The role of extracellular matrix in the processing of the amyloid protein precursor of Alzheimer's disease.
Alzheimer's disease (AD) is characterized by the presence of extracellular amyloid plaques, which contain a protein referred to as the amyloid or beta A4 protein. The beta A4 protein is derived from a larger precursor protein (APP). Studies of autosomal-dominant forms of AD have established the central role of APP in the pathogenesis of the disease. Despite considerable research, the function of APP is unknown. APP can be processed by at least two separate routes. The first route involves a protease known as "APP secretase," which cleaves within the amyloid sequence, thereby mitigating amyloid formation. The second route may result in the production of potentially amyloidogenic fragments. Our studies suggest that following release from the cell membrane, APP interacts with components of the extracellular matrix (ECM) such as the heparan sulfate proteoglycans (HSPG's). The interaction of APP with HSPG's may be important for the function of APP. Substratum-bound APP was found to dramatically increase neurite outgrowth and survival of chick sympathetic neurons in vitro. This effect was dependent upon the presence of substratum-bound HSPG. The results suggest that normally, when bound to the ECM, APP functions to promote neurite outgrowth and/or cell survival. Loss of this normal trophic function might occur in AD, when APP is proteolytically processed via the amyloidogenic pathway.
Small
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Department of Pathology, University of Melbourne, Victoria, Australia.
Nurcombe
V
V
Clarris
H
H
Beyreuther
K
K
Masters
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CL
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D016384:Consensus Sequence; D005109:Extracellular Matrix / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D006493:Heparin