Abstract
Alzheimer’s disease (AD) patients display widespread mitochondrial defects. Brain hypometabolism occurs alongside mitochondrial defects, and correlates well with cognitive decline. Numerous theories attempt to explain AD mitochondrial dysfunction. Groups propose AD mitochondrial defects stem from: (1) mitochondrial-nuclear DNA interactions/variations; (2) amyloid and neurofibrillary tangle interactions with mitochondria, and (3) mitochondrial quality control defects and oxidative damage. Cells respond to mitochondrial dysfunction through numerous retrograde responses including the Integrated Stress Response (ISR) involving eukaryotic initiation factor 2α (eIF2α), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). AD brains activate the ISR and we hypothesize mitochondrial defects may contribute to ISR activation. Here we review current recognized contributions of the mitochondria to AD, with an emphasis on their potential contribution to brain stress responses.
Highlights
Sporadic Alzheimer’s disease (AD) brains possess profound mitochondrial defects, including changes in number, morphology, and enzyme activity [1,2,3]
The authors argue cytochrome oxidase (COX) deficiency occurs during normal aging and accelerated COX deficiency contributes to AD progression [31]
Changes in endoplasmic reticulum (ER) calcium levels and protein glycosylation as well as misfolded protein accumulation trigger ER stress leading to eukaryotic initiation factor 2α (eIF2α) phosphorylation and increased activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) [119,120]
Summary
Sporadic Alzheimer’s disease (AD) brains possess profound mitochondrial defects, including changes in number, morphology, and enzyme activity [1,2,3]. Mitochondrial dysfunction in AD is not restricted to the nervous system. Systemic mitochondrial defects occur in AD patients compared to controls [4,5]. Metabolic defects occur alongside mitochondrial abnormalities in AD, providing early markers of disease progression [6]. Mitochondrial dysfunction may contribute to hallmark AD pathology and stimulate stress response pathways
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