Mitochondrial SIRT3 Deficiency Results in Neuronal Network Hyperexcitability, Accelerates Age-Related Aß Pathology, and Renders Neurons Vulnerable to Aß Toxicity.
Neuromolecular Med
; 25(1): 27-39, 2023 03.
Article
em En
| MEDLINE
| ID: mdl-35749057
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 ß-peptide (Aß) results in a reduction in SIRT3 levels and SIRT3-deficient neurons exhibit heightened sensitivity to Aß toxicity. Finally, SIRT3 haploinsufficiency in middle-aged App/Ps1 double mutant transgenic mice results in a significant increase in Aß 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 Aß pathology and excitotoxicity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sirtuína 3
/
Doença de Alzheimer
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Neuromolecular Med
Assunto da revista:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos