Therapeutic potential for amyloid surface inhibitor: only amyloid-beta oligomers formed by secondary nucleation disrupt lipid membrane integrity

Tian, Yao1; Liu, Jianbo2; Yang, Fadeng3; Lian, Chenshan2; Zhang, Huawei4; Viles, John H.1; Li, Zigang2,3

2022-06-01

10.1111/febs.16550

FEBS Journal   影响因子和分区

1742-464X

1742-4658

Inhibition of amyloid-beta peptide (A beta) aggregation is a promising therapeutic strategy for Alzheimer's disease (AD), as A beta aggregation is generally believed to trigger AD pathology. Pre-fibril A beta-oligomers induce membrane disruption and are crucial to neurotoxicity. We have previously designed a short peptide called cyclic helical amyloid surface inhibitor (cHASI) that can selectively bind to the A beta fibril surface. Here, we use cHASI to efficiently inhibit the surface-catalysed secondary nucleation process of A beta in a lipid membrane environment. By incubating A beta monomers with lipid vesicles, we show that during the assembly of A beta into amyloid fibrils, oligomers are formed that markedly disrupt the lipid bilayer. Remarkably, when A beta monomers are incubated with cHASI, although A beta forms amyloid fibrils via primary nucleation and elongation, this pathway to fibrils does not damage the lipid bilayer. This indicates that only oligomers produced during secondary surface nucleation disrupt membrane integrity. The protective effect of cHASI is confirmed by cytotoxicity assays. Our study highlights the therapeutic potential for inhibiting the secondary nucleation process in A beta aggregation, rather than inhibiting all pathways to fibril formation.

amyloid-beta inhibitor large unilamellar vesicles membrane disruption secondary nucleation

SCI

英语

其他

Natural Science Foundation of China[21778009] ; Beijing National Laboratory of Molecular Science open grant BNLMS[20160112] ; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions[2019SHIBS0004] ; National Natural Science Foundation of China[31900046] ; BBSRC[BB/M023877/1]

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:000812698200001

WILEY

Web of Science

1.Queen Mary Univ London, Sch Biol & Chem Sci, Mile End Rd, London E1 4NS, England
2.Shenzhen Bay Lab, Pingshan Translat Med Ctr, Lan Jing Rd 16, Shenzhen 518118, Peoples R China
3.Peking Univ, Shenzhen Grad Sch, Sch Chem Biol & Biotechnol, State Key Lab Chem Oncogen, Shenzhen, Peoples R China
4.Southern Univ Sci & Technol, Dept Biomed Engn, Shenzhen, Peoples R China

Tian, Yao,Liu, Jianbo,Yang, Fadeng,et al. Therapeutic potential for amyloid surface inhibitor: only amyloid-beta oligomers formed by secondary nucleation disrupt lipid membrane integrity[J]. FEBS Journal,2022.

Tian, Yao.,Liu, Jianbo.,Yang, Fadeng.,Lian, Chenshan.,Zhang, Huawei.,...&Li, Zigang.(2022).Therapeutic potential for amyloid surface inhibitor: only amyloid-beta oligomers formed by secondary nucleation disrupt lipid membrane integrity.FEBS Journal.

Tian, Yao,et al."Therapeutic potential for amyloid surface inhibitor: only amyloid-beta oligomers formed by secondary nucleation disrupt lipid membrane integrity".FEBS Journal (2022).