Mitochondria, cognitive impairment, and Alzheimer's disease

Abstract

To date, the beta amyloid (Abeta) cascade hypothesis remains the main pathogenetic model of Alzheimer's disease (AD), but its role in the majority of sporadic AD cases is unclear. The "mitochondrial cascade hypothesis" could explain many of the biochemical, genetic, and pathological features of sporadic AD. Somatic mutations in mitochondrial DNA (mtDNA) could cause energy failure, increased oxidative stress, and accumulation of Abeta, which in a vicious cycle reinforce the mtDNA damage and the oxidative stress. Despite the evidence of mitochondrial dysfunction in AD, no causative mutations in the mtDNA have been detected so far. Indeed, results of studies on the role of mtDNA haplogroups in AD are controversial. In this review we discuss the role of the mitochondria, and especially of the mtDNA, in the cascade of events leading to neurodegeneration, dementia, and AD.

Figure 1

A proposed mechanism of mitochondrial induced cell death in Alzheimer's disease. Legend: Aβ; amyloid-β; ROS reactive oxygen species; ETC electron transport chain; mtPTP mitochondrial permeability transition pore; C cytochrome c ; IMM inner mitochondrial membrane; OMM outer mitochondrial membrane; APP amyloid precursor protein; TOM and TIM protein importation translocases of the mitochondrial outer and inner membranes. For further details, see text. (Modified from Mancuso M et al., Antioxid Redox Signal 2007;9:1631–1646).