The Role of Oxidative Stress in the Pathophysiology of Cerebrovascular Lesions in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) and stroke are two leading causes of age‐associated dementia. A rapidly growing body of evidence indicates that increased oxidative stress from reactive oxygen radicals is associated with the aging process and age‐related degenerative disorders such as atherosclerosis, ischemia/reperfusion, arthritis, stroke, and neurodegenerative diseases. New evidence has also indicated that vascular lesions are a key factor in the development of AD. This idea is based on a positive correlation between AD and cardiovascular and cerebrovascular diseases such as arterio‐ and atherosclerosis and ischemia/reperfusion injury. In this review we consider recent evidence supporting the existence of an intimate relationship between oxidative stress and vascular lesions in the pathobiology of AD. We also consider the opportunities for therapeutic interventions based on the molecular pathways involved with these causal relationships.

Nucleic acid oxidation in Alzheimer disease

“…Immunocytochemical approaches further enabled confirmation that the oxidized RNAs were localized predominantly in neuronal and vascular wall (especially endothelial) cells compared with glial cells [10,58,172]. In addition, coexistence of RNA oxidation with mtDNA overproliferation and deletion in a select population of vulnerable neurons and vascular wall cells was demonstrated [173,174].…”

Estrogen suppresses brain mitochondrial oxidative stress in female and male rats

“…Since mitochondria have limited DNA protection mechanisms, these cellular power plants are thus vulnerable to oxidative stress (Chance et al, 1979;Clayton, 1984;Wallace, 2005). In fact, excess ROS production (Aliev et al, 2002) leading to mitochondrial dysfunction (Castellani et al, 2002) is among the mechanisms thought to underlie the pathogenesis of neurodegenerative diseases. Recently mitochondria have been suggested as a target of the neuroprotective effects of estrogen (Nilsen and Brinton, 2004;Singh et al, 2006).…”

Untitled

“…However, disruption of the intracellular redox balance leads to a state of oxidative stress, during which proteins, nucleic acids, lipids, and other macromolecules can accumulate severe damage (282). Oxidative stress appears to be a major factor in aging and has been implicated in numerous diseases such as Alzheimer's, diabetes, and cancer (3,29,182). TrxRs and GPxs, through the action of Sec within their catalytic sites, serve housekeeping redox functions by controlling the activity of cellular proteins and reduction of hydroperoxides, respectively.…”

“…DIO1 and DIO2 catalyze the reduction of T 4 to yield the active form of hormone T 3 , or, reverse T 3 , rT 3 , to yield T 2 . DIO1 and DIO3 catalyze the deiodination of T 4 to rT 3 , and of T 3 to T 2 .…”