Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-β clearance and improves cognition in APP/PS1 mice.

Cell Death & Disease
Zitian HeZhibin Yao

Abstract

Autophagy is a major self-degradative process that maintains cellular homeostasis and function in mammalian cells. Autophagic dysfunction occurs in the early pathogenesis of Alzheimer's disease (AD) and directly regulates amyloid-β (Aβ) metabolism. Although it has been proven that the cytokine IFN-γ enhances autophagy in macrophage cell lines, whether the signaling cascade is implicated in Aβ degradation in AD mouse models remains to be elucidated. Here, we found that 9 days of the intraperitoneal administration of IFN-γ significantly increased the LC3II/I ratio and decreased the level of p62 in APP/PS1 mice, an AD mouse model. In vitro, IFN-γ protected BV2 cells from Aβ toxicity by upregulating the expressions of Atg7 and Atg5 and the LC3II/I ratio, whereas these protective effects were ablated by interference with Atg5 expression. Moreover, IFN-γ enhanced autophagic flux, probably through suppressing the AKT/mTOR pathway both in vivo and in vitro. Importantly, using intravital two-photon microscopy and fluorescence staining, we found that microglia interacted with exogenous IFN-γ and Aβ, and surrounded Aβ in APP/PS1;CX3CR1-GFP+/- mice. In addition, IFN-γ treatment decreased the Aβ plaque load in the cortex and hippocampus and...Continue Reading

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Citations

Jul 27, 2021·Frontiers in Cellular Neuroscience·Sarah K LotzKristen E Funk
Aug 23, 2021·Current Opinion in Pharmacology·Beatrice Paola FestaDavid C Rubinsztein
Nov 30, 2021·Inflammation Research : Official Journal of the European Histamine Research Society ... [et Al.]·Jiamin HuangBingwei Sun
Jan 16, 2022·Drug Discovery Today·Pieter DujardinLien Van Hoecke

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Methods Mentioned

BETA
flow cytometry
PCR
transgenic
transfection
ELISA
protein assay

Software Mentioned

GraphPad
TopScanTM
Image J
GraphPad Prism
ImageJ

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