Abstract
Cerebral hypometabolism is a pathophysiological hallmark of Alzheimer’s disease (AD). Our previous studies found that a mitochondrial protein, sirtuin3 (Sirt3), was down-regulated in human AD postmortem brains. Sirt3 protected neurons against oligo-amyloid β-42 induced hypometabolism in human Apolipoprotein E4 (ApoE4) transgenic mice. However, how ApoE affects mitochondrial function and its proteins such as Sirt3 remains unclear.We characterized and compared levels of Sirt3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α, a Sirt3 activator), oxidative stress proteins, synaptic proteins, cognitive task performance and ATP production in 12-month old human ApoE4 and ApoE3 transgenic mice, and assessed changes in Sirt3 expression on cellular metabolism in primary neurons from ApoE4 and ApoE3 transgenic mice.Compared to ApoE3 mice, Sirt3 and PGC-1α levels were significantly lower in ApoE4 mice. Learning and memory, synaptic proteins, the NAD+/ NADH ratios, and ATP production were significantly lower in ApoE4 mice as well. Sirt3 knockdown reduced the oxygen consumption and ATP production in primary neurons with the human ApoE3, while Sirt3 overexpression protected these damages in ApoE4 neurons.Our findings suggest that ApoE4 suppresses mitochondrial function via the PGC-1α- Sirt3 pathway. This discovery provides us novel therapeutic targets for the treatment and prevention of AD.
Highlights
Apolipoprotein E4 (ApoE4) is the major genetic risk factor for late-onset Alzheimer’s disease (AD) [1]
Our findings suggest that ApoE4 suppresses mitochondrial function via the PGC-1α- Sirt3 pathway
Sirt3 is an NAD+-dependent protein, which deacetylates and activates multiple substrates that are related with ATP production [24,25,26], we tested the effect of ApoE4 on NAD+/ NADH ratio and ATP production
Summary
Apolipoprotein E4 (ApoE4) is the major genetic risk factor for late-onset Alzheimer’s disease (AD) [1]. ApoE4 carriers have reduced glucose metabolism in brain and this reduction may develop at earliest stage of amyloid-β deposition [2,3,4,5,6,7,8,9,10]. We and others reported ApoE4 was associated with reduced ATP levels in the cerebral cortex and this reduction in cerebral energy production was detrimental to learning and memory in mouse models of AD [11,12,13,14]. Increasing Sirt expression by genetic engineering improved energy production and neuroprotection against oligo-amyloid β-42 induced hypometabolism in ApoE4 transgenic mice [17, 18]. How ApoE affects mitochondrial function and Sirt3-related pathway remains unclear
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