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

Dana Shulman, Serafima Dubnov, Tamara Zorbaz, Nimrod Madrer, Iddo Paldor, David A. Bennett, Sudha Seshadri, Elliott J. Mufson, David S. Greenberg, Yonatan Loewenstein, Hermona Soreq

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Introduction: 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). Methods: 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. Results: 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. Discussion: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

Original languageEnglish (US)
Pages (from-to)5159-5172
Number of pages14
JournalAlzheimer's and Dementia
Issue number11
StatePublished - Nov 2023
Externally publishedYes


  • Alzheimer's disease
  • bioinformatics
  • cholinergic system
  • cognitive impairment
  • sex-differences
  • tRNA fragments (tRFs)

ASJC Scopus subject areas

  • Clinical Neurology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Health Policy
  • Developmental Neuroscience
  • Epidemiology


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