Studies On The Vaccines And Inhibitors Targeting To N-terminal Truncated Or Modified A?

Abnormal aggregation and deposition of?-amyloid?A??in the brain of patients has long been considered as one of the causative agents for Alzheimer's disease?AD?.The amyloid cascade hypothesis believes that the oligomers and fibers formed during the aggregation of A?are toxic to the neurons and will eventually lead to the death of neurons,resulting in symptoms such as poor memory.Various A?species of different lengths and different modifications co-exist in the AD patients'brain.Researchers have been focused on full-length unmodified A?,A?_1-40and A?_1-42.Variety of strategies have been developed for A?_1-40 and A?_1-42,hoping to slow down the pathological process of AD by reducing A?or inhibiting the aggregation of A?.Unfortunately,although these strategies have been successful in AD model mice,there are currently no positive results reported in clinical trials.On one hand,the damage caused by A?may be irreversible,suggesting that we need to develop preventive strategies.On the other hand,studies have shown that N-terminal truncated and modified A?aggregated faster and were more toxic to neurons,while previous strategies may not be effective on these A?s.It has been shown that pyroglutamated A?(p EA?_3-X)could induce unmodified A?to form toxic oligomers and p EA?_3-X could not be targeted by antibodies targeting to unmodified A?.Vaccines targeting to Pyroglutamated A?were designed and synthesized based on these reports.After screening the B and T epitopes,a peptide vaccine capable of inducing high titers of antibodies was obtained,namely p EA?_3-15-P2.Further prophylactic immunization of AD model mice showed that this vaccine could alleviate cognitive impairment and reduce the deposition of A?plaques.Currently,no molecules except antibodies could specifically recognize/distinguish N-terminal truncated and modified A?,which is an obstacle to study their function.By means of isothermal titration calorimetry and mass spectrometry,it was confirmed that CB[7]and CB[8]bound more strongly to A?_4-X than A?_1-X.Further Th T aggregation kinetics,transmission electron microscopy and cytotoxicity experiments showed that CB[7]and CB[8]could better regulate the aggregation of A?_4-40 than A?_1-40.By utilizing chemical kinetics,the inhibiting mechanisms of tryptophan-glycan conjugates and small molecules extracted from Chinese herbal were explored.Combination of these two kinds of molecules showed better inhibiting effects towards the aggregation of A?.These results provide new ideas for developing treatment strategies for AD.