NAD + reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C
- Ruixue Ai
- Lipeng Mao
- Xurui Jin
- Carlos Campos-Marques
- Shi-qi Zhang
- Junping Pan
- Maria Jose Lagartos-Donate
- Shu-Qin Cao
- Beatriz Barros-Santos
- Rita Nóbrega-Martins
- Filippos Katsaitis
- Guang Yang
- Chenglong Xie
- Xiongbin Kang
- Pingjie Wang
- Manuele Novello
- Yang Hu
- Linda Hildegard Bergersen
- Jon Storm-Mathisen
- Hidehito Kuroyanagi
- Beatriz Escobar-Doncel
- Noemí Villaseca González
- Farrukh Abbas Chaudhry
- Zeyuan Wang
- Qiang Zhang
- Guang Lu
- Ioannis Sotiropoulos
- Zhangming Niu
- Guobing Chen
- Rajeevkumar Raveendran Nair
- Joana Margarida Silva
- Oscar Junhong Luo
- Evandro Fei Fang
2025-11-07
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.