Cleavage of fluorogenic substrates for APP-processing proteases by human brain extracts - Ca2+-substrate interaction is responsible for Ca2+ stimulation of the neural protease activity

Gary T. Wang*, Uri S. Ladror, Thomas F. Holzman, William L. Klein, Grant A. Krafft

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The proteases that cleave amyloid precursor protein (APP) leading to generation of amyloid Aβ peptide are potential targets for therapeutical intervention of Alzheimer disease. We have been pursuing the identification and characterization of these proteases using as probes the fluorogenic substrates encompassing the cleavage sites of APP that we described recently (Wang, G. T., Krafft, G. A. [1992]Bioorg. Med. Chem. Lett. 2, 1665). This article describes results of experiments designed to examine the effect of Ca2+ on the cleavage of these substrates by human brain extracts. Fluorogenic substrates encompassing either the N-terminal amyloidogenic cleavage site or the secretory cleavage site were synthesized in five formats with various peripheral residues. Incubation with extracts from normal brain tissue revealed that more negatively charged amyloidogenic substrates were less reactive and exhibited larger rate enhancement in the presence of Ca2+. The results imply that Ca2+ stimulation of substrate cleavage by brain proteases occurs primarily as a result of Ca2+-substrate interactions, and caution against interpretations that invoke the involvement of Ca2+-stimulated proteases in Aβ formation.

Original languageEnglish (US)
Pages (from-to)191-199
Number of pages9
JournalMolecular and Chemical Neuropathology
Volume23
Issue number2-3
DOIs
StatePublished - Oct 1994

Keywords

  • Ab peptide
  • Alzheimer disease
  • Amyloid precursor protein
  • Ca effect
  • fluorogenic substrates
  • protease

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology

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