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Unveiling age-associated immune priming properties of astrocytes for trigerring microglial Aβ clearance in an APOE isoform-dependent manner [hMG_RNA-seq]

ABSTRACT: Alzheimer's disease (AD)-associated allele, apolipoprotein E4 (APOE4), exhibits pathological characteristics in an age-dependent manner despite its presence from birth. The molecular and cellular changes leading to disease onset are largely unexplored. We observed using human-induced pluripotent stem cells (hiPSCs)-derived models that astrocytes acquire immune priming functions through repetitive inflammatory stimuli, with recovery periods, causing transcriptome changes similar to those in the aged brain. Astrocytic priming by amyloid-β (Aβ) promoted cytokine release, leading to enhanced microglial phagocytic activity against Aβ. Conversely, APOE4 astrocytes showed impaired priming and reduced cytokine secretion in response to Aβ, leading to decreased microglial Aβ phagocytosis. Further, using a humanized APOE knock-in mouse model, we validated the positive effect of astrocyte priming on Aβ clearance in vivo. Our findings suggest that aging astrocytes may enhance Aβ clearance through the acquisition of immune priming functions and positively regulate Aβ clearance, while APOE4 impairs this process, leading to Aβ accumulation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE274869 | GEO | 2025/07/06

REPOSITORIES: GEO

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Project description: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). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. 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 animal model of AD. Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of 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 hypertrophic reactive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Ab 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.

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Unveiling age-associated immune priming properties of astrocytes for trigerring microglial Aβ clearance in an APOE isoform-dependent manner [hMG_RNA-seq]

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