The Interaction Between Small Molecules And Aβ42 In Lipid Membranes And The Aggregation Mechanism Of Aβ42 Oligomers

Alzheimer’s disease(AD)is a common neurodegenerative disease.Its pathological features are Aβ peptide deposition and Tau protein neurofibrillary tangles.The Aβ peptide is mainly composed of 39-43 amino acid residues.Among them,the content of Aβ40 accounts for about 90%,and the content of Aβ42 is low which accounts for about 10%.But its toxicity is high and it is easy to aggregate.Therefore,the research on the process of Aβ42 aggregation,mechanism,prevention and control is more meaningful than Aβ40.In the research of this thesis,we mainly carried out two aspects of work,(1)to explor the modulation mechanism of three small molecules curcumin,melatonin and aspirin on Aβ42 monomer and two dimers in anionic mixed lipid membrane POPC-DMPS(Pc Ps)(2)to study the effect of three different phospholipid membranes of POPG,POPC and POPC-POPG(Pc Pg)on the aggregation of natural Aβ42 pentamers and decamers.In the simulation of Aβ42 monomer and dimer systems,we inserted the Cterminal(residues 17-42)of Aβ42 into the Pc Ps phospholipid membrane,and the Nterminal(residues 1-16)was outside the phospholipid membrane.In addition,three small molecules are inserted into the water environment over the upper and lower sides of the phospholipid membrane.After simulation,we found that all three small molecules can automatically insert into the phospholipid membrane and some small molecules will approach the Aβ42 peptide and interact with it to generate hydrogen bonds.The study found that curcumin can significantly reduce the β-sheet content of the Aβ42 peptide,and melatonin can also reduce the β-sheet content of the Aβ42peptide,but it is not as significant as the small molecule curcumin.Aspirin can not significantly reduce the β-sheet content of Aβ42 peptide.They all can reduce the diffusion coefficient and order parameters of the phospholipid membrane,as well as the order and fluidity of the phospholipid membrane.In the monomeric Aβ42 system,the small molecule melatonin can greatly decrease the diffusion coefficient of the phospholipid membrane,curcumin has the smallest decrease effect on the degree of order,followed by melatonin,and then aspirin.In the dimeric Aβ42 system,the changes of two parameters are similar.The difference from the monomer system is that both melatonin and aspirin take the similar decrease effect on the order of phospholipid membrane,and curcumin reduces the diffusion coefficient the most.In the monomeric and dimeric systems,curcumin will thin the phospholipid membrane,whereas aspirin reverses,and melatonin is in the middle,which means,melatonin has little effect on the phospholipid membrane thickness.The three small molecules can also change the properties of the phospholipid membrane to regulate the aggregation of Aβ peptides.Studies have shown that both curcumin and melatonin can inhibit peptide aggregation by reducing the β-sheet structure,whereas aspirin is not obvious.During the aggregation of Aβ42 oligomers on the surface of different phospholipid membranes,Aβ42 pentamer can bind to the negatively charged POPG and Pc Pg phospholipid membranes,but to the neutral phospholipid membrane POPC.The time required for the pentamer to bind to the negatively charged phospholipid membrane is relatively short(about 1000-5500ns).After the pentamer binds to the POPG phospholipid membrane,the structure of the pentamer will stretch and expand into an ellipsoid shape on the surface of the phospholipid membrane.The pentamer can also bind to the Pc Pg-the mixed phospholipid membrane,but it neither spread out on the surface of the membrane,nor form an ellipsoid,showing the effect of different phospholipid membranes on the structure of the pentamer.After interaction with Aβ42pentamer,the order parameters of the three phospholipid membranes will all become smaller.Among them,POPC phospholipid membrane has the largest deuterium order parameter,followed by Pc Pg,and then by POPG phospholipid membrane.The selfdiffusion coefficient of the pentamer was significantly reduced after it binds to the phospholipid membrane compared with that in the aqueous solution,the calculated average self-diffusion coefficient of Aβ pentamer on the Pc Pg surface is reduced by about half relative to its value in aqueous solution.When Aβ42 pentamer is inserted in POPG phospholipid membrane,its average self-diffusion coefficient drops further,which showing the damage effect of Aβ42 pentamer on the phospholipid membrane.Aβ42 decamer can only bind to the negatively charged phospholipid membrane POPG,but not to others,and it takes a long time(about 11000ns)to complect the binding.Aβ42 decamer binding to POPG phospholipid membrane does not unfold on the surface of the phospholipid membrane as Aβ42 pentamer does.When Aβ42decamer binds to the phospholipid membrane,the degree of order of the membrane is reduced but less than that of pentamers,and the density of the membrane is not decreased,indicating that Aβ42 decamer has less damage to the phospholipid membrane than pentamers The above results can provide vital information for both the aggregation of Aβ42 and understanding the putative toxicity mechanism in the pathogenesis of Alzheimer’s disease.