NADreverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of.

Abstract

Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer's disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NADenhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NADaugmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD-induced memory retention is partially dependent on EVA1C, as adeno-associated virus-basedknockdown in the hippocampal CA1 region annuls NAD-induced memory improvement in pathological Tau-bearing mice. We propose that NADreduces AD pathologies, at least partially, via amplification of the NAD-splicing axis, pointing to a potential splice-switching therapy for AD.