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Systems proteomic analysis reveals that clusterin and tissue inhibitor of metalloproteinases 3 increase in leptomeningeal arteries affected by cerebral amyloid angiopathy

Lookup NU author(s): Mary Johnson, Professor Raj Kalaria, Professor Johannes Attems

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 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.


Publication metadata

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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