Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies

Abstract

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by the progressive loss of cholinergic neurons, leading to the onset of severe behavioral, motor and cognitive impairments. It is a pressing public health problem with no effective treatment. Existing therapies only provide symptomatic relief without being able to prevent, stop or reverse the pathologic process. While the molecular basis underlying this multifactorial neurodegenerative disorder remains a significant challenge, mitochondrial dysfunction appears to be a critical factor in the pathogenesis of this disease. It is therefore important to target mitochondrial dysfunction in the prodromal phase of AD to slow or prevent the neurodegenerative process and restore neuronal function. In this review, we discuss mechanisms of action and translational potential of current mitochondrial and bioenergetic therapeutics for AD including: mitochondrial enhancers to potentiate energy production; antioxidants to scavenge reactive oxygen species and reduce oxidative damage; glucose metabolism and substrate supply; and candidates that target apoptotic and mitophagy pathways to remove damaged mitochondria. While mitochondrial therapeutic strategies have shown promise at the preclinical stage, there has been little progress in clinical trials thus far.

African locust bean (Parkia biglobosa, Jacq Benth) leaf extract affects mitochondrial redox chemistry and inhibits angiotensin-converting enzyme in vitro

“…Decreased ΔΨm, due to the uncoupling of electron flow from ATP synthesis by increased proton permeability of the inner mitochondrial membrane, can reduce ROS production at complex I by decreasing NAD(P)H/NAD(P) + and possibly by decreasing the life span of the semiquinone radical [39]. Such decrease in the mitochondrial membrane potential (ΔΨm) primarily attenuates mitochondrial RO production with a consequential decrease in mitochondrial Ca 2+ uptake [40], preventing mitochondrial calcium overload and the a b c d e f Fig. 5 Respective effect of Parkia biglobosa leaf extract (PBE) and catechin on basal ROS production (a and b), Ca 2+ − induced (c and d) and SNP-induced (e and f) aggravation of ROS generation in isolated rats' liver mitochondria.…”

“…This might account for the superior mitochondrial ROS mitigating property of PBE over catechin. Such mild depolarization has been attributed to the neuroprotective effect of a plant extract [42] and the protection of cardiomyocytes from oxidative stress [40]. In the case of PBE, further studies are warranted to identify the active molecules and the underlying mechanisms involved in its mild mitochondrial potential depolarization propensity.…”

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

“…Several studies have identified structural and functional mitochondrial abnormalities in hippocampal neurones of AD patients compared with age-and sex-matched controls [213][214][215][216]. Such abnormalities include a significant reduction in mitochondrial numbers and exaggerated levels of oxidised mitochondrial DNA (mtDNA) and nitrated proteins in the cytoplasm in a pattern suggestive of impaired mitophagy or fission dynamics [215][216][217]. These mitochondrial abnormalities are accompanied by oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine, indicating that the mitochondria are damaged by ROS and RNS during disease progression [213,218,219].…”

Oxidative Stress and Ageing: The Influence of Environmental Pollution, Sunlight and Diet on Skin

“…This leads to a continuous "vicious cycle" where dysfunctional mitochondria contribute to further ROS production, which can lead to further ROS-mediated oxidative damage to mitochondria [8]. Mitochondrial dysfunction is heavily implicated in the ageing process and the pathogenesis of age-related diseases such as Alzheimer's disease (AD) [16]. In AD it is believed that the accumulation of amyloid beta peptide interacts with mitochondria, leading to mitochondrial dysfunction.…”