Characterization of Insulin Degrading Enzyme and Other Amyloid-β Degrading Proteases in Human Serum: A Role in Alzheimer's Disease?

Article type: Research Article

Authors: Liu, Zhiheng^{a; f; 1} | Zhu, Haihao^{a; 1} | Fang, Guang Guang^{a; g} | Walsh, Kathryn^a | Mwamburi, Mkaya^d | Wolozin, Benjamin^{a; c} | Abdul-Hay, Samer O.^e | Ikezu, Tsuneya^{a; c} | Leissring, Malcolm A.^e | Qiu, Wei Qiao^{a; b; *}

Affiliations: [a] Departments of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA, USA | [b] Departments of Psychiatry, Boston University Medical Campus, Boston, MA, USA | [c] Departments of Neurology, Boston University Medical Campus, Boston, MA, USA | [d] Department of Public Health and Family Medicine, Tufts University, Boston, MA, USA | [e] Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL, USA | [f] Departments of Anesthesiology, The Second People's Hospital of Shenzhen, Guandong Province, PR China | [g] Departments of Gynecology, The Second People's Hospital of Shenzhen, Guandong Province, PR China

Correspondence: [*] Correspondence to: Wendy Wei Qiao Qiu, M.D., Ph.D., Boston University Medical Campus, 72 East Concord Street, R-623D, Boston, MA 02118, USA. Tel.: +1 617 638 4336; Fax: +1 617 638 5254; E-mail: [email protected].

Note: [1] These authors contributed equally to the manuscript.

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.

Keywords: Aβ degradation, Alzheimer's disease, angiotensin converting enzyme, insulin degrading enzyme, protease, serum

DOI: 10.3233/JAD-2011-111472

Journal: Journal of Alzheimer's Disease, vol. 29, no. 2, pp. 329-340, 2012