The nature, specificity and consequences of amyloid beta obligomers interacting with the prion protein. (360G-Wellcome-086782_Z_08_Z)

A key pathogenic event in Alzheimer's Disease (AD) is the accumulation and aggregation of the 39-43 residue, amyloid-beta (A?) peptide (3). A?1-42 peptides aggregate to form oligomers of various morphologies and eventually deposits as amyloid fibrils in affected brains. The neurotoxic culprit(s) in this amyloidogenic pathway have yet to be identified unequivocally. Accumulating evidence implicates soluble oligomers, not fibrils as previously thought, as the principal toxic species in AD and indeed other disorders of protein aggregation. This year, it was shown than A?1-42 oligomers bind to the cellular prion protein (PrPc) (4). This observation fits will numerous links between AD and prion diseases, including the discovery made by Prof Hooper and colleagues in 2007 that PrPc inhibits the A?-producing enzyme BACE-1 (?-site APP cleaving enzyme-1) We wish to study in detail the biological effects that various types of A? oligomers, both synthetic and naturally derived, exert upon PrPc Main aim: To Investigate the nature, specificity and consequences of amyloid beta oligomers binding to th1 cellular prion protein. We will address the following questions: 1. How does the nature of the A? oligomer preparation correlate with binding to PrPc? 2. Do other amyloidogenic proteins bind to PrPc or is this a specific interaction? 3. Do pathophysiological PrPc mutants have altered oligomer binding? 4. Do AP oligomers inhibit, enhance or distort the functions of PrPc? 5. What is the fate of the oligomeric A?:PrPc complex and Is a co-factor involved?