期刊
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
卷 43, 期 6, 页码 492-504出版社
WILEY
DOI: 10.1111/nan.12342
关键词
clusterin; complement pathway; extracellular matrix remodelling; leptomeningeal arteries; proteomics; TIMP3
资金
- BBSRC
- Rosetrees Trust
- Wessex Cancer Trust
- Medical Research, UK
- King Saud University
- Deanship of Scientific Research Chair
- Prince Mutaib Bin Abdullah Chair for Biomarkers of Osteoporosis
- College of Science
- King Saud University, Riyadh, Saudi Arabia
- UK Medical Research Council [G0400074]
- Alzheimer's Society
- Alzheimer's Research UK
- MRC [G0502157, G0900652, G0400074, G1100540, MR/L016400/1] Funding Source: UKRI
- Alzheimers Research UK [ARUK-NCG2013B-1] Funding Source: researchfish
- Medical Research Council [MR/L016400/1, G0400074, G0502157, G1100540, G0900652] Funding Source: researchfish
- Rosetrees Trust [M273] Funding Source: researchfish
- Stroke Association [TSAMRCPPA201702] Funding Source: researchfish
AimsAmyloid beta (A) 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. MethodsFreshly 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. ResultsBioinformatics 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 A and to be up-regulated in leptomeningeal arteries from CAA patients compared to young and elderly controls. ConclusionsGlobal 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.
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