglial transcriptomics showed a LEM-mediated shift toward pro-phagocytic and antigen-presentation gene signatures. Depleting microglia via CSF1R inhibition abolished LEM’s anti-amyloid effects, underscoring microglia as essential mediators. Conclusions: These results demonstrate that dual orexin receptor antagonism with lemborexant can augment microglial function to mitigate AD pathology.2026/05/01GSE312840GSM9355322GSM935532324247312840Mus musculus