Frontiers in Immunology (Jul 2021)

Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

  • Shady Estfanous,
  • Shady Estfanous,
  • Kylene P. Daily,
  • Mostafa Eltobgy,
  • Nicholas P. Deems,
  • Midhun N. K. Anne,
  • Kathrin Krause,
  • Kathrin Krause,
  • Asmaa Badr,
  • Kaitlin Hamilton,
  • Cierra Carafice,
  • Ahmad Hegazi,
  • Arwa Abu Khweek,
  • Arwa Abu Khweek,
  • Hesham Kelani,
  • Shahid Nimjee,
  • Hamdy Awad,
  • Xiaoli Zhang,
  • Estelle Cormet-Boyaka,
  • Hesham Haffez,
  • Hesham Haffez,
  • Sameh Soror,
  • Sameh Soror,
  • Adel Mikhail,
  • Gerard Nuovo,
  • Ruth M. Barrientos,
  • Mikhail A. Gavrilin,
  • Amal O. Amer

DOI
https://doi.org/10.3389/fimmu.2021.705581
Journal volume & issue
Vol. 12

Abstract

Read online

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.

Keywords