AMYLOID-2 AND OSERVE ANTIOXIDANT FUNCTIONS IN THE AGING AND ALZHEIMER BRAIN

Authors: SMITH, MARK - CASE WESTERN RES UNIV; CASADESUS, GEMMA - TUFTS-HNRCA; Joseph, James; PERRY, GEORGE - CASE WESTERN RES UNIV

Submitted to: Free Radicals in Biology and Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/11/2002
Publication Date: 11/1/2002
Citation: Smith, M.A., Casadesus, G., Joseph, J.A., and Perry, G. Amyloid-ß and t serve antioxidant functions in the aging and Alzheimer brain. Free Rad. Biol. Med. 2002, 33: 1194-1199.

Interpretive Summary: This review paper summarizes and reviews recent work that has called into question that two of the hall marks of Alzheimer disease i.e., amyloid plaques and neurofibrillary tangles (NTT's). are both necessary a sufficient for the development of this disease. Previous research had indicated that these two pathological entities were involved in actually contributing to the formation of free radicals and their deleterious consequences (e.g., oxidative stress). However work cited in this review indicates that rather than causes of the disease amyloid plaques and NFT's may actually be a response by the brain to protect itself and that they are actually protective components against additional damage by oxidative stress. Results of studies of normal aging using very specific counting techniques indicate that cells are not lost during normal aging despite the presence of numerous amyloid beta plaques, suggesting that the production and deposition of these plaques may actually stave off oxidative stress. However, in Alzheimer disease even the presence of a large number of plaques cannot stop the neuronal degeneration. Instead, it may be, that the number of plaques increase in response to the oxidative stress. Similar results to those described for amyloid beta plaques are reviewed for NFT's which also show that the tangles and abnormal proteins that form them occur in response to oxidative stress. Given these considerations this paper questions the current efforts (e.g., amyloid beta vaccine) that attempts to remove these markers from the brain as a therapeutic approach

Technical Abstract: This paper reviews data which suggest that the historically held view that the major components of amyloid plaques and neurofibrillary tangles as the central mediators of the pathogenesis of Alzheimer disease may require re-interpretation in light of recent findings. The overwhelming view currently held concerning disease pathogenesis is the premise that amyloid beta causes the disease. Amyloid beta is the obligate feature of the disease and may correlate with disease severity. Moreover, amyloid beta is often found in regions showing degeneration during Alzheimer disease. Finally, amyloid beta is increased by all the mutated genes associated with the disease. However, an alternate interpretation of these findings is that amyloid beta plaques may be formed in response to oxidative stress and are actually protect the neurons. Research has indicated that the soluble form of amyloid beta and not the plaques may be a better predictor of Alzheimer disease. Moreover it also appears that findings of numerous cell culture studies that have shown toxic effects of amyloid beta may actually be the result of an artifact of the media that were utilized with the cells. Work is also reviewed which suggests that since unbiased stereology indicates that there is no loss of neurons in normal aging even in areas that contain a large number of plaques, the plaques may be protective in the normal aged brain but appear to be ineffective in affording this protection in Alzheimer Disease. Thus, amyloid beta may play a key role in redox homeostasis. Although there is some indication that amyloid beta may act as a pro-oxidant in the presence of transition metals. In a similar manner the accumulation of phosphorylated tau protein in neurofibrillary tangles (NFT's) is also associated with an antioxidant response. Given these considerations it is perhaps not surprising that the increased sensitivity of oxidative stress in the aged brain even in control individuals is invariably marked by the appearance of both amyloid and tau. Additionally, Alzheimer disease where chronic oxidative stress persists and is superimposed upon an age-related vulnerable environment, one would predict, and there is, an increased lesion load. The notion that amyloid beta and tau function as protective components brings into serious question the rationale of current therapeutic efforts targeted toward lesion removal.