Abstract
The pathology of Alzheimer's disease (AD) is characterized by amyloid plaques (aggregates of amyloid-β (Aβ)) and neurofibrillary tangles (aggregates of tau) and is accompanied by mitochondrial dysfunction, but the mechanisms underlying this dysfunction are poorly understood. In this review, we discuss the critical role of mitochondria and the close inter-relationship of this organelle with the two main pathological features in the pathogenic process underlying AD. Moreover, we summarize evidence from AD post-mortem brain as well as cellular and animal AD models showing that Aβ and tau protein trigger mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production, alteration of mitochondrial dynamics, and interaction with mitochondrial proteins. A vicious cycle as well as several vicious circles within the cycle, each accelerating the other, can be drawn, emphasizing the synergistic deterioration of mitochondria by tau and Aβ.
Highlights
With the increasing average lifespan of humans, Alzheimer’s disease (AD) is the most common neurodegenerative disorder among elderly individuals
Using neuronal PC12 cells, we found that expression of one known amyloid precursor protein (APP) gene mutation, the ‘Swedish APP (APPSw)’ double mutation (KM670/671NL), leads to an enhanced vulnerability of these cells to oxidative stress and mitochondrial dysfunction, mediated by different caspases and the stress-activated protein kinase pathway [34,35,36] (Figure 3)
Our findings indicate that mitochondria in tau transgenic pR5 mice display enhanced vulnerability towards Aβ insult in vitro [57,65], suggesting a synergistic action of tau and Aβ pathologies
Summary
With the increasing average lifespan of humans, Alzheimer’s disease (AD) is the most common neurodegenerative disorder among elderly individuals. In another transgenic mouse model, APPS/L, which combines the Swedish (K670M/N671L) with the London (V717I) mutation in the human APP gene, an early energy dysfunction was found as shown by a decreased mitochondrial membrane potential as well as decreased ATP levels at 3 months of age, when Aβ levels are elevated but plaques are not yet present [5,14,37].
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