Sofie Lautrup, Shu-Qin Cao, Xi Long, Bonnie Hei Man Liu, Beatriz Escobar-Doncel, Aristide Ferrante, Johannes Frank, Tomas Schmauck-Medina, Geoffrey Ho Duen Leung, Kristina Xiao Liang, Ning Lu, Katerina Veverova, Martin Vyhnalek, Frank W Pun, Alex Zhavoronkov, Evandro Fei Fang
The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
INTRODUCTION: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+-mitophagy axis contributes to brain aging and neurodegeneration.
METHODS: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.
RESULTS: The NAD+-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.
DISCUSSION: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+-mitophagy axis as a central player in brain aging and AD.