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CAA is characterized by the aggregation of amyloid-\u03b2 (A\u03b2) peptides and formation of A\u03b2 deposits in the brain vasculature resulting in a disruption of the angioarchitecture. Capillaries are a critical site of A\u03b2 pathology in CAA type 1 and become dysfunctional during disease progression. Here, applying an advanced protocol for the isolation of parenchymal microvessels from post-mortem brain tissue combined with liquid chromatography tandem mass spectrometry (LC\u2013MS\/MS), we determined the proteomes of CAA type 1 cases (n\u2009=\u200912) including a patient with hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D), and of AD cases without microvascular amyloid pathology (n\u2009=\u200913) in comparison to neurologically healthy controls (n\u2009=\u200912). ELISA measurements revealed microvascular A\u03b2<jats:sub>1-40<\/jats:sub> levels to be exclusively enriched in CAA samples (mean:\u2009&gt;\u20093000-fold compared to controls). The proteomic profile of CAA type 1 was characterized by massive enrichment of multiple predominantly secreted proteins and showed significant overlap with the recently reported brain microvascular proteome of patients with cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary cerebral small vessel disease (SVD) characterized by the aggregation of the Notch3 extracellular domain. We found this overlap to be largely attributable to the accumulation of high-temperature requirement protein A1 (HTRA1), a serine protease with an established role in the brain vasculature, and several of its substrates. Notably, this signature was not present in AD cases. We further show that HTRA1 co-localizes with A\u03b2 deposits in brain capillaries from CAA type 1 patients indicating a pathologic recruitment process. Together, these findings suggest a central role of HTRA1-dependent protein homeostasis in the CAA microvasculature and a molecular connection between multiple types of brain microvascular disease.<\/jats:p>","DOI":"10.1186\/s40478-021-01303-6","type":"journal-article","created":{"date-parts":[[2022,1,24]],"date-time":"2022-01-24T11:03:52Z","timestamp":1643022232000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["Proteomic profiling in cerebral amyloid angiopathy reveals an overlap with CADASIL highlighting accumulation of HTRA1 and its substrates"],"prefix":"10.1186","volume":"10","author":[{"given":"Andreas","family":"Zellner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan A.","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Lindner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Beaufort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemieke J. 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