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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alzheimer Disease / genetics*
-
Alzheimer Disease / metabolism
-
Amyloid Precursor Protein Secretases / metabolism
-
Amyloid beta-Peptides / chemistry*
-
Amyloid beta-Protein Precursor / chemistry*
-
Animals
-
Aspartic Acid Endopeptidases / metabolism
-
Benzothiazoles
-
Cell Line, Tumor
-
Enzyme-Linked Immunosorbent Assay / methods
-
Humans
-
Maze Learning
-
Memory*
-
Mice
-
Mice, Transgenic
-
Microscopy, Electron, Transmission / methods
-
Peptide Library
-
Peptides / chemistry*
-
Protein Binding
-
Protein Structure, Tertiary
-
Sequence Analysis, DNA
-
Spatial Behavior*
-
Tetrazolium Salts / pharmacology
-
Thiazoles / chemistry
-
Thiazoles / pharmacology
Substances
-
Amyloid beta-Peptides
-
Amyloid beta-Protein Precursor
-
Benzothiazoles
-
Peptide Library
-
Peptides
-
Tetrazolium Salts
-
Thiazoles
-
thioflavin T
-
Amyloid Precursor Protein Secretases
-
Aspartic Acid Endopeptidases
-
BACE1 protein, human
-
thiazolyl blue
Grants and funding
This work was supported by grants from the National Natural Science Foundation of China (NSFC) (30971012 and 81171014), the National Science and Technology Major Projects of New Drugs (2012ZX09103301-001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.