Nicotinamide nucleotide transhydrogenase deficiency impairs neuronal function via energy metabolism dysregulation in Alzheimer's disease

  • Free Radic Biol Med. 2026 Sep:253:681-697. doi: 10.1016/j.freeradbiomed.2026.05.341.
Xinyao Wan  1 ,  Wenwen Lu  1 ,  Shanyu Liu  1 ,  Yi Zhao  1 ,  Jiawen Hu  1 ,  Xinyu Ding  1 ,  Panhua Gu  1 ,  Yan Zou  2 ,  Biao Jiang  3 ,  Yifeng Yang  4
Affiliations
  • 1. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
  • 2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
  • 3. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
  • 4. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China. Electronic address: [email protected].
PMID: 42250783 DOI: 10.1016/j.freeradbiomed.2026.05.341
Abstract

Alzheimer's disease (AD) is characterized by mitochondrial dysfunction and oxidative stress, which drive synaptic damage. Proteomic analysis in an AD mouse model identified significant downregulation of Nicotinamide Nucleotide Transhydrogenase (NNT), a mitochondrial enzyme crucial for maintaining redox balance by regenerating NADPH. This loss created a pro-oxidant shift, sensitizing neurons to Amyloid-β (Aβ) toxicity and triggering mitochondrial collapse-evidenced by loss of membrane potential and depletion of energy and Antioxidants. NNT deficiency alone was sufficient to induce AD-like synaptic loss and cognitive deficits, independent of amyloid or tau pathology. Functionally, NNT acted as a metabolic-transcriptional hub, promoting pro-synaptic gene expression and synaptic protein homeostasis. It supported synaptic resilience through dual mechanisms: preserving redox balance to protect synaptic components and facilitating clearance of toxic Aβ accumulation. These findings could position NNT dysfunction as a critical, non-amyloid factor in AD pathogenesis, linking mitochondrial bioenergetics to synaptic integrity. Enhancing NNT activity thus represents a promising therapeutic strategy to bolster metabolic resilience and cognitive function in AD.

Keywords
Alzheimer's disease; Amyloid-β; Animal model; Mitochondrial dysfunction; Nicotinamide nucleotide transhydrogenase; Reactive oxygen species.
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