NAD <sup>+</sup> reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of <i>EVA1C</i>
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
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.