Amyloid-β peptide levels in brain are inversely correlated with insulysin activity levels in vivo

Bonnie C. Miller, Elizabeth A. Eckman, Kumar Sambamurti, Nicole Dobbs, K. Martin Chow, Christopher B. Eckman, Louis B. Hersh, Dwain L Thiele

Research output: Contribution to journalArticle

246 Scopus citations

Abstract

Factors that elevate amyloid-β (Aβ) peptide levels are associated with an increased risk for Alzheimer's disease. Insulysin has been identified as one of several proteases potentially involved in Aβ degradation based on its hydrolysis of Aβ peptides in vitro. In this study, in vivo levels of brain Aβ40 and Aβ42 peptides were found to be increased significantly (1.6- and 1.4-fold, respectively) in an insulysin-deficient gene-trap mouse model. A 6-fold increase in the level of the γ-secretase-generated C-terminal fragment of the Aβ precursor protein in the insulysin-deficient mouse also was found. In mice heterozygous for the insulysin gene trap, in which insulysin activity levels were decreased ≊50%, brain A> peptides were increased to levels intermediate between those in wild-type mice and homozygous insulysin gene-trap mice that had no detectable insulysin activity. These findings indicate that there is an inverse correlation between in vivo insulysin activity levels and brain A> peptide levels and suggest that modulation of insulysin activity may alter the risk for Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)6221-6226
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number10
DOIs
StatePublished - May 13 2003

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