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 ß-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.
Subject(s)
Apolipoprotein E3/metabolism , Apolipoprotein E4/metabolism , Mitochondria/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Sirtuin 3/metabolism , Animals , Apolipoprotein E3/genetics , Apolipoprotein E4/genetics , Cells, Cultured , Cerebral Cortex/cytology , Gene Expression Regulation , Mice, Knockout, ApoE , Mice, Transgenic , Neurons/physiology , Oxygen Consumption , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Sirtuin 3/geneticsABSTRACT
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-ß (Aß)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aß-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 Aß. Sirt3 plays an important role in regulating Aß-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.
