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, 13 (1), 19-25

Modulation of Mitochondrial Bioenergetics as a Therapeutic Strategy in Alzheimer's Disease


Modulation of Mitochondrial Bioenergetics as a Therapeutic Strategy in Alzheimer's Disease

Isaac G Onyango. Neural Regen Res.


Alzheimer's disease (AD) is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.

Keywords: Alzheimer's disease; antioxidants; bioenergetics; caloric restriction; clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/ Cas9); hypometabolism; mitochondria; mitochondrial DNA; mitochondrial biogenesis; mitochondrial transcription activator-like effector nucleases; mitohormesis; mitophagy; neuroinflammation; proteasome; recombinant-human mitochondrial transcription factor A; stem cells.

Conflict of interest statement

None declared.


Figure 1
Figure 1
Approaches to enhance bioenergetic capacity in Alzheimer's disease (AD). Cellular therapy and biologics can enhance mitochondrial biogenesis. Drug therapy can be used to reduce detrimental reactive oxygen species (ROS) without altering ROS signaling, rejuvenate proteasome function, inhibit the inflammasome. Gene therapy can manipulate mitochondrial DNA (mtDNA) without altering genomic DNA and also be targeted at regulating mitochondrial cholesterol. Exercise and caloric restriction can enhance mitochondrial function by mitohormesis. mitoROS: Mitochondrial ROS.

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