Kim, Woojin Kim, Yunkyoung Min, Jaeki Kim, Dong Jin Chang, Young-Tae Hecht, Michael H. 2024-01-21T02:35:07Z 2024-01-21T02:35:07Z 2021-09-02 2006-08 1554-8929 https://pubs.kist.re.kr/handle/201004/135287 Aggregation of the Alzheimer's peptide A beta produces toxic multimeric species that play a key role in the development of Alzheimer's disease. Compounds that inhibit this aggregation may prove useful as therapeutic agents for the prevention or treatment of Alzheimer's disease. Although aggregation inhibitors may already exist in combinatorial libraries, finding these compounds in a cost-effective high-throughput manner poses an enormous challenge. To meet this challenge, we have developed a novel high-throughput screen capable of isolating inhibitors of A beta aggregation from large libraries of inactive candidates. The screen uses a fusion of A beta 42 to GFP. In the absence of inhibition, the rapid misfolding and aggregation of A beta 42 causes the entire fusion protein to misfold, thereby preventing fluorescence. Compounds that inhibit A beta 42 aggregation enable GFP to fold into its native structure and be identified by the resulting fluorescent signal. By implementing the screen on a pilot library of triazine derivatives, we have identified several putative inhibitors. One of the selected compounds was studied in detail by a series of biochemical and biophysical methods. These studies confirmed that the selected compound inhibits aggregation of synthetic A beta 42 peptide. The fluorescence-based method described here is rapid and inexpensive and can be used to screen large libraries for inhibitors of A beta 42 aggregation and/or amyloidogenesis. English AMER CHEMICAL SOC BETA-AMYLOID FIBRILS GREEN FLUORESCENT PROTEIN LONG-TERM POTENTIATION CENTRAL-NERVOUS-SYSTEM A-BETA SEQUENCE DETERMINANTS A-BETA-42 PEPTIDE DISEASE BRAIN IN-VIVO OLIGOMERS A high-throughput screen for compounds that inhibit aggregation of the Alzheimer's peptide Article 10.1021/cb600135w 1 ACS CHEMICAL BIOLOGY, v.1, no.7, pp.461 - 469 ACS CHEMICAL BIOLOGY 1 7 461 469 scie scopus 000243894000020 Biochemistry & Molecular Biology Biochemistry & Molecular Biology Article BETA-AMYLOID FIBRILS GREEN FLUORESCENT PROTEIN LONG-TERM POTENTIATION CENTRAL-NERVOUS-SYSTEM A-BETA SEQUENCE DETERMINANTS A-BETA-42 PEPTIDE DISEASE BRAIN IN-VIVO OLIGOMERS Alzheimer HTS screen Aggregation inhibit Beta amyloid