Studies On The Modulation Effects Of Helical Intermediates Towards Amyloid-? Aggregation Process

Alzheimer's disease(AD),which is widely taken as one of the hazards to the aging society,occurs with a common pathological feature primarily including intracerebral insoluble amyloid deposits mainly consisting of amyloid-?(A?)and Tau.Although the A? fibrillation process can be elucidated as a successive conformational rearrangement process from intrinsically disordered states to the in-register ?-sheet-enriched deposits.During this process,the transition from ?-helix to ?-sheet in certain structural regions play important roles.The formation of these A? intermediates with different conformation as partially folded monomer,oligomer and protofibrils were reported to be the most cytotoxic species during A? aggregation process.Specially,the N-terminal residues were prone to form helical conformation.The helical structure of A? inspired us to study whether stabilizing A(3 residues in helical conformation would strongly redirect the self-assembly process of A? and further reduce its toxicity.To verify our hypothesis,reported A(3 residues 17-23,10-16 and 13-22 were chosen as the A(3 residues with strong helical tendency.Hydrogen bonding surrogates was used to mimic the stable helical A? fragments and to work out the unclear protein-protein interactions of A? helix.HBS1 was synthesized by using the olefin metathesis to induce the helical conformation of A?(17-23).HBS2 and HBS3 with the thioether for their N-terminal linkages mimicked A(3(10-16)and A?(13-22)respectively.And the N-terminal linkages induced and stabilized the helical comformation of each HBS peptides.Afterwards these artificial A? helical fragments were used to interact with natural A? and to uncover their different modulation effects on A? aggregation process.As a result,different A? residues stabilizing in helical conformation conducted totally different modulation.HBS1 show strong inhibition effects towards A? fibrillization and cytotoxicity.HBS2 seldom redirected A? aggregation process.And HBS3 accelerated the toxic aggregation process of A?.Therefore,we found that stabilizing the helical conformation of A(3 residues(13-22)could accelerate A? aggregation without definite decrease for A? toxicity.By this way,A? resedues(17-23)stabilized in helical conformation could transformed twisted,cytotoxic A? fibrils to short,nontoxic fibrils and be a target for some inhibitors to interact with.