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

Abstract

Females with Alzheimer's disease (AD) present accelerated damage to cholinergic neurons and undergo accelerated cognitive decline compared to males, but the underlying mechanisms are incompletely understood. Here, we report that tRNA fragments (tRFs) carrying complementary sequences to cholinergic transcripts (CholinotRFs) may causally contribute to both these phenomena. We found that the nucleus accumbens of female brains, a brain region enriched in cholinergic neurons, exhibits larger CholinotRF decreases compared to hypothalamic or cortical tissues. These CholinotRFs are largely of mitochondrial genome origin, and their reduced levels are correlated with elevated levels of their predicted cholinergic associated mRNA targets. Additionally, AD temporal cortices showed sex-specific changes in distinct cell populations' levels of cholinergic transcripts. Moreover, cholinergic differentiation of human-originated neuronal cell lines was accompanied by sex-specific elevation of CholinotRFs, supporting the role of CholinotRFs in cholinergic regulation. Our findings highlight possible CholinotRF involvement in the AD sex-specific cholinergic loss and cognitive deterioration.

Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via beta-Klotho and Perilipin 2

“…Unlike the ‘ changing of the guards’ exchange of Cholinergic-targeting miRs to tRFs in blood cells from ischemic stroke patients [31], or the sex- and disease-related loss of tRFs in the brain of women living with Alzheimer’s disease [32], we observed hepatic ‘in tandem’ decline of LysTTT-5’tRFs and miR-194-5p, which may jointly contribute to the steatosis process through complementary impacts on distinct pathways. Supporting human relevance, miR-194-5p decline also occurred in human-originated Hep G2 cells following a short 48h exposure to OA (∼10%), with further reduction after 72h and one week exposure to OA (∼20%).…”

“…The initial elevation in LysTTT-5’tRF following short exposure to OA is potentially an attempt of the cells to cope with the cellular stress due to the lipid overload exposure, which may lead to enhanced tRNA cleavage and LysTTT-5’tRF production. However, after long exposure to OA, the hepatocytes tRNA reservoir may be depleted, ultimately resulting in decreased levels of LysTTT-5’tRFs and weaker protection from LDs accumulation, and in essence mimicking the female-specific depletion of mitochondrial-originated tRFs from nucleus accumbens [32].…”

“…Notably, tRFs are generated by nucleolytic processing of intact tRNAs of nuclear and mitochondrial genome origins, and were recently found to be causally involved in the surveillance of cell proliferation, regulation of gene expression, RNA processing, tumor suppression, and neurodegeneration [27–30]. In ischemic stroke patients, we found tRFs targeted to cholinergic transcripts to replace cholinergic-targeting miRs in nucleated blood cells [31]; and in women living with Alzheimer’s disease, we identified depletion of such tRFs, but not miR stores, to reflect the females-accelerated cognitive decline [32].…”

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

“…tRFs that modulate cholin-ergic 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. Basal forebrain cholinergic neurons express estrogen receptors, 58 and estradiol regulates cholinergic neurotransmission by increasing choline acetyltransferase levels in the basal forebrain and hippocampal ACh release.…”

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

“…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.…”