gms | German Medical Science

Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS)

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie

22.09.-24.09.2016, Hamburg

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The Tau/Ala152Thr mutation, a risk factor for frontotemporal-spectrum disorders, leads to neuroinflammation, cognitive decline and NR2B receptor-mediated excitotoxicity in a novel transgenic mouse model

Meeting Abstract

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  • presenting/speaker Astrid Sydow - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Katja Hochgräfe - Max-Planck-Institute for Metabolism Research (Hamburg Outstation), Hamburg, Germany
  • Jochen Decker - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Lars Krüger - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Stefanie Könen - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Daniela Cadinu - Max-Planck-Institute for Metabolism Research (Hamburg Outstation), Hamburg, Germany
  • Dorthe Matenia - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Olga Petrova - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Maria Joseph - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Frank Dennissen - German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
  • Eckhard Mandelkow - Max-Planck-Institute for Metabolism Research (Hamburg Outstation), Hamburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; CAESAR Research Center, Bonn, Germany
  • Eva-Maria Mandelkow - Max-Planck-Institute for Metabolism Research (Hamburg Outstation), Hamburg, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; CAESAR Research Center, Bonn, Germany

Deutsche Gesellschaft für Neuropathologie und Neuroanatomie. Scandinavian Neuropathological Society. Joint-Meeting of the German Society for Neuropathology and Neuroanatomy (DGNN) and the Scandinavian Neuropathological Society (SNS). Hamburg, 22.-24.09.2016. Düsseldorf: German Medical Science GMS Publishing House; 2016. Doc16dgnnP19

doi: 10.3205/16dgnn27, urn:nbn:de:0183-16dgnn277

Veröffentlicht: 14. September 2016

© 2016 Sydow et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.

Gliederung

Text

Question: Mutations of Tau are associated with several neurodegenerative disorders. Recently, the Tau mutation Ala152Thr was described as a novel risk factor for frontotemporal dementia spectrum disorders. In vitro Tau/Ala152Thr shows a decreased binding to microtubules and a reduced tendency to form abnormal fibers. To study the effects of this mutation we generated a mouse model expressing human full-length Tau with this mutation (hTau40AT) and characterized the pathological and functional effects under physiological conditions.

Methods/Results: At young age (2-3 months) immunohistological analysis reveals pathological Tau conformation, hyperphosphorylation and missorting. With increasing age there is Tau aggregation which includes co-aggregation with endogenous mouse Tau and with exogenous human Tau, accompanied by loss of synapses (especially presynaptic failure) and neurons. Deficits in spatial reference memory are manifest at ~16months.

From ~10months onwards the mice show a prominent neuroinflammatory response as judged by activation of microglia and astrocytes. This progressive neuroinflammation becomes visible by in vivo bioluminescence imaging after crossbreeding of hTau40AT mice and Gfap-luciferase reporter mice.

Characterizing acute and organotypic slices of hTau40AT mice reveals a pathophysiology which includes enhanced presynaptic neurotransmitter release, leading to increased extracellular glutamate, activation of extrasynaptic (NR2B containing) NMDA receptors, elevated postsynaptic calcium, and enhanced epileptiform activity and results in axonal sprouting in the hippocampal CA3 region.

Conclusions: The hTau40AT mice mimic pathological hallmarks of tauopathies comprising a cognitive phenotype combined with pronounced neuroinflammation and excitotoxicity. Currently, treatments with different therapeutic approaches (Tau aggregation inhibitors and anti-inflammatory drugs) are under investigation.