Characterization of insulin degrading enzyme and other amyloid-β degrading proteases in human serum: a role in Alzheimer's disease?
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.
Departments of Pharmacology and Experimental Therapeutics, Boston University Medical Campus, Boston, MA 02118, USA.
Zhiheng
Z
Liu
Haihao
H
Zhu
Guang Guang
GG
Fang
Kathryn
K
Walsh
Mkaya
M
Mwamburi
Benjamin
B
Wolozin
Samer O
SO
Abdul-Hay
Tsuneya
T
Ikezu
Malcolm A
MA
Leissring
Wei Qiao
WQ
Qiu
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000097:blood*; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000473:pathology; D060825:Cognitive Dysfunction / Q000097:blood* / Q000235:genetics; D005260:Female; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007339:Insulysin / Q000097:blood*; D058228:Islet Amyloid Polypeptide / Q000097:blood; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000097:blood*; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D011569:Psychiatric Status Rating Scales; D044967:Serum / Q000201:enzymology*; D018709:Statistics, Nonparametric; D013997:Time Factors
D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D005456:Fluorescent Dyes; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D007703:Peptidyl-Dipeptidase A; D007339:Insulysin