How does oxidative damage trigger Alzheimer's disease? by Connie b. Dellobuono
Answer by Connie b. Dellobuono:
Oxygen promotes health. We promote use of anti-oxidants (Vit E, omega 3, CQ10, whole foods, others) because they help us reduce the aging of our cells.
From http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1606384/ :
1. In support of a mechanistic role for processes suppressed by NSAIDs or AOs in early phases of AD pathogenesis, transgenic mice that express mutant human amyloid precursor protein and accumulate Aβ deposits in brain with advancing age show significantly less Aβ accumulation when treated with NSAIDs.15 Moreover, a variety of interventions have been reported to increase or decrease Aβ accumulation in transgenic mouse models of cerebral Aβ amyloidogenesis by promoting or suppressing free radical damage to brain.15–18 Using different transgenic mice, others have shown that neuronal overexpression of one COX isozyme, COX-2, in brain leads to neurodegeneration and age-related cognitive deficits.19 The major in vivo activity of the NSAIDs used in these studies is inhibition of both COX isozymes, although several alternatives have been proposed based on in vitro or cell culture data.20–22 It is noteworthy that, despite many proposals for alternative actions of NSAIDs, we are aware of no data demonstrating major therapeutic action in vivo other than through COX suppression. For example, the recent proposal from cell culture data that NSAIDs may act via γ-secretase suppression23 has not been supported by in vivo investigation.24
These reproducible and intriguing epidemiological data, in addition to the mechanistic data from animal models, have fueled substantial interest in polyunsaturated fatty acid (PUFA) oxidation, either enzyme-catalyzed or free radical-mediated, in the molecular pathogenesis of AD (Figure 1). Much of this recent investigation has focused on two PUFAs, arachidonic acid (AA, 20:4ω6) whose oxidation products are called eicosanoids, and docosahexaenoic acid (DHA, 22:6ω3) whose oxidation products are termed docosanoids. A critical distinction exists between AA and DHA. AA is evenly distributed in gray matter and white matter and among the different cell types in brain whereas DHA is highly enriched in neuronal membranes.25,26 Thus, eicosanoids reflect oxidation reactions occurring in brain tissue, but not necessarily in neurons, while docosanoid formation is relatively specific for biochemical reactions occurring in neurons.
From http://www.ncbi.nlm.nih.gov/pubmed/17034348 :
2. Oxidative damage to DNA may play an important role in aging and neurodegenerative diseases such as Alzheimer's disease (AD). Attack on DNA by reactive oxygen species, particularly hydroxyl radicals, can lead to strand breaks, DNA-DNA and DNA-protein cross-linking, sister chromatid exchange and translocation, and formation of at least 20 oxidized base adducts. Modification of DNA bases can lead to mutation and altered protein synthesis. In late-stage AD brain, several studies have shown an elevation of the base adducts 8 hydroxyguanine (8-OHG), 8-hydroxyadenine (8-OHA), 5-hydroxycytosine (5-OHC), and 5-hydroxyuracil, a chemical degradation product of cytosine. Several studies have shown a decline in repair of 8-OHG in AD. Most recently, our studies have shown elevated 8-OHG, 8-OHA, and 5,6-diamino-5-formamidopyrimidine in nuclear and mitochondrial DNA in mild cognitive impairment, the earliest detectable form of AD, suggesting that oxidative damage to DNA is an early event in AD and not a secondary phenomenon.