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

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<sup>+</sup>) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD<sup>+</sup> enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD<sup>+</sup> 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<sup>+</sup>-induced memory retention is partially dependent on EVA1C, as adeno-associated virus-based <i>Eva1c</i> knockdown in the hippocampal CA1 region annuls NAD<sup>+</sup>-induced memory improvement in pathological Tau-bearing mice. We propose that NAD<sup>+</sup> reduces AD pathologies, at least partially, via amplification of the NAD<sup>+</sup>-<i>EVA1C</i> splicing axis, pointing to a potential splice-switching therapy for AD.

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Publication Details

Journal
Science Advances
Published
2025-11-07
DOI
https://doi.org/10.1126/sciadv.ady9811
Citations
4
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
3.22
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article

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

Ioannis Sotiropoulos, Ruixue Ai, Oscar Junhong Luo, Zhangming Niu et al.
4 citations
Science Advances
RNA Research and Splicing
3.22
article

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

Ioannis Sotiropoulos, Ruixue Ai, Oscar Junhong Luo, Zhangming Niu, Pingjie Wang, Jon Storm‐Mathisen, Qiang Zhang, Guang Xiu Lu, Zeyuan Wang, Evandro Fei Fang, Linda H. Bergersen, Xurui Jin, Manuele Novello, Mariá José Lagartos-Donate, Joana Silva, Farrukh A. Chaudhry, Rajeevkumar Raveendran Nair, Hidehito Kuroyanagi, Shiqi Zhang, Guang Yang, Yang Hu, Chenglong Xie, Guobing Chen, Xiongbin Kang, Carlos Campos‐Marques, Filippos Katsaitis, Shuqin Cao, Junping Pan, Lingyan Mao, N. González, Beatriz Escobar-Doncel, Beatriz Barros‐Santos, Rita Nóbrega‐Martins
article en
4 citations

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<sup>+</sup>) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD<sup>+</sup> enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD<sup>+</sup> 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<sup>+</sup>-induced memory retention is partially dependent on EVA1C, as adeno-associated virus-based <i>Eva1c</i> knockdown in the hippocampal CA1 region annuls NAD<sup>+</sup>-induced memory improvement in pathological Tau-bearing mice. We propose that NAD<sup>+</sup> reduces AD pathologies, at least partially, via amplification of the NAD<sup>+</sup>-<i>EVA1C</i> splicing axis, pointing to a potential splice-switching therapy for AD.

Science AdvancesVol. 11(45)
Oslo University Hospital (NO), Sun Yat-sen University (CN), Jinan University (CN), Zhejiang University of Science and Technology (CN), King's College London (GB), University of Oslo (NO), Bielefeld University (DE), National Centre of Scientific Research "Demokritos" (GR), Wenzhou Medical University (CN), Akershus University Hospital (NO), First Affiliated Hospital of Wenzhou Medical University (CN), University of the Ryukyus (JP), Royal Brompton Hospital (GB), First Affiliated Hospital of Guangzhou Medical University (CN), St Olav's University Hospital (NO), First Affiliated Hospital of Guangzhou University of Chinese Medicine (CN), NORCE Research AS (NO), Guangdong-Hongkong-Macau Joint Laboratory of Collaborative Innovation for Environmental Quality (CN), First Affiliated Hospital of Zhengzhou University (CN), Mindray (China) (CN), First Affiliated Hospital of Jinan University (CN), Imperial College London (GB), King Abdullah University of Science and Technology (SA), Zhejiang University (CN), University of Castilla-La Mancha (ES), Guangzhou Medical University (CN), University of Minho (PT)
Openalex Percentile: Top 7%
RNA Research and Splicing
3.22
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