Potential βPP-processing proteinase activities from alzheimer's and control brain tissues

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Fluorogenic peptide substrates designed to encompass the reported α-secretory and amyloidogenic cleavage sites of the amyloid-β precursor protein (βPP) were used to analyze proteinase activities in brain extracts from control patients and those with Alzheimer's disease (AD). Activity against the secretory substrate at pH 7.5 in control and AD brains produced a major endopeptidase cleavage at the Lys687-Leu688 bond (βPP770 numbering), consistent with the βPP secretase cleavage. Activity in control brains against the amyloidogenic substrate at pH 7.5 produced one cleavage at the Ala673-Glu674 bond, two residues C-terminal to the amyloidogenic Met-Asp site. However, in three of four AD brains, the major cleavage was at the Asp-Ala bond, one residue from the amyloidogenic site. Both endopeptidase and carboxypeptidase activities in AD brains were lower than in control brains. Proteinase activities against the secretory substrate had a major optimum at pH 3.0-4.0 and another at pH 6.0-7.5. Proteinase activities against the amyloidogenic substrate had a major optimum at or below pH 3.0 and another at pH 6.0. Using both substrates, activities at low pH were higher in AD brains than in controls, while at pH above 6.5, activities in control brains were higher than in AD. These results indicate that the levels of proteolytic enzymes in AD brains are altered relative to controls.

Original languageEnglish (US)
Pages (from-to)357-366
Number of pages10
JournalJournal of Protein Chemistry
Volume13
Issue number4
DOIs
StatePublished - May 1994

Keywords

  • Alzheimer's disease
  • amyloid formation
  • proteinase
  • secretase

ASJC Scopus subject areas

  • Biochemistry

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