Elevated expression of Mirc1/Mir17-92 in microglia of Alzheimer's disease patients abrogates autophagy-mediated Amyloid-β degradation
Loading...
Date
2021-04
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer's Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. NBR1 expression was determined to be negatively correlated with expression of cluster component miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function.
Description
Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Autophagy, Microglia, NBR1, microRNA, Amyloid-β, Alzheimer's disease