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Brain Microvascular Accumulation and Distribution of the NOTCH3 Ectodomain and Granular Osmiophilic Material in CADASIL

Lookup NU author(s): Yumi Yamamoto, Dr Lucinda Craggs, Dr Trevor Booth, Professor Johannes Attems, Arthur Oakley, Professor Raj KalariaORCiD

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of familial brain arteriopathy, which is associated with deposition of granular osmiophilic material (GOM). We used conventional immunohistochemistry and immunogold electron microscopy (EM) to examine the distribution of GOM and NOTCH3 ectodomain (N3ECD) protein in the brain microvasculature within the grey and white matter of CADASIL, non-CADASIL hereditary small vessel disease (SVD) and sporadic agerelated degenerative disease and comparable age control subjects. We observed intense staining patterns with two different N3ECD antibodies in CADASIL in contrast to young and older controls and other SVDs. CADASIL samples exhibited moderate to strong immunoreactivity in the arterial walls as well as in most capillaries. As expected from H&E and periodic acid-Schiff stained sections, EM revealed profound and widespread extracellular distribution of GOM deposits of 0.2-2μm associated with meningeal vessels, perforating arteries and arterioles. GOM was evident juxtaposed tocapillaries even within the white matter. Immunogold EM with antibody A1-1 to N3ECD revealed abundant particles in GOM within microvessels, vascular smooth muscle cell membranes and perivascular cells. GOM did not contain immunogold labelling for smooth muscle α-actin or collagen IV. These results showed the specificity of the antibodies and confirm the predominant localisation of N3ECD within GOM deposits. The extensive distribution of N3ECD-GOM complexes within the meninges, arteries, arterioles and particularly capillaries in brains of CADASIL subjects is remarkable. Our observations suggest that NOTCH3 fragments are key to GOM deposits, which may be eliminated via perivascular routes.

Publication metadata

Author(s): Yamamoto Y, Craggs LJL, Watanabe A, Booth T, Attems J, Low RWC, Oakley AE, Kalaria RN

Publication type: Article

Publication status: Published

Journal: Journal of Neuropathology and Experimental Neurology

Year: 2013

Volume: 72

Issue: 5

Pages: 416-431

Print publication date: 01/05/2013

ISSN (print): 0022-3069

ISSN (electronic): 1554-6578

Publisher: Lippincott Williams & Wilkins

URL: http://journals.lww.com/jneuropath/Abstract/2013/05000/Brain_Microvascular_Accumulation_and_Distribution.6.aspx

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