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

Abstract

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.

Sex‐dependent cholinergic effects on amyloid pathology: A translational study

“…Additionally, sex‐dependent changes in transfer‐RNA‐fragments (tRFs), which are non‐coding RNA regulators, have been reported in AD. tRFs that modulate cholinergic transcripts in the nucleus accumbens may potentially lead to accelerated cognitive decline in females with AD 57 . Furthermore, sex hormones influence numerous neural/behavioral functions.…”

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer’s disease-linked brain microRNAs and tRNA fragments

“…Considering our recent findings of cognition-related female-specific AD declines of tRF regulators of cholinergic mRNAs 24 , this suggests links between Klotho-KO-induced transcriptomic perturbations to sex differences in dementia. Indeed, both miR-129-5p and miR-335-5p are also altered in the Nucleus Accumbens of female AD patients, compared to controls with no cognitive impairment 16 (Fig. 2J; Supplementary Table 5), and with the same direction of change in human AD and murine Klotho KO brains.…”

“…I) Log 2 (CPM) counts of hsa-miR-129-5p and hsa-miR-335-5p in AD paPents’ CSF and cogniPvely healthy controls, divided by sex 36 (**: p adj <0.01). J) Log 2 (CPM) counts of hsa-miR-129-5p and hsa-miR-335-5p in the Nucleus Accumbens of AD paPents (cogdx=4), compared to cogniPvely healthy individuals (cogdx=1), divided by sex 16 (**: p adj <0.01).…”

Biogenesis, function, and landscape of tsRNAs in central nervous system diseases

“…[59][60][61][62][63] An intriguing recent study revealed the contribution of cholinergic targeting tRFs in the nucleus accumbens to the phenomenon of accelerated dementia and cholinergic neuron loss in female AD patients, suggesting the potential of sex-adjusted anticholinesterase therapy in the treatment of AD. 64 As mentioned above, chemical modifications regulate the production of tsRNAs and are involved in the stress response. Zhang et al measured small RNA modification profiles in autopsy samples of prefrontal cortex tissue from AD patients and controls and found that modifications in 30-40-nt fragments (with the majority of tsRNAs), compared with controls, the levels of 2′-O-methylcytidine, 2′-O-methyluridine, and 7-methylguanosine were higher in the AD group.…”

“…Numerous studies have focused on the pathogenic role of calcium dysregulation caused by RyR channel leakage in AD 59–63 . An intriguing recent study revealed the contribution of cholinergic targeting tRFs in the nucleus accumbens to the phenomenon of accelerated dementia and cholinergic neuron loss in female AD patients, suggesting the potential of sex‐adjusted anticholinesterase therapy in the treatment of AD 64 . As mentioned above, chemical modifications regulate the production of tsRNAs and are involved in the stress response.…”