Insulysin hydrolyzes amyloid β peptides to products that are neither neurotoxic nor deposit on amyloid plaques

A. Mukherjee, E. S. Song, M. Kihiko-Ehmann, Jr Goodman, J. St. Pyrek, S. Estus, L. B. Hersh

Research output: Contribution to journalArticlepeer-review

125 Scopus citations

Abstract

Insulysin (EC. 3.4.22.11) has been implicated in the clearance of β amyloid peptides through hydrolytic cleavage. To further study the action of insulysin on Aβ peptides recombinant rat insulysin was used. Cleavage of both Aβ(1-40) and Aβ(1-42) by the recombinant enzyme was shown to initially occur at the His13-His(14), His(14)-Gln(15), and Phe(19)-Phe(20) bonds. This was followed by a slower cleavage at the Lys(28)-Gly(29), Val(18)-Phe(19), and Phe(20)-Ala(21) positions. None of the products appeared to be further metabolized by insulysin. Using a rat cortical cell system, the action of insulysin on Aβ(1-40) and Aβ(1-42) was shown to eliminate the neurotoxic effects of these peptides. Insulysin was further shown to prevent the deposition of Aβ(1-40) onto a synthetic amyloid. Taken together these results suggest that the use of insulysin to hydrolyze Aβ peptides represents an alternative gene therapeutic approach to the treatment of Alzheimer's disease.

Original languageEnglish
Pages (from-to)8745-8749
Number of pages5
JournalJournal of Neuroscience
Volume20
Issue number23
DOIs
StatePublished - Dec 1 2000

Keywords

  • Amyloid peptide metabolism
  • Aβ cleavage
  • Aβ deposition
  • Aβ neurotoxicity
  • Insulysin
  • Metallopeptidase

ASJC Scopus subject areas

  • Neuroscience (all)

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