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

作者：Ruixue Ai, Lingyan Mao, Xurui Jin, Carlos Campos‐Marques, Shiqi Zhang, J. Pan, Mariá José Lagartos-Donate, Shuqin Cao, Beatriz Barros‐Santos, Rita Nóbrega‐Martins, Filippos Katsaitis, Guang Yang, Chenglong Xie, Xiongbin Kang, Pingjie Wang, Manuele Novello, Yang Hu, Linda H. Bergersen, Jon Storm‐Mathisen, Hidehito Kuroyanagi, Beatriz Escobar-Doncel, Noemí Villaseca González, Farrukh A. Chaudhry, Zeyuan Wang, Qiang Zhang, Guang Lu, Ioannis Sotiropoulos, Zhangming Niu, Guobing Chen, Rajeevkumar Raveendran Nair, Joana Silva, Oscar Junhong Luo, Evandro Fei Fang · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.ady9811 · 被引用次数：12 · 研究领域：RNA Research and Splicing、Genetic Neurodegenerative Diseases、RNA modifications and cancer

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.