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Lookup NU author(s): Mary Johnson, Professor Raj KalariaORCiD, Professor Johannes Attems
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2016 British Neuropathological Society. Aims: 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.
Author(s): Manousopoulou A, Gatherer M, Smith C, Nicoll JAR, Woelk CH, Johnson M, Kalaria R, Attems J, Garbis SD, Carare RO
Publication type: Article
Publication status: Published
Journal: Neuropathology and Applied Neurobiology
Year: 2017
Volume: 43
Issue: 6
Pages: 492-504
Print publication date: 01/10/2017
Online publication date: 20/08/2016
Acceptance date: 16/08/2016
Date deposited: 07/04/2017
ISSN (print): 0305-1846
ISSN (electronic): 1365-2990
Publisher: Wiley-Blackwell
URL: https://doi.org/10.1111/nan.12342
DOI: 10.1111/nan.12342
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