THE ALZHEIMER A-BETA-PEPTIDE DEVELOPS PROTEASE RESISTANCE IN ASSOCIATION WITH ITS POLYMERIZATION INTO FIBRILS

An intriguing property of the polypeptide constituents of amyloid is t hat they apparently can escape the proteolytic mechanisms that normall y catalyze turnover and prevent abnormal tissue accumulation of polype ptides. Here, we demonstrate that the AP peptide, the principal compon ent of cerebrovascular amyloid deposits in Alzheimer's disease, become s resistant to an array of proteases as a result of structural changes associated with its polymerization into amyloid fibrils. It is furthe r demonstrated that fibril formation per se does not lead to protease resistance but probably structural changes associated with polymerizat ion. The results suggest that higher order structural changes, regulat ed by the primary structure, enable amyloidogenic polypeptides to esca pe proteolytic degradation and accumulate in tissues.