Cargando…
Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease
Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capill...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985582/ https://www.ncbi.nlm.nih.gov/pubmed/29860944 http://dx.doi.org/10.1186/s40478-018-0540-2 |
_version_ | 1783328780580814848 |
---|---|
author | Hondius, David C. Eigenhuis, Kristel N. Morrema, Tjado H. J. van der Schors, Roel C. van Nierop, Pim Bugiani, Marianna Li, Ka Wan Hoozemans, Jeroen J. M. Smit, August B. Rozemuller, Annemieke J. M. |
author_facet | Hondius, David C. Eigenhuis, Kristel N. Morrema, Tjado H. J. van der Schors, Roel C. van Nierop, Pim Bugiani, Marianna Li, Ka Wan Hoozemans, Jeroen J. M. Smit, August B. Rozemuller, Annemieke J. M. |
author_sort | Hondius, David C. |
collection | PubMed |
description | Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits. By contrasting the quantitative proteomics data between the three groups, 29 potential CAA-selective proteins were identified. A selection of these proteins was analysed by immunoblotting and immunohistochemistry to confirm regulation and to determine protein localization and their relation to brain pathology. In addition, specificity of these markers in relation to other small vessel diseases including prion CAA, CADASIL, CARASAL and hypertension related small vessel disease was assessed using immunohistochemistry. Increased levels of clusterin (CLU), apolipoprotein E (APOE) and serum amyloid P-component (APCS) were observed in AD cases with CAA. In addition, we identified norrin (NDP) and collagen alpha-2(VI) (COL6A2) as highly selective markers that are clearly present in CAA yet virtually absent in relation to parenchymal amyloid plaque pathology. NDP showed the highest specificity to CAA when compared to other small vessel diseases. The specific changes in the proteome of CAA provide new insight in the pathogenesis and yields valuable selective biomarkers for the diagnosis of CAA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0540-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5985582 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-59855822018-06-07 Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease Hondius, David C. Eigenhuis, Kristel N. Morrema, Tjado H. J. van der Schors, Roel C. van Nierop, Pim Bugiani, Marianna Li, Ka Wan Hoozemans, Jeroen J. M. Smit, August B. Rozemuller, Annemieke J. M. Acta Neuropathol Commun Research Alzheimer’s disease (AD) is characterized by amyloid beta (Aβ) deposits as plaques in the parenchyma and in the walls of cortical and leptomeningeal blood vessels of the brain called cerebral amyloid angiopathy (CAA). It is suggested that CAA type-1, which refers to amyloid deposition in both capillaries and larger vessels, adds to the symptomatic manifestation of AD and correlates with disease severity. Currently, CAA cannot be diagnosed pre-mortem and disease mechanisms involved in CAA are elusive. To obtain insight in the disease mechanism of CAA and to identify marker proteins specifically associated with CAA we performed a laser dissection microscopy assisted mass spectrometry analysis of post-mortem human brain tissue of (I) AD cases with only amyloid deposits in the brain parenchyma and no vascular related amyloid, (II) AD cases with severe CAA type-1 and no or low numbers of parenchymal amyloid deposits and (III) cognitively healthy controls without amyloid deposits. By contrasting the quantitative proteomics data between the three groups, 29 potential CAA-selective proteins were identified. A selection of these proteins was analysed by immunoblotting and immunohistochemistry to confirm regulation and to determine protein localization and their relation to brain pathology. In addition, specificity of these markers in relation to other small vessel diseases including prion CAA, CADASIL, CARASAL and hypertension related small vessel disease was assessed using immunohistochemistry. Increased levels of clusterin (CLU), apolipoprotein E (APOE) and serum amyloid P-component (APCS) were observed in AD cases with CAA. In addition, we identified norrin (NDP) and collagen alpha-2(VI) (COL6A2) as highly selective markers that are clearly present in CAA yet virtually absent in relation to parenchymal amyloid plaque pathology. NDP showed the highest specificity to CAA when compared to other small vessel diseases. The specific changes in the proteome of CAA provide new insight in the pathogenesis and yields valuable selective biomarkers for the diagnosis of CAA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0540-2) contains supplementary material, which is available to authorized users. BioMed Central 2018-06-04 /pmc/articles/PMC5985582/ /pubmed/29860944 http://dx.doi.org/10.1186/s40478-018-0540-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Hondius, David C. Eigenhuis, Kristel N. Morrema, Tjado H. J. van der Schors, Roel C. van Nierop, Pim Bugiani, Marianna Li, Ka Wan Hoozemans, Jeroen J. M. Smit, August B. Rozemuller, Annemieke J. M. Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease |
title | Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease |
title_full | Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease |
title_fullStr | Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease |
title_full_unstemmed | Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease |
title_short | Proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in Alzheimer’s disease |
title_sort | proteomics analysis identifies new markers associated with capillary cerebral amyloid angiopathy in alzheimer’s disease |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985582/ https://www.ncbi.nlm.nih.gov/pubmed/29860944 http://dx.doi.org/10.1186/s40478-018-0540-2 |
work_keys_str_mv | AT hondiusdavidc proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT eigenhuiskristeln proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT morrematjadohj proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT vanderschorsroelc proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT vannieroppim proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT bugianimarianna proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT likawan proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT hoozemansjeroenjm proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT smitaugustb proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease AT rozemullerannemiekejm proteomicsanalysisidentifiesnewmarkersassociatedwithcapillarycerebralamyloidangiopathyinalzheimersdisease |