Comment; Reduced cerebral NAD+/NADH ratio means impaired energy metabolism in the cell. Supplementation with Nicotinamide Riboside lessened the damage, the pTau pathology and reversed the DNA damage, neuroinflammation, hippocampal apoptosis (cell death where memory is formed), and hippocampal neural synaptic connections.
Emerging findings suggest that compromised cellular bioenergetics
and DNA repair contribute to the pathogenesis of Alzheimer’s
ease (AD), but their role in disease-defining pathology is unclear
We developed a DNA repair-deficient 3xTgAD/Polβ+/− mouse that
exacerbates major features of human AD including phosphorylated
Tau (pTau) pathologies, synaptic dysfunction, neuronal death,
cognitive impairment. Here we report that 3xTgAD/Polβ+/− mice
have a reduced cerebral NAD+/NADH ratio indicating impaired cere
bral energy metabolism, which is normalized by nicotinamide riboside
(NR) treatment. NR lessened pTau pathology in both 3xTgAD and
3xTgAD/Polβ+/−mice but had no impact on amyloid βpeptide
accumulation. NR-treated 3xTgAD/Polβ+/− mice exhibited reduced
DNA damage, neuroinflammation, and apoptosis of hippocampal
neurons and increased activity of SIRT3 in the brain. NR improved
cognitive function in multiple behavioral tests and restored hippo
campal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ+/−mice
In general, the deficits between genotypes and the benefits of
were greater in 3xTgAD/Polβ+/− mice than in 3xTgAD mice.
findings suggest a pivotal role for cellular NAD+depletion upstream
of neuroinflammation, pTau, DNA damage, synaptic dysfunction
and neuronal degeneration in AD. Interventions that bolster neuro
nal NAD+ levels therefore have therapeutic potential for AD.
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