Living Neurons with Tau Filaments Aberrantly Expose Phosphatidylserine and Are Phagocytosed by Microglia

Jack Brelstaff,Aviva M Tolkovsky,Bernardino Ghetti,Michel Goedert,Maria Grazia Spillantini

doi:10.1016/j.celrep.2018.07.072

Abstract

SUMMARYTau protein forms insoluble filamentous inclusions that are closely associated with nerve cell death in many neurodegenerative diseases. How neurons die in these tauopathies is unclear. We report that living neurons with tau inclusions from P301S-tau mice expose abnormally high amounts of phosphatidylserine because of the production of reactive oxygen species (ROS). Consequently, co-cultured phagocytes (BV2 cells or primary microglia) identify and phagocytose the living neurons, thereby engulfing insoluble tau inclusions. To facilitate engulfment, neurons induce contacting microglia to secrete the opsonin milk-fat-globule EGF-factor-8 (MFGE8) and nitric oxide (NO), whereas neurons with tau inclusions are rescued when MFGE8 or NO production is prevented. MFGE8 expression is elevated in transgenic P301S-tau mouse brains with tau inclusions and in tau inclusion-rich brain regions of several human tauopathies, indicating shared mechanisms of disease. Preventing phagocytosis of living neurons will preserve them for treatments that inhibit tau aggregation and toxicity.

Highlights

The assembly of tau protein into abnormal inclusions underlies many human neurodegenerative diseases (Spillantini and Goedert, 2013), but how neurons die in tauopathies is still unknown
We reported that the pentameric oligothiophene dye pFTAA detects filamentous tau aggregates in dorsal root ganglion (DRG) neurons from P301S-tau mice (Brelstaff et al, 2015a, 2015b), enabling investigation of how tau aggregates may lead to cell death
Microglial activation has been associated with tau aggregation in frontotemporal dementia (FTDP-17T) (Bellucci et al, 2011) and P301S-tau mouse brains (Bellucci et al, 2004) and has been implicated in tau spreading through phagocytosis (Bolos et al, 2016; Maphis et al, 2015)

Summary

Introduction

The assembly of tau protein into abnormal inclusions underlies many human neurodegenerative diseases (Spillantini and Goedert, 2013), but how neurons die in tauopathies is still unknown. Transgenic mice that express neuron-specific human mutant 0N4R P301S-tau reproduce much of the tau pathology observed in a family with frontotemporal dementia due to a P301S-tau mutation (Bugiani et al, 1999), with neurons in the central and peripheral nervous systems developing filamentous tau inclusions and progressive neurodegeneration between 3 and 5 months of age (Allen et al, 2002; Mellone et al, 2013). Observing pFTAA+ cultured DRG neurons showed that they are slowly removed, without showing signs of apoptosis or necroptosis (Brelstaff et al, 2015a). Such slow kinetics accord with phagocytic cell death of live neurons by microglia (Neher et al, 2011). Microglial activation has been associated with tau aggregation in frontotemporal dementia (FTDP-17T) (Bellucci et al, 2011) and P301S-tau mouse brains (Bellucci et al, 2004) and has been implicated in tau spreading through phagocytosis (Bolos et al, 2016; Maphis et al, 2015)

Results

Discussion

Conclusion