title: Matrix Metalloproteinases in Alzheimer's Disease and Concurrent Cerebral Microbleeds.
abstract: Matrix metalloproteinases (MMPs) are a family of enzymes able to degrade components of the extracellular matrix, which is important for normal blood-brain barrier function. Their function is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). We investigated whether MMPs and TIMPs in cerebrospinal fluid (CSF) and plasma were altered in Alzheimer's disease (AD) and vascular dementia (VaD), and whether this effect was modified by presence of cerebral micro-bleeds in AD patients. In addition, we assessed associations of MMPs and TIMPs with CSF amyloid-β(1-42) (Aβ42), tau, and tau phosphorylated at threonine-181 (p-tau). We measured MMP2, MMP9, and MMP10, and TIMP1 and TIMP2 in CSF and plasma of 52 AD patients, 26 matched controls, and 24 VaD patients. AD patients showed higher plasma MMP2 levels compared to VaD patients (p <  0.05), and higher CSF MMP10 levels compared to controls (p <  0.05). Microbleeds in AD were associated with lower CSF TIMP1, TIMP2 and MMP9 in a dose-response relation. In addition, CSF MMP2 was associated with p-tau (St.B 0.23, p <  0.05), and CSF MMP10 with tau (St.B 0.38, p <  0.001) and p-tau (St.B 0.40, p <  0.001). Our findings suggest involvement of MMP2 and MMP10 in AD pathology. Lower levels of TIMPs in AD patients with microbleeds suggest less MMP inhibition in patients with concurrent cerebral microbleeds, which may hypothetically lead to a more vulnerable blood-brain barrier in these patients.
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Flora H
authors.initials: FH
authors.lastname: Duits
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca, Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Hernandez-Guillamon
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca, Barcelona, Spain.|Neurovascular Unit, Neurology & Medicine Departments, Universitat Autònoma de Barcelona. Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Jereon D C
authors.initials: JD
authors.lastname: Goos
authors.affiliation: Neurovascular Research Laboratory, Institut de Recerca, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Montañola
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam,VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mike P
authors.initials: MP
authors.lastname: Wattjes
authors.affiliation: Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam,VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Teunissen
authors.affiliation: Alzheimer Center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.|Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001774:Blood Chemical Analysis; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D002543:Cerebral Hemorrhage / Q000473:pathology / Q000503:physiopathology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020782:Matrix Metalloproteinases / Q000097:blood* / Q000134:cerebrospinal fluid*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D019714:Tissue Inhibitor of Metalloproteinases / Q000097:blood / Q000134:cerebrospinal fluid; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; D019714:Tissue Inhibitor of Metalloproteinases; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D020782:Matrix Metalloproteinases
keywords: Alzheimer’s disease; cerebral amyloid angiopathy; cerebrospinal fluid; matrix metalloproteinases; microbleeds; tissue inhibitors of matrix metalloproteinases