Inhibition of amyloid β-peptide production by blockage of β-secretase cleavage site of amyloid precursor protein

Chan Hyun Na, Sang Hee Jeon, Guangtao Zhang, Gary L. Olson, Chi Bom Chae

Research output: Contribution to journalArticlepeer-review

Abstract

Amyloid β-peptide (Aβ) is implicated as the major causative agent in Alzheimer's disease (AD). Aβ is produced by the processing of the amyloid precursor protein (APP) by BACE1 (β-secretase) and γ-secretase. Many inhibitors have been developed for the secretases. However, the inhibitors will interfere with the processing of not only APP but also of other secretase substrates. In this study, we describe the development of inhibitors that prevent production of Aβ by specific binding to the β-cleavage site of APP. We used the hydropathic complementarity (HC) approach for the design of short peptide inhibitors. Some of the HC peptides were bound to the substrate peptide (Sub W) corresponding to the β-cleavage site of APP and blocked its cleavage by recombinant human BACE1 (rhBACE1) in vitro. In addition, HC peptides specifically inhibited the cleavage of Sub W, and not affecting other BACE1 substrates. Chemical modification allowed an HC peptide (CIQIHF) to inhibit the processing of APP as well as the production of Aβ in the treated cells. Such novel APP-specific inhibitors will provide opportunity for the development of drugs that can be used for the prevention and treatment of AD with minimal side effects.

Original languageEnglish (US)
Pages (from-to)1583-1595
Number of pages13
JournalJournal of Neurochemistry
Volume101
Issue number6
DOIs
StatePublished - Jun 1 2007
Externally publishedYes

Keywords

  • APP-specific inhibitor
  • Alzheimer's disease
  • Amyloid precursor protein
  • BACE1
  • Hydropathic complementarity
  • β-amyloid

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'Inhibition of amyloid β-peptide production by blockage of β-secretase cleavage site of amyloid precursor protein'. Together they form a unique fingerprint.

Cite this