NAD+ - and EVA1-C-dependent reversal of neurological deficits is mediated by differential alternative RNA splicing in tauopathic animal models

Aberrant alternative splicing events (ASEs) are emerging as a new hallmark of aging and are linked to age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). AD brains are characterized by abundant intracellular proteinaceous aggregates, including neurofibrillary tangles (NFTs). Although NAD+ and related metabolites can slow down AD progression, the effects of NAD+ on ASEs in AD remain unclear. This study investigates the relationships between NAD+ metabolism, ASEs and AD or AD-like pathologies including tauopathies using deep-learning AI-based algorithms to predict protein structures and protein-protein interactions as well as experimental tauopathy models including hTau.P301S transgenic mice and transgenic hTau[P301L] Caenorhabditis elegans. Mouse transcriptomic data were mined to detect ASEs that were differentially induced in the presence of NAD+ precursor nicotinamide riboside (NR) with specific focus on the Eva1-C locus. The results reveal that the relative abundance of Eva1-C isoforms is sensitive to both the concentration of NR and to tauopathy genotype. NAD+ abundance/metabolic status modulates ASEs and the expression of EVA1-C isoforms, which in turn regulate the interaction with the key proteins, BAG-1 and HSP70, involved in orchestrating protein homeostasis. Importantly, EVA1-C is dramatically reduced in the postmortem entorhinal cortex and hippocampal neurons from 20 Braak 5/6 AD patients compared to 20 of cognitive normal humans. Thus, this study supports the novel idea that NAD+ metabolism modulates abundance of specific mRNA isoforms, and that ASEs influence disease progression in model tauopathies and potentially AD. These results could facilitate future development of NAD+-based splice-switching therapeutics for AD.