Upregulation of Autophagy in Astrocytes Reduces Amyloid-β Aggregates in the Mouse Brain
Researchers here provide evidence for autophagy in astrocytes, a large supporting cell population in brain tissue, to be important in determining amyloid-β plaque burden in the aging brain. Autophagy is a recycling mechanism capable of breaking down unwanted proteins and structures. Astrocytes increase autophagic activity in the presence of the amyloid-β protein aggregates (plaques) characteristic of Alzheimer's disease, and in a mouse model that exhibits these plaques the degree of autophagy appears to determine the degree to which problematic amyloid-β is cleared from brain tissue.
Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer's disease (AD). We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of an animal model of AD.
Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of the LC3B gene and turns on a prolonged transcription of the SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal markers and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients.
Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.