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

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Abstract

Aging 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 acetylation 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 hyperexcitability. 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. Finally, SIRT3 haploinsufficiency in middle-aged App/Ps1 double mutant transgenic mice results in a significant increase in Aβ load compared with App/Ps1 double mutant mice with normal SIRT3 levels. Collectively, our findings suggest that SIRT3 plays an important role in protecting neurons against Aβ pathology and excitotoxicity.

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Data Availability

Data are available from the National Institute on Aging Intramural Research Program.

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Acknowledgements

We thank Dr. David Gius (NCI) for providing breeding pairs of Sirt3-/- mice. This work was supported by the Intramural Research Program of the National Institute on Aging, NIH.

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This research was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health.

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IP, NG, JW, CM, RW, SM, and AC performed experiments and analyzed data. AC, MPM, IP, NG, and MG wrote the manuscript.

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Correspondence to Aiwu Cheng or Mark P. Mattson.

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Perone, I., Ghena, N., Wang, J. et al. Mitochondrial SIRT3 Deficiency Results in Neuronal Network Hyperexcitability, Accelerates Age-Related Aβ Pathology, and Renders Neurons Vulnerable to Aβ Toxicity. Neuromol Med 25, 27–39 (2023). https://doi.org/10.1007/s12017-022-08713-2

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