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.
Highlights
Alzheimer’s disease (AD), which is the most common type of dementia in older people, is characterized by the abnormal accumulation of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) in the brain, which results in progressive synaptic dysfunction and cognitive deficits[1,2,3,4]
IFN-γ treatment increased autophagy induction in microglia in APP/PS1 mice The previous research showed that IFN-γ elicits autophagy in macrophages[20], to investigate whether IFNγ increases autophagy induction in vivo, APP/PS1 mice (8 months old) were intraperitoneally (i.p.) injected with murine IFN-γ (5 × 104 U) and IFN-γ reached the brain within 30 min after i.p. injection (Fig. S1)
LC3 is a reliable marker of autophagic vacuoles, which are necessary for the elongation of autophagosome membranes and regarded as an indicator of the autophagy induction[22]
Summary
Alzheimer’s disease (AD), which is the most common type of dementia in older people, is characterized by the abnormal accumulation of amyloid-β (Aβ) and intracellular neurofibrillary tangles (NFTs) in the brain, which results in progressive synaptic dysfunction and cognitive deficits[1,2,3,4]. Autophagy is an important cellular pathway for the degradation and clearance of damaged organelles and denatured and aggregated peptides[9]. It is a highly conserved homeostatic process by which cytoplasmic macromolecules, excess or damaged. Official journal of the Cell Death Differentiation Association He et al Cell Death and Disease (2020)11:440 organelles, and some pathogens are delivered to lysosomes for degradation[10]. It has been reported that AAV-induced murine IFN-γ expression in the neonatal brain of APP mice reduces Aβ accumulation through the synergistic effects of activated glia and complement expression that promote Aβ clearance. It has been reported that IFN-γ could elicit macrophage autophagy mediated by PI3K and p38 MAPK in vitro[20]
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