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Sulfation of heparan sulfate associated with amyloid-β plaques in patients with Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is characterized by pathological lesions such as amyloid-β (Aβ) plaques and cerebral amyloid angiopathy. Both these lesions consist mainly of aggregated Aβ protein and this aggregation is affected by macromolecules such as heparan sulfate (HS) proteoglycans. Previous studies demonstrated that HS enhances fibrillogenesis of Aβ and that this enhancement is dependent on the degree of sulfation of HS. In addition, it has been reported that these sulfation epitopes do not occur randomly but have a defined tissue distribution. Until now, the distribution of sulfation epitopes of HS has not yet been studied in human brain. We investigated whether a specific HS epitope is associated with Aβ plaques by performing immunohistochemistry on occipital neocortical and hippocampal tissue sections from AD patients using five HS epitope-specific phage display antibodies. Antibodies recognizing highly N-sulfated HS demonstrated the highest level of staining in both fibrillar Aβ plaques and non-fibrillar Aβ plaques, whereas antibodies recognizing HS regions with a lower degree of N-sulfate modifications were only immunoreactive with fibrillar Aβ plaques. Thus, our results suggest that a larger variety of HS epitopes is associated with fibrillar Aβ plaques, but the HS epitopes associated with non-fibrillar Aβ plaques seem to be more restricted, selectively consisting of highly N-sulfated epitopes.

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Acknowledgments

We thank Dr. R. Koopmans, Dr. J.H.M. Cox-Claessens and Dr. G. Woestenburg (Psychogeriatric Centers “Joachim en Anna” and “Margriet”, Nijmegen, the Netherlands) for their cooperation in the rapid autopsy protocol. We would also like to thank Irene Otte-Höller and Arie Oosterhof for their technical advice. This study was supported by a grant from the Internationale Stichting Alzheimer Onderzoek (ISAO, no. 07510), the Netherlands Organisation for Scientific Research (NWO/ZonMW, Vidi program, no. 917.46.331) and the Hersenstichting Nederland (no. 14F06.18).

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Authors and Affiliations

  1. Department of Neurology and Alzheimer Centre, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Ilona B. Bruinsma & Marcel M. Verbeek

  2. Laboratory of Pediatrics and Neurology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen Medical Centre, 830 LKN, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands

    Ilona B. Bruinsma, Luuk te Riet, Tom Gevers & Marcel M. Verbeek

  3. Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Gerdy B. ten Dam & Toin H. van Kuppevelt

  4. Department of Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium

    Guido David

  5. Department of Pathology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Benno Küsters & Robert M. W. de Waal

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  1. Ilona B. Bruinsma
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Correspondence to Ilona B. Bruinsma.

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Bruinsma, I.B., te Riet, L., Gevers, T. et al. Sulfation of heparan sulfate associated with amyloid-β plaques in patients with Alzheimer’s disease. Acta Neuropathol 119, 211–220 (2010). https://doi.org/10.1007/s00401-009-0577-1

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  • DOI: https://doi.org/10.1007/s00401-009-0577-1

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