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60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN)

German Society for Neuropathology and Neuroanatomy

26. - 28.08.2015, Berlin

Human Tau transgenic mice as a model for granulovacuolar degeneration

Meeting Abstract

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  • corresponding author presenting/speaker Christioph Köhler - University Hospital Cologne, Neuroanatomy, Cologne, Germany
  • Kerstin Morcinek - University Hospital Cologne, Neuroanatomy, Cologne, Germany
  • Maja Dinekov - University Hospital Cologne, Neuroanatomy, Cologne, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. 60th Annual Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN). Berlin, 26.-28.08.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. Doc15dgnnP17

doi: 10.3205/15dgnn41, urn:nbn:de:0183-15dgnn413

Published: August 25, 2015

© 2015 Köhler et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at http://creativecommons.org/licenses/by/4.0/.


Outline

Text

Introduction: Granulovacuolar degeneration (GVD) is a neurodegenerative change that appears as granule-containing vacuoles in the cytoplasm of neurons. GVD usually occurs together with neurofibrillary tangles that consist of abnormal fibrils of the microtubule-associated protein tau. Severe GVD in the hippocampus is a histopathological hallmark of Alzheimer’s disease. Recently, a staging system for GVD has been established. In Alzheimer’s disease, GVD inclusions are present in neurons together with hyperphosphorylated tau and can be labeled with markers of the activated unfolded protein response (UPR), a stress response that becomes activated by the accumulation of unfolded proteins in the endoplasmic reticulum.

Objective: The relationship between GVD, tau pathology and the UPR is not well understood and only very few models for GVD exist.

Material & methods: We performed immunostaining for light microscopy, immunofluorescence double labeling and confocal microscopy with antibodies to phosphorylated tau, markers of GVD and markers of the UPR to study the presence of GVD and the UPR in transgenic pR5 mice that express the longest human tau isoform together with the pathogenic mutation P301L. We also studied mice with an Aβ-plaque pathology. Transgenic pR5 mice and non-transgenic littermates were analyzed at 5 weeks, 3-4 months, 8.5 months, 18.5 months, 24 months, and 28 months of age. APPSLxPS1mut mice with an Aβ-plaque pathology were analyzed at 20 months of age.

Results: Neurons that developed an advanced stage of tau hyperphosphorylation and early tau fibrillary pathology in pR5 mice displayed inclusions with the morphology of GVD, but we rarely saw GVD in neurons with mature neurofibrillary tangles or early tau hyperphosphorylation. GVD inclusions in pR5 mice display casein kinase 1δ, 1ε and CHMP2B immunoreactivity and are labeled with markers of the activated UPR, similar to what has been observed in studies on human autopsy cases. We did not find neurons affected with GVD in mice with an Aβ-plaque pathology and only exceptionally in very old non-transgenic mice.

Conclusion: Tau transgenic pR5 mice develop GVD inclusions with a similar protein composition as in humans. The results suggest a linkage between GVD and tau pathology.