The investigators of Project 2 previously demonstrated that the antigen that reacts with the A2B5 antibody is localized to sites of degeneration in the AD brain including both senile plaques and neurofibrillary tangles (NM). We now propose to carry out a detailed analysis of the expression of this epitope, in collaboration with Project 2, and to identify the epitope itself. It is not known whether the antigen that is reactive in the AD case is the same or different in non-AD tissues; and, since antibody reactivity may vary with regard to variations in membrane constituents (e.g., numbers of sialic acid residues at an exposed site), it is essential to identify of the reactive epitope associated with NFTs and plaques. A focal point for a number of the proposed studies is the fact that the A2B5 epitope is a membrane antigen and that the amyloid precursor protein has properties of a transmembrane protein. Therefore, in conjunction with the Project 2, we shall ask whether or not disruption of membrane constituents in response to amyloid accumulation is an aspect of the molecular pathogenesis of AD that can result in the expression of the A2B5 reactive epitope. We propose to identify the glycolipid antigen (s) that react with the A2B5 antibody and determine their structure. Based upon the identification of A2B5 epitope, the metabolic pathway responsible for the increased appearance of the A2B5 epitope will be determined. Synthetic and degradative enzymes that may be involved in the increased expression will be evaluated. These studies may allow us to generate hypotheses concerning the role of the A2B5 antigen in AD that takes into account the possibility that the expression of this epitope may be related to either a neuronal survival mechanism or may be associated with the molecular pathogenesis of Alzheimer's Disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Mc Lean Hospital (Belmont, MA)
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