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Small heat shock protein HspB8: its distribution in Alzheimer’s disease brains and its inhibition of amyloid-β protein aggregation and cerebrovascular amyloid-β toxicity

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Abstract

Alzheimer’s disease (AD) is characterized by pathological lesions, such as senile plaques (SPs) and cerebral amyloid angiopathy (CAA), both predominantly consisting of a proteolytic cleavage product of the amyloid-β precursor protein (APP), the amyloid-β peptide (Aβ). CAA is also the major pathological lesion in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), caused by a mutation in the gene coding for the Aβ peptide. Several members of the small heat shock protein (sHsp) family, such as αB-crystallin, Hsp27, Hsp20 and HspB2, are associated with the pathological lesions of AD, and the direct interaction between sHsps and Aβ has been demonstrated in vitro. HspB8, also named Hsp22 of H11, is a recently discovered member of the sHsp family, which has chaperone activity and is observed in neuronal tissue. Furthermore, HspB8 affects protein aggregation, which has been shown by its ability to prevent formation of mutant huntingtin aggregates. The aim of this study was to investigate whether HspB8 is associated with the pathological lesions of AD and HCHWA-D and whether there are effects of HspB8 on Aβ aggregation and Aβ-mediated cytotoxicity. We observed the expression of HspB8 in classic SPs in AD brains. In addition, HspB8 was found in CAA in HCHWA-D brains, but not in AD brains. Direct interaction of HspB8 with Aβ1–42, Aβ1–40 and Aβ1–40 with the Dutch mutation was demonstrated by surface plasmon resonance. Furthermore, co-incubation of HspB8 with D-Aβ1–40 resulted in the complete inhibition of D-Aβ1–40-mediated death of cerebrovascular cells, likely mediated by a reduction in both the β-sheet formation of D-Aβ1–40 and its accumulation at the cell surface. In contrast, however, with Aβ1–42, HspB8 neither affected β-sheet formation nor Aβ-mediated cell death. We conclude that HspB8 might play an important role in regulating Aβ aggregation and, therefore, the development of classic SPs in AD and CAA in HCHWA-D.

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Acknowledgments

We thank Dr. P. Seubert and Dr. W.E. Van Nostrand for their generous gifts of antibodies. This work was supported by grants from the ‘Internationale Stichting Alzheimer Onderzoek’ (ISAO, grants 01506 and 03517), Zon-MW Innovational Research (number 917.46.331, “Vidi program”) and the ‘Hersenstichting Nederland’ (number 11F03(2)11).

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Authors and Affiliations

  1. Department of Neurology and Alzheimer centre, 830 LKN, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500, Nijmegen, The Netherlands

    Micha M. M. Wilhelmus, Bram Kamps & Marcel M. Verbeek

  2. Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    Micha M. M. Wilhelmus, Irene Otte-Höller, Benno Kusters & Robert M. W. de Waal

  3. Department of Biochemistry, Radboud University Nijmegen, Nijmegen, The Netherlands

    Wilbert C. Boelens

  4. Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands

    Marion L. C. Maat-Schieman

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  1. Micha M. M. Wilhelmus
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Correspondence to Marcel M. Verbeek.

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Wilhelmus, M.M.M., Boelens, W.C., Otte-Höller, I. et al. Small heat shock protein HspB8: its distribution in Alzheimer’s disease brains and its inhibition of amyloid-β protein aggregation and cerebrovascular amyloid-β toxicity. Acta Neuropathol 111, 139–149 (2006). https://doi.org/10.1007/s00401-005-0030-z

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