Neurons Expressing Pathological Tau Protein Trigger Dramatic Changes in Microglial Morphology and Dynamics.

Rahma Hassan-Abdi,Mohamed Bennis,Alexandre Brenet,Nadia Soussi-Yanicostas,Constantin Yanicostas

doi:10.3389/fnins.2019.01199

Abstract

Microglial cells, the resident macrophages of the brain, are important players in the pathological process of numerous neurodegenerative disorders, including tauopathies, a heterogeneous class of diseases characterized by intraneuronal Tau aggregates. However, microglia response in Tau pathologies remains poorly understood. Here, we exploit a genetic zebrafish model of tauopathy, combined with live microglia imaging, to investigate the behavior of microglia in vivo in the disease context. Results show that while microglia were almost immobile and displayed long and highly dynamic branches in a wild-type context, in presence of diseased neurons, cells became highly mobile and displayed morphological changes, with highly mobile cell bodies together with fewer and shorter processes. We also imaged, for the first time to our knowledge, the phagocytosis of apoptotic tauopathic neurons by microglia in vivo and observed that microglia engulfed about as twice materials as in controls. Finally, genetic ablation of microglia in zebrafish tauopathy model significantly increased Tau hyperphosphorylation, suggesting that microglia provide neuroprotection to diseased neurons. Our findings demonstrate for the first time the dynamics of microglia in contact with tauopathic neurons in vivo and open perspectives for the real-time study of microglia in many neuronal diseases.

Highlights

Microglia, the resident brain macrophages, are highly plastic and multifunctional cells that continuously monitor the health of neuronal networks (Kierdorf and Prinz, 2017)
Given that microglial cells are highly dynamic, we used in vivo real-time confocal imaging combined with Imaris software (Bitplane Inc.) image analysis to determine whether the presence of hTauP301L-expressing neurons modified microglia dynamics
Quantification of the signal ratio of hyperphosphorylated hTau protein on brain sections from Tg(HuC-hTauP301L:DsRed; nlrc3-likest73/73) embryos confirmed the significant increase of this ratio displayed in protein extracts from Tg(HuC-hTauP301L:DsRed) embryos microglia-depleted with morpholino (Figure 2J)

Summary

Introduction

The resident brain macrophages, are highly plastic and multifunctional cells that continuously monitor the health of neuronal networks (Kierdorf and Prinz, 2017). In some disease contexts, such as tauopathies, microglia appear to have harmful activities (Bhaskar et al, 2010; Eyo and Dailey, 2013; Maphis et al, 2015b; Laurent et al, 2018). While the causal role of Tau in the disease is supported by several inherited tauopathies triggered by dominant missense mutations in the protein, such as TauP301L, causing fronto-temporal dementia with parkinsonism on chromosome 17 (FTDP-17) (Hutton et al, 1998), the etiology of these disorders and the contribution of microglia to their physiopathology remain poorly understood (Hansen et al, 2018; Laurent et al, 2018; Perea et al, 2018)

Methods

Results

Conclusion