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Hyperphosphorylated tau aggregates in the cortex and hippocampus of transgenic mice with mutant human FTDP-17 Tau and lacking the PARK2 gene

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Abstract

Mutations in the PARK2 gene encoding parkin cause autosomal recessive juvenile parkinsonism, but have also been found in patients diagnosed with certain tauopathies. Conversely, mutations in the MAPT gene encoding tau are present in some types of parkinsonism. In order to investigate the possible relationship between these two proteins, we generated a double mutant mouse that is deficient in PARK2 and that over-expresses the hTauVLW transgene, a mutant form of the tau protein present in FTDP-17. Independent deletion of PARK2 or over-expression of the hTauVLW transgene produces mild phenotypic alterations, while a substantial increase in parkin expression is observed in hTauVLW transgenic mice. However, double mutant mice present memory and exploratory deficits, and accumulation of PHF-1 and AT8 hyperphosphorylated tau epitopes in neurons. These phenomena are coupled with reactive astrocytosis, DNA fragmentation, and variable cerebral atrophy. Here, we show that cortical and hippocampal neurons of double mutant mice develop argyrophilic Gallyas-Braak aggregates of phosphorylated tau from 3 months of age. Their number decreases in old animals. Moreover, numerous phosphorylated tau aggregates were identified with the conformation-dependent Alz-50 antibody and the S-Thioflavin staining. Ventral motor nuclei of the spinal cord also present Alz-50, AT8, and PHF1 hyperphosphorylated tau aggregates when parkin is deleted in mice over-expressing the hTauVLW transgene, begining at early ages. Thus, the combination of PARK2 gene deletion with hTauVLW over-expression in mice produces abnormal hyperphosphorylated tau aggregates, similar to those observed in the brain of patients diagnosed with certain tauopathies. In the light of these changes, these mice may help to understand the molecular processes responsible for these diseases, and they may aid the development of new therapeutic strategies to treat neurodegenerative diseases related to tau and parkin proteins.

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Acknowledgments

The authors would like to thank Drs Jeremy Park, Jesus Benavides and Filip Lim for the use of the Park−/− and TauVLW mice; Drs Francisco Wandosell and Jose Javier Lucas for critical reading of the manuscript and for helpful discussions; and Dr. Jose Luis Sarasa for supervising the neuropathological analysis. They are also grateful to Izaskun Rodal for technical support and to the Animal Facility of the Fundación Jiménez Díaz-Capio. This work was supported by grants from the Fondo de Investigaciones Sanitarias (PI030165 and PI070023) from the Spanish Ministry of Health; P.N. and A.M.G.C. were supported by fellowships from the Fundación Conchita Rábago. Dr. Avila acts as an advisor for Neuropharma (Spain).

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Authors and Affiliations

  1. Laboratory of Neurology, Fundacion Jimenez Diaz-Capio/Clinica Ntra. Sra. Concepción, Avda Reyes Catolicos 2, 28040, Madrid, Spain

    Rosa Guerrero, Paloma Navarro, Eva Gallego, Ana M. Garcia-Cabrero & Marina P. Sanchez

  2. Centro de Biologia Molecular “Severo Ochoa” CSIC/Universidad Autonoma de Madrid, Madrid, Spain

    Jesus Avila

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  1. Rosa Guerrero
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  2. Paloma Navarro
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  5. Jesus Avila
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Correspondence to Marina P. Sanchez.

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Guerrero, R., Navarro, P., Gallego, E. et al. Hyperphosphorylated tau aggregates in the cortex and hippocampus of transgenic mice with mutant human FTDP-17 Tau and lacking the PARK2 gene. Acta Neuropathol 117, 159–168 (2009). https://doi.org/10.1007/s00401-008-0470-3

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  • DOI: https://doi.org/10.1007/s00401-008-0470-3

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