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Cerebral Accumulation, Distribution and Clearance of GOM and NOTCH3 fragments in CADASIL

Lookup NU author(s): Dr Lucinda Craggs, Janet Slade, Professor Johannes Attems, Arthur Oakley, Professor Raj KalariaORCiD


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Introduction: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of familial arteriopathy with a pathological hallmark of vascular accumulation of granular osmiophilic material (GOM). The cerebral distribution of GOM accumulation and NOTCH3 associated proteins has not yet been described. Materials and Methods: Conventional immunohistochemistry alongside a modified immunogold electron microscopy (EM) technique was used to study GOM, NOTCH 3 protein and its ligands, JAGGED 1, DELTA 1 and DELTA 4 in post-mortem cerebral tissue from CADASIL patients and comparable age controls. Results: Characteristic staining patterns were observed with three different N3ECD antibodies in CADASIL cases but not in controls. CADASIL cases exhibited N3ECD immunoreactivity in vessel walls, including punctuate reactivity in capillaries. Immunogold labelling of GOM using N3ECD antibody A-1 followed by EM imaging revealed profound extracellular distribution of 0.2-2 μm GOM, associated with meningeal, pial, perforating arteries and arterioles, as well as capillaries and arterioles within the white matter. Immunogold labelling of GOM was not observed in negative controls or sections stained for smooth muscle α-actin, collagen IV or the NOTCH3 ligands; JAGGED 1, DELTA 1 and DELTA 4. Phagocytic activity of perivascular macrophages associated with GOM deposits was observed.Conclusions: These results suggest that NOTCH3 fragments are key to GOM accumulation and that the latter is cleared via perivascular routes.

Publication metadata

Author(s): Craggs LJL, Yamamoto Y, Watanabe A, Low WC, Slade JY, Attems J, Oakley AE, Kalaria RN

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: 10th European Congress on Neuropathology

Year of Conference: 2012