Abstract Body

Early deficits in the acetylcholine network have long been known for Alzheimer’s Disease (AD), and the cholinergic nuclei are damaged long before the emergence of disease symptoms. However, the role of non-coding RNA (ncRNA) regulators of the cholinergic network in the early emergence of damage to the deep brain nuclei and in the progression of the disease process remains unknown. Here, we report expression changes of specific transfer RNA fragments (tRFs) in the nucleus accumbens from AD patient brains. Transfer RNA fragments (tRFs) are a recently re-discovered small non coding RNA class shown to operate like microRNAs to block the expression of mRNA targets whose levels increase in blood cells from ischemic stroke patients (Winek et al., 2020). Specifically, we analyzed short RNA-sequencing datasets from 348 nucleus accumbens tissues of AD patients and matched controls from the Religious Orders Study. Our analysis identified significant changes in the levels of several tRFs, whose levels increased in correlation with the cognitive decline of the donor patients, but was not corelated with age. Notably, the identified tRFs carry complementary sequence motifs to several AD-related coding transcripts including the inflammation-regulating lipoxygenase ALOX5, the ATP-biding transporter ABCC2 and the beta-amyloid regulator SOAT1, which is known to catalyze the formation of fatty acid cholesterol esters. Our findings add these tRF candidates to the growing list of non-coding RNA regulators of gene expression in the brain of AD patients and open new venues for pursuing their roles as therapeutic targets.