biostudies-literatureShulman DNIA NIH HHSIsrael Science FoundationNational Institutes of HealthNIH HHSGatsby Charitable Foundation5159-5172https://www.ebi.ac.uk/biostudies/studies/S-EPMC10632545biostudies-literatureUnknown19(11)<h4>Introduction</h4>Females 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).<h4>Methods</h4>We 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.<h4>Results</h4>NAc 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.<h4>Discussion</h4>Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.Alzheimer's & dementia : the journal of the Alzheimer's AssociationSex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.PMC10632545P30AG72975R01 AG015819U01 AG061356U01AG613565P01AG014449-21P01 AG014449P30 AG0101613213/19P30AG10161P30 AG072975U01 AG046152U01AG461521016/185P01AG014449‐21R01 AG017917R01AG15819R01AG17917Dubnov SBennett DAMufson EJZorbaz TMadrer NGreenberg DSShulman DPaldor ISeshadri SLoewenstein YSoreq HfalseSex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.<h4>Introduction</h4>Females 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).<h4>Methods</h4>We 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.<h4>Results</h4>NAc 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.<h4>Discussion</h4>Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.2023-01-01T00:00:00Z2023 Nov2026-06-02T23:01:53.225Z2025-04-04T22:47:45.442ZS-EPMC106325453715831210.1002/alz.13095