期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 24, 页码 15078-15091出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.610931
关键词
-
资金
- National Institutes of Health [AG030539, NS051715, P30 NS050276, U24 CA126485]
- Alzheimer's Association
Matrix metalloproteases (MMPs) MMP-2 and MMP-9 have been implicated in the physiological catabolism of Alzheimer's amyloid-beta (A beta). Conversely, their association with vascular amyloid deposits, blood-brain barrier disruption, and hemorrhagic transformations after ischemic stroke also highlights their involvement in pathological processes. To better understand this dichotomy, recombinant human (rh) MMP-2 and MMP-9 were incubated with A beta 40 and A beta 42, and the resulting proteolytic fragments were assessed via immunoprecipitation and quantitative mass spectrometry. Both MMPs generated A beta fragments truncated only at the C terminus, ending at positions 34, 30, and 16. Using deuterated homologues as internal standards, we observed limited and relatively slow degradation of A beta 42 by rhMMP-2, although the enzyme cleaved >80% of A beta 40 during the 1st h of incubation. rhMMP-9 was significantly less effective, particularly in degrading A beta(1-42), although the targeted peptide bonds were identical. Using A beta(1-34) and A beta(1-30), we demonstrated that these peptides are also substrates for both MMPs, cleaving A beta(1-34) to produce A beta(1-30) first and A beta(1-16) subsequently. Consistent with the kinetics observed with full-length A beta, rhMMP-9 degraded only a minute fraction of A beta(1-34) and was even less effective in producing A beta(1-16). Further degradation of A beta(1-16) by either MMP-2 or MMP-9 was not observed even after prolonged incubation times. Notably, all MMP-generated C-terminally truncated A beta fragments were highly soluble and did not exhibit fibrillogenic properties or induce cytotoxicity in human cerebral microvascular endothelial or neuronal cells supporting the notion that these truncated A beta species are associated with clearance mechanisms rather than being key elements in the fibrillogenesis process.
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