PhD Student King Abdullah University of Science and Technology (KAUST) Thuwal, Makkah, Saudi Arabia
Abstract: Alzheimer's Disease (AD) stands as a prominent age-related neurodegenerative disease, and its connection to amyloid-β (Aβ) accumulation in the aging brain is well-documented. Cellular senescence, marked by irreversible cell cycle arrest, is emerging as a critical factor in AD pathogenesis. In this study, we investigate the role of irradiated primary human astrocytes and human embryonic stem cell-derived astrocytes displaying a senescent-like phenotype (SLP) in Aβ production and aggregation. Our findings reveal that SLP human astrocytes promote Aβ aggregation through enhanced expression of amyloidogenic mRNA transcripts APP and BACE1. Mechanistically, we identify G3BP1, an RNA-binding protein, as a key regulator of post-transcriptional stability for APP and BACE1 mRNAs in astrocytes. Importantly, SLP-irradiated astrocytes exhibit reduced G3BP1 expression, causing APP and BACE1 to be more stable and increasing Aβ production. These results provide insights into potential radiation-induced cognitive impairment and suggest therapeutic avenues targeting G3BP1 to mitigate cognitive decline and delay the onset of AD.
