Characterization of insulin degrading enzyme and other amyloid-β degrading proteases in human serum: A role in alzheimer's disease?

Zhiheng Liu, Haihao Zhu, Guang Guang Fang, Kathryn Walsh, Mkaya Mwamburi, Benjamin Wolozin, Samer O. Abdul-Hay, Tsuneya Ikezu, Malcolm A. Leissring, Wei Qiao Qiu

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Sporadic Alzheimer's disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system. The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aβ. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD.

Original languageEnglish (US)
Pages (from-to)329-340
Number of pages12
JournalJournal of Alzheimer's Disease
Volume29
Issue number2
DOIs
StatePublished - 2012

Keywords

  • Alzheimer's disease
  • Aβ degradation
  • angiotensin converting enzyme
  • insulin degrading enzyme
  • protease
  • serum

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

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    Liu, Z., Zhu, H., Fang, G. G., Walsh, K., Mwamburi, M., Wolozin, B., Abdul-Hay, S. O., Ikezu, T., Leissring, M. A., & Qiu, W. Q. (2012). Characterization of insulin degrading enzyme and other amyloid-β degrading proteases in human serum: A role in alzheimer's disease? Journal of Alzheimer's Disease, 29(2), 329-340. https://doi.org/10.3233/JAD-2011-111472