Targeting the prodromal stage of Alzheimer's disease: bioenergetic and mitochondrial opportunities.

TitleTargeting the prodromal stage of Alzheimer's disease: bioenergetic and mitochondrial opportunities.
Publication TypeJournal Article
Year of Publication2015
AuthorsCaldwell CC, Yao J, Brinton RDiaz
Date Published2015 Jan
KeywordsAlzheimer Disease, Animals, Energy Metabolism, Humans, Mitochondria, Prodromal Symptoms

Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

Alternate JournalNeurotherapeutics
PubMed ID25534394
PubMed Central IDPMC4322082
Grant ListR01 AG033288 / AG / NIA NIH HHS / United States
R01AG033288 / AG / NIA NIH HHS / United States
P01AG026572 / AG / NIA NIH HHS / United States
R01AG032236 / AG / NIA NIH HHS / United States
R01 AG032236 / AG / NIA NIH HHS / United States
P01 AG026572 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D