Role of Cholinergic Transcripts in Sex-Specific Declines of Alzheimer Disease: Hermona Seroq, PhD

WATCH TIME: 9 minutes

"There are 2 genetic sources from which transfer RNAs are decoded. One is the nuclear DNA, the other is mitochondrial DNA. Mitochondria we inherit from our mothers, so this is a mother to daughter process."

Alzheimer disease (AD), the most common cause of dementia, contains neuropathic features in subcortical nuclei that precede neurofibrillary tangle (NFT) development within the mesial temporal cortex. AD lesions involve accumulation of multimeric amyloid-ß fibrils forming neuritic plaques and NFTs consisting of hyperphosphorylated tau and leading to loss of synapses, dendrites, and eventually, neurons. Females with AD tend to suffer dementia and loss of cholinergic neurons compared with males, although the underlying mechanisms are unknown.

Recently published in Alzheimer’s & Dementia, a study aimed to assess causal contributors to this phenomena, specifically, looking at changes in transfer RNS fragments targeting cholinergic transcripts (CholinotRFs). Led by Hermona Seroq, PhD, the trial included RNA-sequencing data derived from the nucleus accumbens (NAc) brain region of participants in the Rush Alzheimer’s Disease Center and Memory and Aging (MAP) cohorts. When compared with hypothalamic or cortical tissues from AD brains, findings identified declined CholinotRFs in the NAc of cognitively impaired donors that was greater in females than in males, similar to the more prevalent and rapid cognitive decline in females.

Findings also showed that reduced CholinotRF levels in the NAc of females with AD were accompanied by elevated levels of their complimentary cholinergic mRNA transcripts, indicating that the observed decline interrupted the miR-like properties of CholinotRFs that limit cholinergic features. Following the publication, Seroq, a professor of molecular neuroscience at the Edmond and Lily Safra Center for Brain Sciences, Israel, sat down with NeurologyLive® to provide an overview of the study and its significance. In addition, Seroq discussed the need for research assessing sex-specific differences in AD, and the reasons for it.

REFERENCE
1. Shulman D, Dubnov S, Zorbaz T, et al. Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer’s disease. Alzheim & Dement. Published March 23, 2023. doi:10.1002/alz.13095