Progression and Classification of Granular Osmiophilic Material (GOM) Deposits in Functionally Characterized Human NOTCH3 Transgenic Mice.

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  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: United States NLM ID: 101517297 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1868-601X (Electronic) Linking ISSN: 18684483 NLM ISO Abbreviation: Transl Stroke Res Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York : Springer
    • Subject Terms:
      Brain/*blood supply ; Brain/*pathology ; CADASIL/*genetics ; CADASIL/*pathology ; Receptor, Notch3/*genetics; Animals ; Brain/physiopathology ; Brain/ultrastructure ; Cerebrovascular Circulation ; Humans ; Mice, Inbred C57BL ; Mice, Transgenic
    • Abstract:
      CADASIL is a NOTCH3-associated cerebral small vessel disease. A pathological ultrastructural disease hallmark is the presence of NOTCH3-protein containing deposits called granular osmiophilic material (GOM), in small arteries. How these GOM deposits develop over time and what their role is in disease progression is largely unknown. Here, we studied the progression of GOM deposits in humanized transgenic NOTCH3 Arg182Cys mice, compared them to GOM deposits in patient material, and determined whether GOM deposits in mice are associated with a functional CADASIL phenotype. We found that GOM deposits are not static, but rather progress in ageing mice, both in terms of size and aspect. We devised a GOM classification system, reflecting size, morphology and electron density. Six-month-old mice showed mostly early stage GOM, whereas older mice and patient vessels showed predominantly advanced stage GOM, but also early stage GOM. Mutant mice did not develop the most severe GOM stage seen in patient material. This absence of end-stage GOM in mice was associated with an overall lack of histological vascular pathology, which may explain why the mice did not reveal functional deficits in cerebral blood flow, cognition and motor function. Taken together, our data indicate that GOM progress over time, and that new GOM deposits are continuously being formed. The GOM staging system we introduce here allows for uniform GOM deposit classification in future mouse and human studies, which may lead to more insight into a potential association between GOM stage and CADASIL disease severity, and the role of GOM in disease progression.
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    • Grant Information:
      HA2016-02-03 International Hersenstichting
    • Contributed Indexing:
      Keywords: CADASIL; Cerebral small vessel disease; Cerebrovascular reactivity (CVR); Electron microscopy (EM); Granular osmiophilic material (GOM); NOTCH3
    • Accession Number:
      0 (NOTCH3 protein, human)
      0 (Receptor, Notch3)
    • Publication Date:
      Date Created: 20191101 Date Completed: 20210727 Latest Revision: 20210727
    • Publication Date:
      20231215
    • Accession Number:
      PMC7235067
    • Accession Number:
      10.1007/s12975-019-00742-7
    • Accession Number:
      31667734