GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE214nnn/GSE214352/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE214352GEOGSEfalsePM20D1-derived treatment induces microglia association with amyloid plaques and improves Alzheimer’s disease pathologiesAlzheimer’s disease (AD) is a growing epidemic threat for which no effective treatment is available. Recently, Peptidase M20 Domain Containing 1 (PM20D1) has emerged as a novel neuroprotective factor epi-genetically altered in AD. PM20D1 low expression carriers show increased AD risk, and PM20D1-overexpressing mice reduced amyloid levels and cognitive deficits, through a still unknown mechanism. PM20D1 overexpression, in turn, has shown to facilitate the synthesis of N-acyl amino acids (NAAAs), particularly of N-oleoyl-L-Leucine (C18:1-Leu), the potential role of which in AD also remains unknown. Here, we report that C18:1-Leu treatment is sufficient to improve AD pathologies and phenotypes in two independent models of AD. We show that it alleviates motility deficits and amyloid aggregation in the GMC101 strain of C.elegans. We demonstrate that C18:1-Leu treatment also reduces cognitive deficits and amyloid burden in APP/PS1 mice. Furthermore, we provide evidence for a C18:1-Leu-induced microglia association with amyloid plaques, thereby reducing their size, number and toxicity, and for an enhanced neuroprotection, thereby reducing neuronal damage. Finally, we show that C18:1-Leu treatment also increases Aβ chemotaxis and clearance in microglia cultures, and increases cell viability in neuronal cells. In sum, our results support the use of C18:1-Leu as a potential therapeutic agent for the treatment of AD.2026/05/12GSE214352GSM6604516GSM660451519057214352Mus musculus