Title

Apolipoprotein E regulates mitochondrial function through the PGC-1α-sirtuin 3 pathway

Document Type

Article

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.

Keywords

apolipoprotein, hypometabolism, sirtuin

Medical Subject Headings

Animals; Apolipoprotein E3 (genetics, metabolism); Apolipoprotein E4 (genetics, metabolism); Cells, Cultured; Cerebral Cortex (cytology); Gene Expression Regulation; Mice, Knockout, ApoE; Mice, Transgenic; Mitochondria (metabolism); Neurons (physiology); Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics, metabolism); Sirtuin 3 (genetics, metabolism)

Publication Date

12-6-2019

Publication Title

Aging

E-ISSN

1945-4589

Volume

11

Issue

23

First Page

11148

Last Page

11156

PubMed ID

31808750

Digital Object Identifier (DOI)

10.18632/aging.102516

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