Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease

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.

Microstructural and Cerebral Blood Flow Abnormalities in Subjective Cognitive Decline Plus: Diffusional Kurtosis Imaging and Three-Dimensional Arterial Spin Labeling Study

“…Several reports have indicated that the mitochondrial function is disrupted in patients with MCI and patients with AD (Delbarba et al, 2016 ; Mastroeni et al, 2017 ; Terada et al, 2020 ). Mitochondrial dysfunction, in turn, accelerates the production of reactive oxygen species, further contributing to oxidative stress and damage to cell membrane lipids, intracellular proteins, and DNA (Butterfield and Boyd-Kimball, 2020 ). The accumulation of β-amyloid (Aβ) peptides decreases ATP production, impairs the mitochondrial membrane potential, and exacerbates oxidative stress (Swomley and Butterfield, 2015 ).…”

Neuroprotective Roles of the Reverse Transsulfuration Pathway in Alzheimer’s Disease

“…Several studies report that oxidative stress may precede symptoms and pathology of AD (Nunomura et al, 2001 ; Zhu et al, 2004 ). Oxidative stress in AD is also linked to mitochondrial dysfunction, inflammation, and hypoxia, and these processes culminate in vicious cycles that contribute to neurodegeneration (Bonda et al, 2014 ; Oliver and Reddy, 2019 ; Merelli et al, 2020 ; Butterfield and Boyd-Kimball, 2020 ).…”

Isoliquiritigenin Confers Neuroprotection and Alleviates Amyloid-β42-Induced Neuroinflammation in Microglia by Regulating the Nrf2/NF-κB Signaling

“…In the past decades, strong evidence has emerged that both neuroinflammation and oxidative stress also contribute to the development of AD ( Heneka et al, 2015 ; Calsolaro and Edison, 2016 ; Butterfield and Boyd-Kimball, 2020 ). In fact, several anti-inflammatory drugs or antioxidants have been shown to alleviate the pathological changes and cognitive disorder caused by AD, both in vivo and in vitro ( Teixeira et al, 2013 ; Calsolaro and Edison, 2016 ).…”