Abstract

BackgroundThe 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 ß structure and hence to aggregate.MethodsTo 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 (TauRDΔKPP) and compared them with slices containing pro-aggregant TauRDΔK. Transgene expression in the hippocampus was monitored via a sensitive bioluminescence reporter gene assay (luciferase).ResultsThe expression of the anti-aggregant TauRDΔKPP 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.ConclusionThe data suggest that the expression of anti-aggregant TauRDΔKPP 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.

Highlights

  • The microtubule-associated protein Tau plays a role in neurodegeneration as well as neurogenesis

  • post-natal day 8 (P8) animals were used for the preparation of organotypic hippocampal slice cultures (OHSCs), and the expression level of anti-aggregant TauRDΔKPP and pro-aggregant Tau Repeat Domain with FTDP-17 mutation ΔK280 (TauRDΔK) pups at P8 was measured by bioluminescence (Fig. 1b)

  • Decrease of microglia in anti-aggregant TauRDΔKPP slices To study the effect of anti-aggregant TauRDΔKPP and pro-aggregant TauRDΔK on glial cells, we investigated the status of microglial morphology and number in the slice cultures

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Summary

Introduction

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 ß structure and to aggregate. Joseph et al Molecular Neurodegeneration (2017) 12:88 not show cognitive deficits even at advanced age These findings supported the view that pathological effects of Tau depend on its ability to aggregate

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