Abstract
Alzheimer’s disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aβ) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aβ is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-β precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aβ1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD.
Highlights
Despite decades of research, our knowledge of Alzheimer’s disease (AD) pathogenesis remains incomplete
A mitochondrial cascade hypothesis was proposed emphasizing the role of mitochondrial bioenergetics in AD [24,25,26,27]. This hypothesis further states that Aβ is an epiphenomenon of AD pathology rather than the primary cause, a notion consistent with the finding that early mitochondrial dysfunction can lead to cognitive impairment, increased Aβ aggregation, and AD pathogenesis [25,26]
Beck et al (2016) reported a 67% reduction in synaptic mitochondrial Fo-adenosine triphosphate (ATP) synthase activity in an AD mouse model compared to age-matched controls, accompanied by a reduction in ATP, increased oxidative stress, and reduced ∆Ψm due to opening of the mitochondrial permeability transition pore, which results in release of apoptotic effectors into the cytoplasm [74]
Summary
Our knowledge of Alzheimer’s disease (AD) pathogenesis remains incomplete. Mitochondrial dysfunction is implicated in a myriad of pathogenic cellular processes, including reactive oxygen species (ROS) generation and ensuing oxidative stress, intracellular calcium deregulation, and apoptosis, strongly suggesting involvement either as a precipitating factor or driver of AD progression [16,17,18,19]. A mitochondrial cascade hypothesis was proposed emphasizing the role of mitochondrial bioenergetics in AD [24,25,26,27] This hypothesis further states that Aβ is an epiphenomenon of AD pathology rather than the primary cause, a notion consistent with the finding that early mitochondrial dysfunction can lead to cognitive impairment, increased Aβ aggregation, and AD pathogenesis [25,26]. Aβ and tau pathology and further free radicals leading to oxidative stress, thereby aggravating the effect of Aβ and tau pathology and further exacerbating exacerbating mitochondrial damage, synaptic dysfunction, cognitive impairment, and memory loss.
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