beta-Amyloid, protein processing and Alzheimer's disease

Haas, C.; Hung, A.Y.; Citron, M.; Teplow, D.B.; Selkoe, D.J.

Arzneimittel-Forschung 45(3a): 398-402


ISSN/ISBN: 0004-4172
PMID: 7763333
Document Number: 449428
Alzheimer's disease (AD) is a neurodegenerative disorder resulting in the deposition of amyloid beta-peptide (A-beta) in senile plaques in cerebral and limbic corteces and the walls of meningeal and cerebral blood vessels. A-beta is a proteolytic break-down product of a membrane bound precursor, the beta-amyloid precursor protein (beta-APP). Conventional secretory processing of beta-APP prevents A-beta formation. An additional processing pathway of beta-APP involving endosomal/lysosomal targeting is described. Within isolated lysosomes amygloidogenic fragments are found which might serve as precursors for A-beta production. From such precursors A-beta might be proteolytically processed. Indeed, secreted A-beta was identified in the media of cultured cells. A-beta is also secreted in vivo and can be detected in human plasma and cerebral spinal fluid. These findings provide a cellular system to analyze the molecular mechanism and the biological regulation of A-beta generation. Furthermore, the effect of inherited mutations within the BETA-APP gene in some cases of familial AD can now be analyzed in such tissue culture cells transfected with the mutant cDNA constructs. A model will be presented proposing that A-beta generation might occur during reinternalization of the full-length molecule.

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