Inhibiting β-secretase activity in Alzheimer's disease cell models with single-chain antibodies specifically targeting APP

Shanta Boddapati, Yona Levites, Michael Sierks

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The Amyloid-β (Aβ) peptide is produced from the amyloid precursor protein (APP) by sequential proteolytic cleavage of APP first by β-secretase and then by γ-secretase. β-Site APP cleaving enzyme-1 (BACE-1) is the predominant enzyme involved in β-secretase processing of APP and is a primary therapeutic target for treatment of Alzheimer's disease. While inhibiting BACE-1 activity has obvious therapeutic advantages, BACE-1 also cleaves numerous other substrates with important physiological activity. Thus, blanket inhibition of BACE-1 function may have adverse side effects. We isolated a single chain variable fragment (scFv) from a human-based scFv yeast display library that selectively inhibits BACE-1 activity toward APP by binding the APP substrate at the proteolytic site. We selected the iBSEC1 scFv, since it recognizes the BACE-1 cleavage site on APP but does not bind the adjacent highly antigenic N-terminal of Aβ, and thus it will target APP but not soluble Aβ. When added to 7PA2 cells, a mammalian cell line that overexpresses APP, the iBSEC1 scFv binds APP on the cell surface, reduces toxicity induced by APP overexpression, and reduces both intracellular and extracellular Aβ levels by around 50%. Since the iBSEC1 scFv does not contain the antibody Fc region, this construct does not pose the risk of exacerbating inflammation in the brain as faced with full-length monoclonal antibodies for potential therapeutic applications.

Original languageEnglish (US)
Pages (from-to)436-447
Number of pages12
JournalJournal of molecular biology
Volume405
Issue number2
DOIs
StatePublished - Jan 14 2011

Keywords

  • Alzheimer's disease
  • immunotherapy
  • scFv
  • yeast display
  • β-secretase

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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