Mitochondrial SIRT3 Deficiency Results in Neuronal Network Hyperexcitability, Accelerates Age-Related A β Pathology, and Renders Neurons Vulnerable to Aβ Toxicity

AbstractAging is the major risk factor for Alzheimer ’s disease (AD). Mitochondrial dysfunction and neuronal network hyperexcitability are two age-related alterations implicated in AD pathogenesis. We found that levels of the mitochondrial protein deacetylase sirtuin-3 (SIRT3) are significantly reduced, and consequently mitochondria protein acetylat ion is increased in brain cells during aging. SIRT3-deficient mice exhibit robust mitochondrial protein hyperacetylation and reduced mitochondrial mass during aging. Moreover, SIRT3-deficient mice exhibit epileptiform and burst-firing electroencephalogram activity indicating neuronal network hyperex citability. Both aging and SIRT3 deficiency result in increased sensitivity to kainic acid-induced seizures. Exposure of cultured cerebral cortical neurons to amyloid β-peptide (Aβ) results in a reduction in SIRT3 levels and SIRT3-deficient neurons exhibit heightened sensitivity to Aβ toxicity. F inally, SIRT3 haploinsufficiency in middle-agedApp/Ps1 double mutant transgenic mice results in a significant increase in A β load compared withApp/Ps1 double mutant mice with normal SIRT3 levels. Collectively, our findings suggest that SIRT3 plays an important role in protecting neurons against A β pathology and excitotoxicity.

Source: NeuroMolecular Medicine - June 24, 2022 Category: Neurology Source Type: research