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Glial reactions and the clearance of amyloid β protein in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type

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Abstract

Although the amyloid β protein (Aβ) E693Q mutation enhances Aβ fibrillization in vitro and cerebral amyloid angiopathy (CAA) in vivo, brain parenchymal Aβ deposition and tau pathology in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) are limited. To evaluate whether clearance of Aβ by glial cells may play a role in this regard, this immunohistochemical study of frontal cortex of 14 HCHWA-D autopsy brains was performed using double staining with glial markers and end-specific antibodies to Aβx–42 (Aβ42) and Aβx–40 (Aβ40). Tau pathology was also assessed. Numerous microglia and/or astrocytes carrying cytoplasmic Aβ42+40− granules were scattered among non-fibrillar (Congo red-negative) Aβ deposits, i.e., clouds, fine diffuse plaques, and Aβ42+40− dense diffuse plaques. On the other hand, activated microglia and reactive astrocytes associated with fibrillar (Congo red-positive) Aβ deposition, i.e., Aβ42+40+ dense diffuse plaques and CAA invading the parenchyma, were virtually devoid of Aβ granules. Tau pathology was scant and most frequently associated with CAA. These results suggest that relatively non-fibrillar parenchymal Aβ deposits may be liable to glial clearance. Aβ sequestration by glial cells may be a factor limiting the levels of neurotoxic soluble Aβ oligomers in HCHWA-D brain.

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Acknowledgements

We thank Mr. Klaas van de Ham and Mr. Gerard van de Giessen for preparation of the figures. H. Yamaguchi was supported by Stichting Rotary Holland and a Grant-in-Aid for Scientific Research I from the Ministry of Education, Science, Sports and Culture, Japan, and a grant from the Takeda Medical Foundation.

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Authors and Affiliations

  1. Department of Neurology, K5Q 97, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands

    Marion L. C. Maat-Schieman, Ingrid M. Hegeman-Kleinn, Corrie Welling-Graafland & Raymund A. C. Roos

  2. Gunma University School of Health Sciences, Gunma, Japan

    Haruyasu Yamaguchi

  3. Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands

    Remco Natté & Sjoerd G. van Duinen

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  1. Marion L. C. Maat-Schieman
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Correspondence to Marion L. C. Maat-Schieman.

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Maat-Schieman, M.L.C., Yamaguchi, H., Hegeman-Kleinn, I.M. et al. Glial reactions and the clearance of amyloid β protein in the brains of patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type. Acta Neuropathol 107, 389–398 (2004). https://doi.org/10.1007/s00401-004-0824-4

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