title: The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease.
abstract: New molecular information about Alzheimer disease (AD) is appearing at an unprecedented rate. Much interest centers on the beta A4 amyloid protein, which is progressively deposited in senile plaques and blood vessels in AD brain tissue. The discovery that some kindreds with familial AD have a mutation in the gene coding for the beta A4 amyloid precursor protein (APP) suggests that this mutation alone may be sufficient to cause the full spectrum of clinical and pathological changes that characterize AD. Although APP point mutations may turn out to be relatively rare causes of AD, the idea that accelerated beta A4 deposition is an early and critical event in many patients continues to gain support from studies in humans, animals, and cultured cells. Identification of the biochemical steps leading to production of the beta A4 peptide from APP is now a critical issue. Recent reports indicate that normal lysosomal processing pathways can produce carboxyl-terminal fragments of APP that contain the entire beta A4 sequence, and are therefore potentially amyloidogenic. The mechanisms by which such intermediate forms are further processed and released, resulting in extracellular beta A4 deposits in plaques and vessels, are yet to be determined. It is likely that full elucidation of the beta A4-producing pathways will ultimately yield new therapeutic approaches to this complex and tragic disorder.
authors.affiliation: Department of Neuropathology, Radcliffe Infirmary, Oxford, England.
authors.forename: C L
authors.initials: CL
authors.lastname: Joachim
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D001921:Brain / Q000473:pathology; D006801:Humans; D008959:Models, Neurological
chemical_list: D016229:Amyloid beta-Peptides