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

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.

Phase Separation and Neurodegenerative Diseases: A Disturbance in the Force

“…C. elegans allows for direct observation of liquid droplets by SRM (Wang et al, 2014). Similarly, Dario renio and Drosophila melanogaster models have been used to model pathological changes associated with tau (Chapuis et al, 2013;Hassan-Abdi et al, 2019), a-synuclein (Prabhudesai et al, 2016), TDP-43 (Anderson et al, 2018;Asakawa et al, 2020), or FUS (Matsumoto et al, 2018;Steyaert et al, 2018). These models offer the advantage of in vivo imaging at the subcellular resolution and with relatively low cost compared with larger animal models.…”

Microglial Morphology Across Distantly Related Species: Phylogenetic, Environmental and Age Influences on Microglia Reactivity and Surveillance States

“…However, while young microglia respond to extracellular ATP by increasing their motility and becoming more ramified, aged microglia exhibits a contrary response, with low phagocytic ability (130), and becoming less dynamic and ramified (131). Thus, purinergic signaling is essential for the modulation of microglial movement in the normal and pathological brain (132,133).…”

Zebrafish Models to Study New Pathways in Tauopathies

“…Hassan-Abdi et al showed that in presence of diseased neurons, microglia exhibited a higher mobility and displayed morphological changes, with fewer and shorter processes. In addition, genetic ablation of microglia in zebrafish hTauP301L line significantly increased Tau hyperphosphorylation, suggesting that microglia provide neuroprotection to diseased neurons [ 38 ]. Mitochondrial behavior defect was also observed from live record of axonal mitochondrial transport.…”