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

IntroductionFemales 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 transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). MethodsWe analyzed small RNA-sequencing (RNA-Seq) data from the nucleus 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.

Automated summary

Females with Alzheimer's disease (AD) experience accelerated dementia and loss of cholinergic neurons compared to males, and the underlying mechanisms may involve changes in transfer RNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). The study found that NAc CholinotRFs of mitochondrial genome origin had reduced levels, which correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA sequencing in AD temporal cortices also indicated altered sex-specific levels of cholinergic transcripts in diverse cell types and sex-specific CholinotRF elevations in neuroblastoma cells under cholinergic differentiation. These findings suggest the involvement of CholinotRFs in cholinergic regulation and their potential role in AD sex-specific cholinergic loss and dementia.