Intraperitoneal injection of IFN-γ restores microglial autophagy, promotes amyloid-ß clearance and improves cognition in APP/PS1 mice.
Cell Death Dis
; 11(6): 440, 2020 06 08.
Article
em En
| MEDLINE
| ID: mdl-32514180
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-ß (Aß) metabolism. Although it has been proven that the cytokine IFN-γ enhances autophagy in macrophage cell lines, whether the signaling cascade is implicated in Aß 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 Aß 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 Aß, and surrounded Aß in APP/PS1;CX3CR1-GFP+/- mice. In addition, IFN-γ treatment decreased the Aß 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 Aß, which represents a potential therapeutic approach for the use of exogenous IFN-γ in AD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interferon-alfa
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Precursor de Proteína beta-Amiloide
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Cognição
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Microglia
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Injeções Intraperitoneais
Limite:
Animals
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China