title: Involvement of matrix metalloproteinase-9 in amyloid-β 1-42-induced shedding of the pericyte proteoglycan NG2.
abstract: Deposition of amyloid-β (Aβ) 1-42, the major component of senile plaques characteristic of Alzheimer disease, affects brain microvascular integrity and causes blood-brain barrier dysfunction, increased angiogenesis, and pericyte degeneration. To understand the cellular events underlying Aβ1-42 effects on microvascular alterations, we investigated whether different aggregation forms of Aβ1-42 affect shedding of the pericyte proteoglycan NG2 and whether they affect proteolytic cleavage mediated by matrix metalloproteinase (MMP)-9. We found decreased levels of soluble NG2, total MMP-9, and MMP-9 activity in pericyte culture supernatants in response to fibril-enriched preparations of Aβ1-42. Conversely, oligomer-enriched preparations of Aβ1-42 increased soluble NG2 levels in the supernatants. This increase was ablated by the MMP-9/MMP-2 inhibitor SB-3CT. There was also a trend toward increased MMP-9 activity observed after oligomeric Aβ1-42 exposure. Our results, demonstrating an Aβ1-42 aggregation-dependent effect on levels of NG2 and MMP-9, support previous studies showing an impact of Aβ1-42 on vascular integrity and thereby add to our understanding of mechanisms behind the microvascular changes commonly found in patients with Alzheimer disease.
authors.affiliation: From the Clinical Memory Research Unit, The Wallenberg Laboratory, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden (NS, LM, MW); and Department of Neuroscience, Mayo Clinic, Jacksonville, Florida (HMN).
authors.forename: Nina
authors.initials: N
authors.lastname: Schultz
authors.forename: Henrietta M
authors.initials: HM
authors.lastname: Nielsen
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.forename: Malin
authors.initials: M
authors.lastname: Wennström
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000941:Antigens / Q000378:metabolism*; D002449:Cell Aggregation; D002460:Cell Line; D002470:Cell Survival; D003470:Culture Media; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D016229:Amyloid beta-Peptides; D000941:Antigens; D003470:Culture Media; D007770:L-Lactate Dehydrogenase; D020781:Matrix Metalloproteinase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D010446:Peptide Fragments; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C075222:amyloid beta-protein (1-42)