Project Type(s):
Basic Science

Alzheimer’s disease (AD) risk is strongly influenced by genetic variation, much of which lies in noncoding regions that regulate gene expression and RNA splicing. Protein-coding variants explain only ~30% of AD heritability, highlighting the need to functionally characterize regulatory variants. TREM2 is a microglia-specific immune receptor in which heterozygous missense variants increase late-onset AD risk, while biallelic loss-of-function variants cause early-onset dementia. TREM2 undergoes alternative splicing, but its transcript repertoire and regulation in human brain remain poorly defined. We identified a novel splice isoform lacking exon 2 (Δe2) that encodes a truncated protein with altered activity. Preliminary data show that AD- and dementia-associated variants shift splicing toward Δe2, reducing functional TREM2 dosage. We will define TREM2 isoforms in human brain, functionally assess regulatory variants affecting splicing, and analyze interactions between cis-variants and trans-acting splicing factors altered in AD, using long-read RNA sequencing and high-throughput functional assays.

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