Abstract
Mutations in MAPT (Tau) have been implicated in several types of tauopathy, but the pathways leading to neurodegeneration have remained elusive and are heterogeneous. Here we describe the effects of two mutations, both linked to AD or FTD, that are located in different domains of Tau and show different pathways of toxicity. The deletion mutation ΔK280 lies in the repeat domain and strongly increases β-structure and hence aggregation, whereas the mutation A152T lies in the N-terminal projection domain, has little effect on aggregation but instead on signalling. Both mutations cause presynaptic dysfunction, but in opposite ways, leading to hypoexcitability/hypoactivity vs. hyperexcitability/excitotoxicity, respectively. In organotypic slices these abnormal states can be reversed by drugs, e.g. Tau aggregation inhibitors or modulators of glutamate uptake. This information could contribute to the understanding of “normal” Tau biology and possible therapeutical strategies.
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Acknowledgements
We are grateful to Dr. Lars Krüger and Dr. Astrid Sydow for their important contributions to the generation and analysis of the transgenic mouse lines and organotypic slices, and Dr. Eckhard Mandelkow for stimulating discussions. This work was supported by the German Center for Neurodegenerative Diseases (DZNE) and the Max-Planck-Society (MPG).
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Decker, J.M., Mandelkow, EM. (2019). Presynaptic Pathophysiology Encoded in Different Domains of Tau – Hyper-Versus Hypoexcitability?. In: Takashima, A., Wolozin, B., Buee, L. (eds) Tau Biology. Advances in Experimental Medicine and Biology, vol 1184. Springer, Singapore. https://doi.org/10.1007/978-981-32-9358-8_8
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