title: A peptide binding to the β-site of APP improves spatial memory and attenuates Aβ burden in Alzheimer's disease transgenic mice.
abstract: Amyloid precursor protein cleaving enzyme 1 (BACE1), an aspartyl protease, initiates processing of the amyloid precursor protein (APP) into β-amyloid (Aβ); the peptide likely contributes to development of Alzheimer's disease (AD). BACE1 is an attractive therapeutic target for AD treatment, but it exhibits other physiological activities and has many other substrates besides APP. Thus, inhibition of BACE1 function may cause adverse side effects. Here, we present a peptide, S1, isolated from a peptide library that selectively inhibits BACE1 hydrolytic activity by binding to the β-proteolytic site on APP and Aβ N-terminal. The S1 peptide significantly reduced Aβ levels in vitro and in vivo and inhibited Aβ cytotoxicity in SH-SY5Y cells. When applied to APPswe/PS1dE9 double transgenic mice by intracerebroventricular injection, S1 significantly improved the spatial memory as determined by the Morris Water Maze, and also attenuated their Aβ burden. These results indicate that the dual-functional peptide S1 may have therapeutic potential for AD by both reducing Aβ generation and inhibiting Aβ cytotoxicity.
authors.affiliation: Tsinghua University School of Medicine, Haidian District, Beijing, China.
authors.forename: Shi-gao
authors.initials: SG
authors.lastname: Yang
authors.forename: Shao-wei
authors.initials: SW
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Ran
authors.initials: R
authors.lastname: Zhang
authors.forename: Wei-wei
authors.initials: WW
authors.lastname: Zhou
authors.forename: Ya-nan
authors.initials: YN
authors.lastname: Li
authors.forename: Ya-jing
authors.initials: YJ
authors.lastname: Su
authors.forename: He
authors.initials: H
authors.lastname: Zhang
authors.forename: Xiao-lin
authors.initials: XL
authors.lastname: Yu
authors.forename: Rui-tian
authors.initials: RT
authors.lastname: Liu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D052160:Benzothiazoles; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D013037:Spatial Behavior; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D052160:Benzothiazoles; D019151:Peptide Library; D010455:Peptides; D013778:Tetrazolium Salts; D013844:Thiazoles; C009462:thioflavin T; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C022616:thiazolyl blue