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

Abnormal aggregation and deposition ofβ-amyloid（Aβ）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 Aβare toxic to the neurons and will eventually lead to the death of neurons,resulting in symptoms such as poor memory.Various Aβspecies of different lengths and different modifications co-exist in the AD patients’brain.Researchers have been focused on full-length unmodified Aβ,Aβ_1-40and Aβ_1-42.Variety of strategies have been developed for Aβ_1-40 and Aβ_1-42,hoping to slow down the pathological process of AD by reducing Aβor inhibiting the aggregation of Aβ.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 Aβmay be irreversible,suggesting that we need to develop preventive strategies.On the other hand,studies have shown that N-terminal truncated and modified Aβaggregated faster and were more toxic to neurons,while previous strategies may not be effective on these Aβs.It has been shown that pyroglutamated Aβ(p EAβ_3-X)could induce unmodified Aβto form toxic oligomers and p EAβ_3-X could not be targeted by antibodies targeting to unmodified Aβ.Vaccines targeting to Pyroglutamated Aβwere 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 EAβ_3-15-P2.Further prophylactic immunization of AD model mice showed that this vaccine could alleviate cognitive impairment and reduce the deposition of Aβplaques.Currently,no molecules except antibodies could specifically recognize/distinguish N-terminal truncated and modified Aβ,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 Aβ_4-X than Aβ_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 Aβ_4-40 than Aβ_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 Aβ.These results provide new ideas for developing treatment strategies for AD.