The long term objective of this proposal is to learn the etiology and the pathogenesis of Alzheimer disease and senile dementia of the Alzheimer type (AS/SDAT), a major public health problem in modern society with its rapidly increasing elderly population. The two most prominent brain lesions in AD/SDAT are the presence of numerous intraneuronal argentophilic fibrillary tangles of paired helical filaments (PHF) and the neuritic (senile) plaques which too contain bundles of PHF in their neurites. PHF are morphologically unlike any of the normal neurofibers, their origin and role in the disease are not understood. It has been shown recently that the microtubule associated protein tau is a major component of the PHF. Tau in the Alzheimer brain both in PHF and in unpolymerized form is abnormally phosphorylated. It therefore appears that a modification of tau, either phosphorylation alone or in conjunction with other modifications yet to be identified might be a factor in the formation of the PHF. To elucidate the role of altered tau in the pathogenesis of AD/SDAT, studies will be undertaken to 1) isolate the unpolymerized abnormally phosphorylated tau to homogeneity, 2) generate peptides and localize the sequence/s containing the abnormal phosphorylation and identify the amino acid/s which is abnormally phosphorylated, 3) raise and characterize monoclonal and polyclonal antibodies to the abnormal tau and to the tau fragment/s containing the abnormal epitope, 4) isolate abnormal tau by immunoaffinity using these antibodies and 5) study the effect of the abnormal tau or microtubule assembly and make preliminary attempts to induce in vitro polymerization of the Alzheimer tau. Establishment of the exact nature of the chemical alteration of tau in AD/SDAT will be a major step towards elucidating the origin of PHF and ultimately the disease mechanism. The development of the specific immunological probes, i.e. antibodies will not only help achieve the above objectives but will also be very valuable for the development of a possible laboratory diagnostic test for the disease by direct immunoassays of CSF and serum.
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