September 29, 2021

iPSC-derived astrocytes as a system to understand late-onset Alzheimer’s disease

Hyo Lee, BA

Additional Authors: Richard Pearse, Cheryl Pan, Sri Goberdhan, Tracy Young-Pearse

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is characterized by accumulation of extracellular amyloid-beta (Aβ) plaques and intracellular tau tangles. Despite the identification of multiple late-onset AD (LOAD) associated genes, the mechanism by which these genes are involved in AD pathogenesis is unclear. Here, we have utilized induce pluripotent stem cells (iPSCs) from individuals with diverse genetic backgrounds to differentiate into astrocytes. We have generated 44 lines of iPSC-derived astrocytes from a cohort with a spectrum of cognitive ability and neuropathology, and performed RNA-seq and proteomic analysis to identify differentially expressed genes and proteins across LPNCI (low pathology-not cognitively impaired), HPNCI (high pathology-not cognitively impaired) and AD. Modules such as oxidative phosphorylation, TCA cycle were downregulated in AD astrocytes whereas modules such as inflammatory response, proteasome, and protein folding were upregulated. We then validated interesting modules by leveraging functional assays such as mitochondria stress test and proteasome activity assay. In conclusion, we identified astrocyte specific signature in late onset AD that helps our understanding of the cell type-specific contribution to LOAD.

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