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Brain Advance Access published online on July 13, 2005
Brain, doi:10.1093/brain/awh591
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© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received April 12, 2005
Revised June 10, 2005
Accepted June 13, 2005

Article

Hereditary Pick's disease with the G272V tau mutation shows predominant three-repeat tau pathology

I. F. Bronner 1, B. C. ter Meulen 2, A. Azmani 2, L. A. Severijnen 3, R. Willemsen 3, W. Kamphorst 4, R. Ravid 5, P. Heutink 1, and J. C. van Swieten 2*

1 Department of Human Genetics, Section Medical Genomics and Center for Neurogenomics and Cognitive Research, VU University Medical Center and VU University, Amsterdam, The Netherlands
2 Department of Neurology, Erasmus Medical Center, Rotterdam, The Netherlands
3 Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
4 Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
5 Netherlands Brain Bank, Amsterdam, The Netherlands

* To whom correspondence should be addressed.
J. C. van Swieten, E-mail: j.c.vanswieten{at}erasmusmc.nl


  Abstract

Frontotemporal dementia and parkinsonism linked to chromosome 17 have been associated with mutations in the microtubule associated protein tau (MAPT or tau) gene. This disorder is characterized by a large spectrum of neuronal and glial tau lesions in different brain regions. Pick bodies were found in a family with hereditary Pick's disease with the G272V mutation and in several families with other tau mutations in exons 9 and 11-13. The biochemical composition of Pick bodies varies between these mutations. Until recently, no detailed biochemical characterization of G272V brain material was done owing to unavailability of fresh frozen brain material. We now report a detailed study using the immunohistochemistry, western blots and electron microscopy of two brains with the G272V mutation that recently became available. Both brains showed severe neuronal loss in the temporal cortex, whereas in the frontal cortex the loss was less; and abundant Pick bodies in the dentate gyrus of the hippocampus, and caudate nucleus. The Pick bodies consisted exclusively of three-repeat (3R) isoforms, as was demonstrated by isoform-specific antibodies and supported by western blot analysis of sarkosyl-insoluble tau. These observations confirm that this family diagnosed with hereditary Pick disease meets all the criteria for this condition, including the presence of Pick bodies that are unphosphorylated at Ser262 and contain twisted filaments with long periodicity consisting only of 3R tau.

Keywords: brain; focal dementias; neuronal degeneration; tau expression.
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