Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease

• Published in: International journal of molecular sciences Vol. 22; no. 9; p. 4850
• Main Authors: Sharma, Chanchal, Kim, Sehwan, Nam, Youngpyo, Jung, Un Ju, Kim, Sang Ryong
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-05-2021; MDPI
• Subjects: Adenosine triphosphate; Age; Aging; Alzheimer's disease; Amyloid precursor protein; Animal cognition; Apoptosis; Bioenergetics; Calcium (intracellular); Calcium (mitochondrial); Calcium buffering; Cholinergic transmission; Cholinergics; Cognitive ability; Degeneration; Enzymes; free radical; Free radicals; Homeostasis; Hypotheses; Impairment; Inflammation; Metabolism; Metabolites; Mitochondria; Mitochondrial DNA; mitophagy; Mutation; Neurodegeneration; Neurofibrillary tangles; Neurons; Neuroprotection; Oxidative stress; Pathogenesis; Pathology; Plaques; Review; Synaptic plasticity; Synaptic transmission
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22094850

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.