NAD+ reverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of EVA1C.

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Title:NAD⁺ reverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of EVA1C.

Author(s):Ai R, Mao L, Jin X, Campos-Marques C, Zhang SQ, Pan J, Lagartos-Donate MJ, Cao SQ, Barros-Santos B, Nóbrega-Martins R, Katsaitis F, Yang G, Xie C, Kang X, Wang P, Novello M, Hu Y, Bergersen LH, Storm-Mathisen J, Kuroyanagi H, Escobar-Doncel B, González NV, Chaudhry FA, Wang Z, Zhang Q, Lu G, Sotiropoulos I, Niu Z, Chen G, Nair RR, Silva JM, Luo OJ, Fang EF.

‌Journal Name, Year, Volume(Issue): Page range: Sci Adv. 2025 Nov 7;11(45):eady9811

DOI: 10.1126/sciadv.ady9811

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 NAD⁺enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD⁺augmentation 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-based Eva1c knockdown in the hippocampal CA1 region annuls NAD⁺-induced memory improvement in pathological Tau-bearing mice. We propose that NAD⁺reduces AD pathologies, at least partially, via amplification of the NAD⁺-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.

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