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 rescued cognitive deficits in APP/PS1 mice. Our data suggest a possible mechanism by which the peripheral injection of IFN-γ restores microglial autophagy to induce the phagocytosis of cerebral Aβ, which represents a potential therapeutic approach for the use of exogenous IFN-γ in AD.
journal_name
Cell Death Disjournal_title
Cell death & diseaseauthors
He Z,Yang Y,Xing Z,Zuo Z,Wang R,Gu H,Qi F,Yao Zdoi
10.1038/s41419-020-2644-4subject
Has Abstractpub_date
2020-06-08 00:00:00pages
440issue
6issn
2041-4889pii
10.1038/s41419-020-2644-4journal_volume
11pub_type
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