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 that they apparently can escape the proteolytic mechanisms that normally catalyze turnover and prevent abnormal tissue accumulation of polypeptides. Here, we demonstrate that the A beta peptide, the principal component of cerebrovascular amyloid deposits in Alzheimer's disease, becomes resistant to an array of proteases as a result of structural changes associated with its polymerization into amyloid fibrils. It is further demonstrated that fibril formation per se does not lead to protease resistance but probably structural changes associated with polymerization. The results suggest that higher order structural changes, regulated by the primary structure, enable amyloidogenic polypeptides to escape proteolytic degradation and accumulate in tissues.