Abstract
Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). A major source of free radicals that lead to oxidative and nitrosative damage is mitochondria. This review paper discusses oxidative and nitrosative stress and markers thereof in the brain, along with redox proteomics, which are techniques that have been pioneered in the Butterfield laboratory. Selected biological alterations in—and oxidative and nitrosative modifications of—mitochondria in AD and MCI and systems of relevance thereof also are presented. The review article concludes with a section on the implications of mitochondrial oxidative and nitrosative stress in MCI and AD with respect to imaging studies in and targeted therapies toward these disorders. Taken together, this review provides support for the notion that brain mitochondrial alterations in AD and MCI 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.
Highlights
Alzheimer disease (AD) is the single largest cause of dementia in the aged population
Hydroxyl radical readily reacts with proteins and allylic H-atoms on the fatty acid tails of phospholipids and sphingolipids. The former leads to the incorporation of carbonyl functionalities in proteins and alterations in protein conformation [8,22,23,24], while OH-mediated allylic hydrogen atom abstraction from unsaturated lipid acyl chains initiates the processes of lipid peroxidation, leading to highly reactive nucleophilic unsaturated aldehydes such as 4-hydroxynonenal (HNE) (Figure 2A) [8,13,25,26,27]
The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) multidomain lifestyle intervention trial found that interventions in nutrition, exercise, cognitive training, and management of metabolic and vascular risk factors benefitted an at-risk population [181], even in APOEε4 carriers [182]; no significant differences in brain volume or cortical thickness were determined by MRI after two years of intervention [183]
Summary
Alzheimer disease (AD) is the single largest cause of dementia in the aged population. Investigators have demonstrated that cognitive decline correlates well with Aβ oligomer and NFT loads, but not SP levels [2,3,4]. Consistent with the lack of correlation of SP with cognitive loss, therapeutic attempts to remove SP largely have not proven successful in modifying the course of AD [5]. Other factors may be involved in the progression of cognitive loss in AD. Oxidative and nitrosative stress in the brain are widely recognized as key aspects of the pathogenesis and progression of AD and MCI [8,9,10,11,12]. This review will focus on mitochondria and oxidative and nitrosative stress in AD and MCI
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