Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling

Neuron. 2023 Nov 15;111(22):3619-3633.e8. doi: 10.1016/j.neuron.2023.08.012. Epub 2023 Sep 8.

Abstract

A pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) protein in the brain. Physical exercise has been shown to reduce Aβ burden in various AD mouse models, but the underlying mechanisms have not been elucidated. Irisin, an exercise-induced hormone, is the secreted form of fibronectin type-III-domain-containing 5 (FNDC5). Here, using a three-dimensional (3D) cell culture model of AD, we show that irisin significantly reduces Aβ pathology by increasing astrocytic release of the Aβ-degrading enzyme neprilysin (NEP). This is mediated by downregulation of ERK-STAT3 signaling. Finally, we show that integrin αV/β5 acts as the irisin receptor on astrocytes required for irisin-induced release of astrocytic NEP, leading to clearance of Aβ. Our findings reveal for the first time a cellular and molecular mechanism by which exercise-induced irisin attenuates Aβ pathology, suggesting a new target pathway for therapies aimed at the prevention and treatment of AD.

Keywords: Alzheimer's disease; Aβ; ERK; STAT3; amyloid-β; astrocytes; integrin αV/β5; irisin; neprilysin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Astrocytes / metabolism
  • Brain / metabolism
  • Down-Regulation
  • Fibronectins / metabolism
  • Mice
  • Neprilysin* / genetics
  • Neprilysin* / metabolism

Substances

  • Neprilysin
  • Fibronectins
  • Amyloid beta-Peptides
  • FNDC5 protein, mouse