Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-ε4 allele

David G. Cook, James B. Leverenz, Pamela J. McMillan, J. Jacob Kulstad, Sasha Ericksen, Richard A. Roth, Gerard D. Schellenberg, Lee-Way Jin, Kristina S. Kovacina, Suzanne Craft

Research output: Contribution to journalArticle

250 Scopus citations

Abstract

Aβ is the major component of amyloid plaques characterizing Alzheimer's disease (AD). Aβ accumulation can be affected by numerous factors including increased rates of production and/or impaired clearance. Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Aβ in the brain. We have previously shown that AD patients exhibit abnormalities in insulin metabolism that are associated with apoliprotein E (APOE) status. The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD. We report that hippocampal IDE protein is reduced by approximately 50% in ε4+ AD patients compared to ε4- patients and controls. The allele-specific decrease of IDE in ε4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status. Hippocampal IDE mRNA levels were also reduced in AD patients with the ε4 allele compared to AD and normal subjects without the ε4 allele. These findings show that reduced IDE expression is associated with a significant risk factor for AD and suggest that IDE may interact with APOE status to affect Aβ metabolism.

Original languageEnglish (US)
Pages (from-to)313-319
Number of pages7
JournalAmerican Journal of Pathology
Volume162
Issue number1
StatePublished - Jan 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Cook, D. G., Leverenz, J. B., McMillan, P. J., Kulstad, J. J., Ericksen, S., Roth, R. A., Schellenberg, G. D., Jin, L-W., Kovacina, K. S., & Craft, S. (2003). Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-ε4 allele. American Journal of Pathology, 162(1), 313-319.