RESUMEN
The "two-hit vascular hypothesis for Alzheimer's disease (AD)" and amyloid-ß (Aß) oligomer hypothesis suggest that impaired soluble Aß oligomers clearance through the cerebral vasculature may be an initial step of the AD process. Soluble Aß oligomers are driven into perivascular spaces from the brain parenchyma and toward peripheral blood flow. The underlying vascular-based mechanism, however, has not been defined. Given that microRNAs (miRNAs), emerging as novel modulators, are involved in numerous physiological and pathological processes, we hypothesized that cerebrovascular miRNAs may regulate the activities of brain blood vessels, which further affects the concentration of Aß in the AD brain. In this study, perivascular Aß deposits, higher vascular activation, increased pericyte coverage and up-regulated capillaries miRNAs at 6 months old (6 mo) were found to correlate with the lower Aß levels of middle AD stage (9 mo) in 3xTg-AD (3xTg) mice. It is implicated that at the early stage of AD when intracellular Aß appeared, higher expression of vessel-specific miRNAs, elevated pericyte coverage, and activated endothelium facilitate Aß oligomer clearance through the perivascular route, resulting in a transient reduction of Aß oligomers at 9 mo. Additionally, ghrelin-induced upregulation of capillary miRNAs and increased pericyte coverage attenuated Aß burden at 9 mo, in further support of the relationship between vascular miRNAs and Aß clearance. This work suggests a cerebral microvessel miRNA may boost endothelial highly activated phenotypes to promote elimination of Aß oligomers through the perivascular drainage pathway and contribute to AD progression. The targeting of brain vessel-specific miRNAs may provide a new rationale for the development of innovative therapeutic strategies for AD treatment.