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.
Highlights
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
Growing evidence suggest that elevated amyloid-β (Aβ) levels contribute to the mitochondrial abnormalities and the mechanism is not clearly established, both amyloid precursor protein (APP) and Aβ are found in mitochondrial membranes and interact with mitochondrial proteins
While mitochondrial biogenesis occurs on a regular basis in healthy cells where mitochondria constantly divide and fuse with each other [25,26,27]; it occurs in response to oxidative stress, increased energy demand, exercise training and certain diseases
Summary
Mitochondrial biogenesis plays an essential role in maintaining an adequate functional neuronal mitochondrial mass by compensating for damaged mitochondria that have been eliminated. The transcription factor nuclear factor erythroid 2related factor 2 (Nrf2) partly regulates P62 expression due to the presence of an antioxidant response element (ARE) in its promoter region [58, 59] Electrophilic natural products such as isothiocyanate compound, sulforaphane which upregulate Nrf by interfering with its regulator protein, the redox sensitive ubiquitination facilitator Keap (Kelch-like ECH-associated protein 1) can potentially induce P62 expression [60,61,62]. Mitophagy inducer (PMI) (HB229), was recently developed to upregulate P62 via stabilization of Nrf and promote mitophagy This compound bypasses the upstream steps of the mitophagic cascade and acts independently of the ΔΨm collapse, and does not mediate any apparent toxic effects on mouse embryonic fibroblast (MEF) cells at the concentrations used in the assays [63]. Selective pharmacologic modulators of mitophagy that would facilitate dissection of the molecular steps involved in the removal of mitochondria from the network via this pathway are not presently available
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
