Artikel
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
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Veröffentlicht: | 14. September 2016 |
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Gliederung
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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.