title: Systems proteomic analysis reveals that clusterin and tissue inhibitor of metalloproteinases 3 increase in leptomeningeal arteries affected by cerebral amyloid angiopathy.
abstract: OBJECTIVE
  Amyloid beta (Aβ) accumulation in the walls of leptomeningeal arteries as cerebral amyloid angiopathy (CAA) is a major feature of Alzheimer's disease. In this study, we used global quantitative proteomic analysis to examine the hypothesis that the leptomeningeal arteries derived from patients with CAA have a distinct endophenotypic profile compared to those from young and elderly controls.
  
  
  METHODS
  Freshly dissected leptomeningeal arteries from the Newcastle Brain Tissue Resource and Edinburgh Sudden Death Brain Bank from seven elderly (82.9 ± 7.5 years) females with severe capillary and arterial CAA, as well as seven elderly (88.3 ± 8.6 years) and five young (45.4 ± 3.9 years) females without CAA were used in this study. Arteries from four patients with CAA, two young and two elderly controls were individually analysed using quantitative proteomics. Key proteomic findings were then validated using immunohistochemistry.
  
  
  RESULTS
  Bioinformatics interpretation of the results showed a significant enrichment of the immune response/classical complement and extracellular matrix remodelling pathways (P < 0.05) in arteries affected by CAA vs. those from young and elderly controls. Clusterin (apolipoprotein J) and tissue inhibitor of metalloproteinases-3 (TIMP3), validated using immunohistochemistry, were shown to co-localize with Aβ and to be up-regulated in leptomeningeal arteries from CAA patients compared to young and elderly controls.
  
  
  CONCLUSIONS
  Global proteomic profiling of brain leptomeningeal arteries revealed that clusterin and TIMP3 increase in leptomeningeal arteries affected by CAA. We propose that clusterin and TIMP3 could facilitate perivascular clearance and may serve as novel candidate therapeutic targets for CAA.
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.|Institute for Life Sciences, University of Southampton, Southampton, UK.
authors.forename: A
authors.initials: A
authors.lastname: Manousopoulou
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Gatherer
authors.affiliation: Pathology Department, University of Edinburgh, Edinburgh, UK.
authors.forename: C
authors.initials: C
authors.lastname: Smith
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: J A R
authors.initials: JAR
authors.lastname: Nicoll
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: C H
authors.initials: CH
authors.lastname: Woelk
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: R
authors.initials: R
authors.lastname: Kalaria
authors.affiliation: Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J
authors.initials: J
authors.lastname: Attems
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.|Institute for Life Sciences, University of Southampton, Southampton, UK.|Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: S D
authors.initials: SD
authors.lastname: Garbis
authors.affiliation: Clinical and Experimental Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: R O
authors.initials: RO
authors.lastname: Carare
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001158:Arteries / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051152:Clusterin / Q000378:metabolism*; D003171:Complement Pathway, Classical; D019295:Computational Biology; D058068:Endophenotypes; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D008875:Middle Aged; D040901:Proteomics; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C495242:CLU protein, human; D051152:Clusterin; D019717:Tissue Inhibitor of Metalloproteinase-3
keywords: TIMP3; clusterin; complement pathway; extracellular matrix remodelling; leptomeningeal arteries; proteomics