AUTHOR=Estfanous Shady , Daily Kylene P. , Eltobgy Mostafa , Deems Nicholas P. , Anne Midhun N. K. , Krause Kathrin , Badr Asmaa , Hamilton Kaitlin , Carafice Cierra , Hegazi Ahmad , Abu Khweek Arwa , Kelani Hesham , Nimjee Shahid , Awad Hamdy , Zhang Xiaoli , Cormet-Boyaka Estelle , Haffez Hesham , Soror Sameh , Mikhail Adel , Nuovo Gerard , Barrientos Ruth M. , Gavrilin Mikhail A. , Amer Amal O. TITLE=Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation JOURNAL=Frontiers in Immunology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.705581 DOI=10.3389/fimmu.2021.705581 ISSN=1664-3224 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 member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation 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 in AD.