There is considerable debate and controversy surrounding the cause(s) of Alzheimer
There is considerable debate and controversy surrounding the cause(s) of Alzheimer Tandutinib (MLN518) disease (AD). in the former scenario have been salvaged from oxidative stress by Aβ. Tau hyperphosphorylation has been demonstrated as a pathological result of oxidative stress59 84 87 It is intriguing to note that most neuronal loss during the course of neurodegeneration occurs where the levels of oxidative stress are the highest and subsequent deposition of NFTs decreases these levels59. Of note and supporting this neurons that accumulate NFTs are able to survive for decades and be functionally integrated Tandutinib (MLN518) in cortical circuits90 91 Mechanistically phosphorylation of tau antagonizes apoptosis by stabilizing beta-catenin92. Regardless the abnormal accumulation of hyperphosphorylated tau in the form of NFTs occurs subsequently to oxidative stress-induced damages. Oxidative Stress and Alzheimer disease: Ubiquity vs. Specificity Disease is defined by the deficits in specific functional output underlied by anatomical and biochemical/structural changes elicited by insults and adaptations and/or failure of adaptations. Interestingly oxidative stress is a prominent biochemical change not only found in AD but also found in almost all major neurodegenerative diseases including Parkinson disease amyotrophic lateral sclerosis and Huntington disease93. Since oxidative stress is considered a major contributor to aging the greatest risk factor for all the age-related neurodegenerative diseases it is perhaps not surprising that oxidative stress is believed to be a causative factor or at least an ancillary factor in the pathogenesis of these diseases. However given the different neuronal populations involved and distinct pathology that developsd in these various neurodegenerative diseases such a ubiquity of the presence of oxidative stress raises the obvious question of specificity of its role in the Rabbit Polyclonal to IRAK3. Tandutinib (MLN518) pathogenesis of each of these diseases. For example how oxidative stress specifically leads to neuronal death in hippocampus and cortex in AD while in substantia nigra in PD? One possibility is that the selective neuronal death may be caused by increased oxidative stress in selective brain regions in these diseases. For example in AD large body of evidence support the elevated oxidative stress in disease-affected area such as hippocampus and cortex but not in disease-spared area such as cerebellum42. Similarly heightened oxidative stress is consistently demonstrated in substantia nigra but not in other unaffected brain region in PD94. If this is the case the question becomes how selective oxidative stress occurs in these diseases especially in the familial cases where causative mutations in specific genes affect all cells? It is likely the specific characteristics of various neuronal populations involved in different diseases contribute to such selectivity. Neurons with long axons and multiple synapses have higher metabolic demands that may render them more prone to oxidative attacks at a steady state level and thus become more vulnerable to additional disease-related changes. For example CA1 neurons of hippocampus demonstrate higher levels of superoxide anion than parietal cortical or CA3 neurons which is at least one of the reasons that they are more vulnerable to global ischemia-induced dell death95. Dopaminergic neurons are exposed higher steady state levels of oxidative stress produced by metabolism of dopamine which make them more vulnerable to insults that Tandutinib (MLN518) affect the dopamine metabolism96. It is also possible the selectivity is due to the specificity of initiating factor(s). Such initiating factor(s) may not be a single event but more likely a complex interaction between the genetic/epigenetic background of each individual and the environment which may determine the specific neuronal population affected. Overall different diseases may each display a distinct oxidative stress pattern that likely will lead to a different homeostatic balance that is finely tuned to minimize cell death and more studies are clearly necessary to understand the role of oxidative stress in each disease. The Age-Related Mitochondrial Cascade of Alzheimer Disease Combining the evidence listed above reveals the following: i) AD is primarily an.