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

Abstract

AbstractIntroductionFemales with Alzheimer’s disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs).MethodsWe analyzed small RNA-sequencing data from thenucleus accumbens(NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation.ResultsNAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations.DiscussionOur findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.