Sequential Amyloid-ß Degradation by the Matrix Metalloproteases MMP-2 and MMP-9.
J Biol Chem
; 290(24): 15078-91, 2015 Jun 12.
Article
em En
| MEDLINE
| ID: mdl-25897080
ABSTRACT
Matrix metalloproteases (MMPs) MMP-2 and MMP-9 have been implicated in the physiological catabolism of Alzheimer's amyloid-ß (Aß). 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 Aß40 and Aß42, and the resulting proteolytic fragments were assessed via immunoprecipitation and quantitative mass spectrometry. Both MMPs generated Aß 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 Aß42 by rhMMP-2, although the enzyme cleaved >80% of Aß40 during the 1st h of incubation. rhMMP-9 was significantly less effective, particularly in degrading Aß(1-42), although the targeted peptide bonds were identical. Using Aß(1-34) and Aß(1-30), we demonstrated that these peptides are also substrates for both MMPs, cleaving Aß(1-34) to produce Aß(1-30) first and Aß(1-16) subsequently. Consistent with the kinetics observed with full-length Aß, rhMMP-9 degraded only a minute fraction of Aß(1-34) and was even less effective in producing Aß(1-16). Further degradation of Aß(1-16) by either MMP-2 or MMP-9 was not observed even after prolonged incubation times. Notably, all MMP-generated C-terminally truncated Aß 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 Aß species are associated with clearance mechanisms rather than being key elements in the fibrillogenesis process.
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MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
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Metaloproteinase 2 da Matriz
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Metaloproteinase 9 da Matriz
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article