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Notch3 ectodomain is a major component of granular osmiophilic material (GOM) in CADASIL

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Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited systemic vascular disorder characterized by recurrent subcortical ischemic strokes leading to vascular dementia. The gold standard to confirm the diagnosis is to identify a mutation in the underlying gene NOTCH3, encoding a transmembrane receptor protein. Granular osmiophilic material (GOM) deposition around vascular smooth muscle cells is a specific diagnostic feature of CADASIL and electron microscopic examination of a skin biopsy is another useful method for its diagnosis. Although accumulation of Notch3 ectodomain on the surface of vascular smooth muscle cells has been reported, the composition of GOM has not been elucidated. To elucidate the relationship between Notch3 protein and GOM, we performed postembedding immunogold electron microscopy using cryofixed and freeze substituted skin taken from two CADASIL patients. Our results demonstrate that GOM around vascular smooth muscle cells was specifically labeled with antibodies against the extracellular portion of Notch3 but not with antibodies recognizing the intracellular Notch3 domain. In non-CADASIL skin sections, no antibody binding was detected around the small dermal arteries. From these results, the major component of GOM in CADASIL patients is the ectodomain of the Notch3 gene product. Our results shed light on the relationship between Notch3 gene mutations and morphological deposition of GOM around the vascular smooth muscle cells.

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Abbreviations

CADASIL:

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

GOM:

Granular osmiophilic material

MRI:

Magnetic resonance imaging

EM:

Electron microscopy

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Acknowledgments

We would like to thank Professor James R. McMillan for proofreading this manuscript.

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Authors and Affiliations

  1. Department of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, 160-8582, Japan

    Akira Ishiko & Atsushi Shimizu

  2. Department of Neurology, Keio University School of Medicine, Tokyo, Japan

    Norihiro Suzuki

  3. Department of Neurology, Saitama City Hospital, Saitama, Japan

    Eiichiro Nagata

  4. National Institute for Longevity Science, National Center for Geriatrics and Gerontology, Aichi, Japan

    Keikichi Takahashi & Takeshi Tabira

Authors
  1. Akira Ishiko
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  2. Atsushi Shimizu
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  3. Eiichiro Nagata
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  4. Keikichi Takahashi
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  5. Takeshi Tabira
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  6. Norihiro Suzuki
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Correspondence to Akira Ishiko.

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This work has no funding sources. The authors have no conflict of interest to disclose.

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Ishiko, A., Shimizu, A., Nagata, E. et al. Notch3 ectodomain is a major component of granular osmiophilic material (GOM) in CADASIL. Acta Neuropathol 112, 333–339 (2006). https://doi.org/10.1007/s00401-006-0116-2

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  • DOI: https://doi.org/10.1007/s00401-006-0116-2

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