The paramount pathological event in AD and related cerebral amyloidoses is the deposition of beta-protein (Abeta) in fibril form. What factors govern the rate, age and location of amyloid remains unclear. Already four different mutations are known to occur in the amyloid precursor protein (APP). Three of these are associated with familial AD (FAD), and one with a related disease: hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D). How these mutations influence fibrillogenesis is unknown. We have preliminary data indicating that the mutation found in HCHWA-D greatly accelerated fibril formation of synthetic peptides in vitro. Amyloid fibril formation in vivo is known to always be accompanied by several proteins, or """"""""pathological chaperones"""""""", such as amyloid P component, proteoglycans, alpha1 anti-chymotrypsin and more recently apolipoprotein E. It is proposed in this grant to 1) study the influence of the known mutations in APP on amyloid fibril formation with synthetic peptides; 2) see how the presence of amyloid associated proteins influences fibril formation, and whether the fibrils are rendered more resistant to proteolysis in the presence of these proteins. Furthermore APP fragments from the alternative pathway of catabolism will be purified for studies into their fibrillogenicity and possible associations with """"""""pathological chaperones""""""""; 3) studies on the transgenic mice model being produced in PROJECT 4 will be done determining similarities and differences with AD. Two agents of known efficacy in systemic amyloidosis will be applied to these mice to see if amyloidogenesis is inhibited.
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