Abstract
SummaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly. Despite decades of study, effective treatments for AD are lacking. Mitochondrial dysfunction has been closely linked to the pathogenesis of AD, but the relationship between mitochondrial pathology and neuronal damage is poorly understood. Sirtuins (SIRT, silent mating type information regulation 2 homolog in yeast) are NAD‐dependent histone deacetylases involved in aging and longevity. The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption. ND2 and ND4 gene expressions were significantly decreased in patients with AD. p53‐ChIP analysis verified the presence of p53‐binding elements in the human mitochondrial genome and increased p53 occupancy of mitochondrial DNA in AD. SIRT3 overexpression restored the expression of ND2 and ND4 and improved mitochondrial oxygen consumption by repressing mito‐p53 activity. Our results indicate that SIRT3 dysfunction leads to p53‐mediated mitochondrial and neuronal damage in AD. Therapeutic modulation of SIRT3 activity may ameliorate mitochondrial pathology and neurodegeneration in AD.
Highlights
Alzheimer’s disease (AD), the most common age-dependent neurodegenerative disease, is characterized by irreversible memory loss and cognitive decline
SIRT3 mRNA and protein levels are decreased in AD
To verify the altered SIRT3 gene expression, we examined mRNA expression in frontal cortex of AD and normal subjects using quantitative PCR analysis and found that SIRT3 mRNA is significantly decreased in patients with AD (n = 13) compared to normal subjects (n = 13) (P < 0.05) (Fig. 1B)
Summary
Alzheimer’s disease (AD), the most common age-dependent neurodegenerative disease, is characterized by irreversible memory loss and cognitive decline. Patients with AD may exhibit a range of behavioral and psychological symptoms including mood changes. Degeneration of subcortical cholinergic basal forebrain neurons may lead to the dysfunction of gamma-amino butyric acid (GABA)ergic and glutamatergic neuronal systems, and degeneration of subcortical serotonergic and aminergic nuclei may contribute to AD symptoms (Coyle et al, 1983; Canter et al, 2016). Epigenetic changes encompass an array of molecular modifications to both DNA and chromatin, including transcription factors and cofactors. SIRTs (mammalian homolog of silent mating type information regulation 2 homolog in yeast) are a family of epigenetic mediators that play various functions in aging, chromatin integrity, metabolic regulation, and longevity (Kim et al, 2007; Hirschey et al, 2010). SIRT1 has been mostly widely studied and its level is changed in AD brains (Shi et al, 2005; Someya et al, 2010; Kim et al, 2011)
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