AMYLOID PRECURSOR IN ALZHEIMER DISEASE

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The major histological lesions consistently found in the brains of Alzheimer patients are neurofibrillary tangles (NFT) and senile plaques (SF). Although NFT are also found in other neurodegenerative conditions, recent results obtained using molecular biological approaches suggest that understanding the NFT and SP may provide an important insight into the etiology of Alzheimer disease (AD). These studies have demonstrated that the gene coding for the protein precursor of amyloid, the major component of SP, is located in the same region of chromosome 21 that is altered in familial AD and duplicate in sporadic AD. The building block of amyloid, a breakdown product of the amyloid precursor protein, possibly results from the ubiquitin-directed proteolytic system. Recent studies have demonstrated that ubiquitin conjugates are present in NFT. The nature and function of the amyloid precursor in normal cell physiology has not been determined. Since the amino acid sequence of the amyloid precursor is published, antibodies to synthetic peptides can be produced. These antibodies will be used to identify which cells produce amyloid precursor and whether it is ubiquitinated. Although NFT and SP share epitopes, the sequences of amyloid precursor found is PHF may not be identical to those found in SP. Amyloid precursor is a membrane receptor protein. Physiologically, proteins of this class interact with the cytoskeleton. The presence of cytoskeletal elements in NFT may be a direct result of the presence of sequences from the intracellular domain of the amyloid precursor. Therefore, it will be important to know whether antibodies to the intracellular domain stain NFT and if cytoskeletal elements bind to these sequences. The finding of a common mechanism of formation of both NFT and SP would advance substantially the understanding of the pathogenesis of AD.