Abstract
Alzheimer’s disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.
Highlights
Alzheimer’s disease (AD) comprises about 60%–70% of all dementia cases [1]
weighted gene co-expression network analysis (WGCNA) revealed that a list of molecules in energy metabolism changed significant in Amyloid precursor protein (APP) mice versus that in control mice including those that were closely related to the Sirtuin 3 (Sirt3) signal pathway (Table 1)
The Nicotinamide adenine dinucleotide (NAD)+ level and NAD+/ NADH ratio were directly related with Sirt3 activity
Summary
Alzheimer’s disease (AD) comprises about 60%–70% of all dementia cases [1]. Around 14–16 million Americans will be diagnosed with AD by 2050 unless new treatments are identified [2]. The incidence and burden of AD increase dramatically with age [3, 4]. Mounting evidence suggests that cerebral hypometabolism is strongly related with cognitive impairment in AD [5,6,7]. Is hypometabolism associated with impaired memory, but it is thought as a predictor for the decline of a multitude of other cognitive functions. There is an inverse relationship between amyloid-β (Aβ) deposition and glucose metabolism [8]. Hypometabolism may be triggered by amyloid toxicity. Hypometabolism can mediate and/ or exacerbate effects of amyloid toxicity
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