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  Anti-aggregant tau mutant promotes neurogenesis

Joseph, M., Anglada-Huguet, M., Paesler, K., Mandelkow, E., & Mandelkow, E.-M. (2017). Anti-aggregant tau mutant promotes neurogenesis. Molecular Neurodegeneration, 12: 88. doi:10.1186/s13024-017-0230-8.

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Item Permalink: https://hdl.handle.net/21.11116/0000-0001-78E2-9 Version Permalink: https://hdl.handle.net/21.11116/0000-0007-50CD-8
Genre: Journal Article

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https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-017-0230-8 (Publisher version)
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 Creators:
Joseph, Maria1, 2, Author
Anglada-Huguet, Marta1, 2, Author
Paesler, Katharina1, 2, Author
Mandelkow, Eckhard1, 2, Author
Mandelkow, Eva-Maria1, 2, Author
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1external, ou_persistent22              
2Center of Advanced European Studies and Research (caesar), Max Planck Society, Ludwig-Erhard-Allee 2, 53175 Bonn, DE, ou_2173675              

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 Abstract: Background: The microtubule-associated protein Tau plays a role in neurodegeneration as well as neurogenesis. Previous work has shown that the expression of the pro-aggregant mutant Tau repeat domain causes strong aggregation and pronounced neuronal loss in the hippocampus whereas the anti-aggregant form has no deleterious effects. These two proteins differ mainly in their propensity to form beta structure and hence to aggregate.
Methods: To elucidate the basis of these contrasting effects, we analyzed organotypic hippocampal slice cultures (OHSCs) from transgenic mice expressing the repeat domain (RD) of Tau with the anti-aggregant mutation (Tau(RD Delta KPP)) and compared them with slices containing pro-aggregant Tau(RD Delta K). Transgene expression in the hippocampus was monitored via a sensitive bioluminescence reporter gene assay (luciferase).
Results: The expression of the anti-aggregant Tau(RD Delta KPP) leads to a larger volume of the hippocampus at a young age due to enhanced neurogenesis, resulting in an increase in neuronal number. There were no signs of activation of microglia and astrocytes, indicating the absence of an inflammatory reaction. Investigation of signaling pathways showed that Wnt-5a was strongly decreased whereas Wnt3 was increased. A pronounced increase in hippocampal stem cell proliferation (seen by BrdU) was observed as early as P8, in the CA regions where neurogenesis is normally not observed. The increase in neurons persisted up to 16 months of age.
Conclusion: The data suggest that the expression of anti-aggregant Tau(RD Delta KPP) enhances hippocampal neurogenesis mediated by the canonical Wnt signaling pathway, without an inflammatory reaction. This study points to a role of tau in brain development and neurogenesis, in contrast to its detrimental role in neurodegeneration at later age.

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 Dates: 2017
 Publication Status: Published online
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 Identifiers: ISI: 000416979800001
DOI: 10.1186/s13024-017-0230-8
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Title: Molecular Neurodegeneration
  Abbreviation : Mol Neurodegener
Source Genre: Journal
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Pages: - Volume / Issue: 12 Sequence Number: 88 Start / End Page: - Identifier: ISSN: 1750-1326