Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

Females with Alzheimer's disease (AD) present accelerated damage to cholinergic neurons and undergo accelerated cognitive decline compared to males, but the underlying mechanisms are incompletely understood. Here, we report that tRNA fragments (tRFs) carrying complementary sequences to cholinergic transcripts (CholinotRFs) may causally contribute to both these phenomena. We found that the nucleus accumbens of female brains, a brain region enriched in cholinergic neurons, exhibits larger CholinotRF decreases compared to hypothalamic or cortical tissues. These CholinotRFs are largely of mitochondrial genome origin, and their reduced levels are correlated with elevated levels of their predicted cholinergic associated mRNA targets. Additionally, AD temporal cortices showed sex-specific changes in distinct cell populations' levels of cholinergic transcripts. Moreover, cholinergic differentiation of human-originated neuronal cell lines was accompanied by sex-specific elevation of CholinotRFs, supporting the role of CholinotRFs in cholinergic regulation. Our findings highlight possible CholinotRF involvement in the AD sex-specific cholinergic loss and cognitive deterioration.