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- W2896468223 abstract "The mechanism of cell death in tauopathy is unknown and of great importance to potential therapies. The presence of filamentous tau aggregates is associated with neuronal death and microglial activation in the P301S tau mouse. Microglia will phagocytose living non-apoptotic neurons if phosphatidylserine (PtdSer) is exposed on their surface due to exogenous stress. Microglial activation and phagocytosis was investigated as a route of neuron cell loss in tauopathy. PtdSer exposure, and reactive oxygen species in cultured dorsal root ganglion cells from transgenic tau mice was measured with fluorescence microscopy. Neurons and microglia were co-cultured and activation assessed by griess reaction and ELISA. Neuronal loss was measured by cell counts. Phagocytosis was confirmed by FACs sorting and membrane filtration assay. Phagocytosis was inhibited by two pharmacological agents. In vivo neuronal-microglial association was analysed with immunohistochemistry and imageJ. Tau inside microglia was imaged with confocal microscopy. Neurons with tau aggregates externalise significantly more PtdSer than tau negative neurons. This can be rescued by treatment with antioxidants. Neurons with tau aggregates from 5 month old P301S mice activate BV2 and primary microglia to produce NO and the opsonin MFGE8, and are subsequently phagocytosed. Phagocytosis of neurons and microglial activation was prevented by two pharmacological inhibitors. In vivo analysis of microglia showed significant proximity association to tau aggregate neurons in P301S mice and confocal analysis confirmed the presence of tau inside microglia. We show for the first time that neurons with tau aggregates directly signal to microglia leading to microglial executed cell death and propose a mechanism linking tau aggregates to reactive oxygen species and neuronal loss. Importantly we demonstrate several points at which this cell death can be prevented pharmacologically." @default.
- W2896468223 created "2018-10-26" @default.
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- W2896468223 date "2018-07-01" @default.
- W2896468223 modified "2023-10-16" @default.
- W2896468223 title "P4‐257: NEURONS WITH TAU AGGREGATES EXPOSE PHOSPHATIDYLSERINE AND ARE PHAGOCYTOSED LIVE BY MICROGLIA" @default.
- W2896468223 doi "https://doi.org/10.1016/j.jalz.2018.07.079" @default.
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