Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease

This review provides support for the notion that brain mitochondrial alterations in Alzheimer disease and mild cognitive impairment are key components of oxidative and nitrosative stress observed in these two disorders, and as such, they provide potentially promising therapeutic targets to slow—and hopefully one day stop—the progression of AD, which is a devastating dementing disorder

D. Allan Butterfield; Debra Boyd-Kimball

2020

Scholarcy highlights

  • Alzheimer disease is the single largest cause of dementia in the aged population
  • The secondary mitochondrial cascade important in AD posited by Swerdlow involves Aβ oligomer-induced changes in mitochondrial function, as well the presence of a dehydrogenase, amyloid-binding alcohol dehydrogenase, in mitochondria, that leads to elevated free radicals, consequent altered glycolytic and mitochondrial proteins structure and function, and resultant Ca2+ elevation, causing neuronal death
  • Evidence consistent with the tenants of the Primary Mitochondrial Cascade hypothesis were obtained, suggesting, similar to that posited by Swerdlow, both cascades are in play in AD and mild cognitive impairment that coalesce in the brain as decreased glucose metabolism evidenced by altered glycolysis and mitochondria
  • Levels of protein-bound carbonyls, 3-NT, and HNE are significantly increased in mitochondria isolated from lymphocytes of MCI and AD patients, which correlate with elevated Aβ levels, decreased levels of small molecule antioxidants, and decreased cognitive test performance
  • More research is needed to understand the impact of increased protein oxidation and lipid peroxidation on the mitochondrial proteome, and a focus on mitochondria from peripheral tissues may lead to the identification of potential biomarkers that are so desperately needed
  • We posit that better understanding of the molecular processes that lead to mitochondrial oxidative and nitrosative stress potentially will lead to selective therapeutic targets in mitochondria that slow or retard the progression of AD

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