Speaker: Prof. Zhong Sheng, UCSD

Time: 10:00-11:30 a.m., Feb 17, 2025, GMT+8

Venue: Room B117, Research Complex #2, PKU

Abstract: 

Virtually all individuals over the age of 65 exhibit at least early-stage Alzheimer’s disease (AD) pathology, yet most do not harbor disease-causing mutations in APP, PSEN, or MAPT, nor do many carry the APOE4 risk allele. This observation raises critical questions about how AD develops in the broader population. Although transcriptional dysregulation has not traditionally been considered a hallmark of AD, recent findings reveal substantial epigenomic changes in late-onset AD (LOAD). Here, we demonstrate that altered expression of a LOAD biomarker modulates AD pathology in mice and human brain organoids. This biomarker protein, which has a previously uncharacterized role in transcriptional regulation, promotes the transcription of key inflammatory genes in astrocytes, suppresses autophagy, and accelerates amyloid pathology. To counter these effects, we developed a blood-brain barrier-permeable small-molecule inhibitor that targets this protein’s transcriptional function, thereby reducing amyloid pathology and improving AD-related behavioral deficits. These findings underscore the importance of transcriptional regulation in LOAD and offer a promising therapeutic avenue beyond targeting familial mutations.

Source: Biomedical Pioneering Innovation Center, PKU