Abstract

AbstractBackgroundIn Alzheimer’s disease (AD), where amyloid beta (Aβ) plaques accumulate in the brain with surrounding reactive glial cells, synapses are weakened and eliminated. Previously, it was thought that synapse elimination and subsequent neuronal death were mainly due to the direct effects of Aβ oligomers and fibrils on neurons. However, recent studies have revealed that abnormal glial function can be an active inducer of the initiation and progression of AD. Reactive astrocytes are found around Aβ plaques and can internalize Aβ in vitro and in vivo, although the molecular mechanism and biological impact of this clearance are unclear.MethodWe have performed RNA‐seq analysis to reveal the changes of astrocytic gene expression upon oligomeric Aβ exposure. Through this analysis, we have isolated specific genes that are highly upregulated and downregulated in astrocytes during the progression of AD. The expression and function of one of the upregulated genes, KAGS1, are under investigation using APP/PS1 mice.ResultKAGS1 was detected in APP/PS1 mouse hippocampus starting from 6‐month‐old APP/PS1 mice and its expression was increased in astrocytes along with the progression of AD. We found that KAGS1 was dramatically accumulated in a subset of astrocytes in the hippocampus. Interestingly, organelles with accumulated KAGS1 were co‐localized with p62 and LC3B, indicating that KAGS1 accumulation was associated with autophagy in astrocytes. This dramatic autophagosome accumulation in the aged AD astrocytes appears to be due to the AD related proteasomal as well as lysosomal dysfunctions in astrocytes. Importantly, we found that many critical membrane receptors in astrocytes, such as MEGF10 and LDLR, get trapped inside of the accumulated autophagosomes, instead of localizing in astrocytic membranes.ConclusionThis finding suggests that the AD astrocytes with accumulated autophagosomes may lose their normal ability for regulating synaptic homeostasis/function and may contribute to AD‐related learning and memory loss.

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