Peripheral Mitochondrial Dysfunction: A Potential Contributor to the Development of Metabolic Disorders and Alzheimer’s Disease

SIMPLE SUMMARY: Alzheimer’s disease (AD) is a progressive disease, where dementia symptoms gradually worsen. The causes of AD are complex and are characterized by changes in the brain that lead to the accumulation of two proteins, amyloid beta and tau, forming structures called plaques and tangles, respectively. It is challenging to identify the mechanisms for the initiation and progression of AD. Therefore, multiple hypotheses have been proposed regarding its origin, suggesting mitochondrial dysfunction or metabolic disorders, or both, playing a role. The association of metabolic diseases such as diabetes with AD has been widely studied and more recently, emerged as a promising strategy for AD prevention through anti-diabetic intervention. Further, oxidative stress and inflammation derived from peripheral mitochondrial dysfunction have also been suggested as alternative contributors of AD pathogenesis; however, the mechanism is still unknown. In this review, we summarize the possible interactions between metabolic disorders, mitochondrial dysfunction and AD, and, accordingly, future therapeutic strategies that could target peripheral mitochondrial impairment to prevent and/or treat AD. ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by loss of function and eventual death of neurons in the brain. Multiple studies have highlighted the involvement of mitochondria in the initiation and advancement of neurodegenerative diseases. Mitochondria are essential for ATP generation, bioenergetics processes, the regulation of calcium homeostasis and free radical scavenging. Disrupting any of these processes has been acknowledged as a major contributor to the pathogenesis of common neurodegenerative diseases, especially AD. Several longitudinal studies have demonstrated type 2 diabetes (T2D) as a risk factor for the origin of dementia leading towards AD. Even though emerging research indicates that anti-diabetic intervention is a promising option for AD prevention and therapy, results from clinical trials with anti-diabetic agents have not been effective in AD. Interestingly, defective mitochondrial function has also been reported to contribute towards the onset of metabolic disorders including obesity and T2D. The most prevalent consequences of mitochondrial dysfunction include the generation of inflammatory molecules and reactive oxygen species (ROS), which promote the onset and development of metabolic impairment and neurodegenerative diseases. Current evidence indicates an association of impaired peripheral mitochondrial function with primary AD pathology; however, the mechanisms are still unknown. Therefore, in this review, we discuss if mitochondrial dysfunction-mediated metabolic disorders have a potential connection with AD development, then would addressing peripheral mitochondrial dysfunction have better therapeutic outcomes in preventing metabolic disorder-associated AD pathologies.