Extracellular tau stimulates phagocytosis of living neurons by activated microglia via Toll-like 4 receptor–NLRP3 inflammasome–caspase-1 signalling axis

Abstract

In tauopathies, abnormal deposition of intracellular tau protein followed by gradual elevation of tau in cerebrospinal fluids and neuronal loss has been documented, however, the mechanism how actually neurons die under tau pathology is largely unknown. We have previously shown that extracellular tau protein (2N4R isoform) can stimulate microglia to phagocytose live neurons, i.e. cause neuronal death by primary phagocytosis, also known as phagoptosis. Here we show that tau protein induced caspase-1 activation in microglial cells via ‘Toll-like’ 4 (TLR4) receptors and neutral sphingomyelinase. Tau-induced neuronal loss was blocked by caspase-1 inhibitors (Ac-YVAD-CHO and VX-765) as well as by TLR4 antibodies. Inhibition of caspase-1 by Ac-YVAD-CHO prevented tau-induced exposure of phosphatidylserine on the outer leaflet of neuronal membranes and reduced microglial phagocytic activity. We also show that suppression of NLRP3 inflammasome, which is down-stream of TLR4 receptors and mediates caspase-1 activation, by a specific inhibitor (MCC550) also prevented tau-induced neuronal loss. Moreover, NADPH oxidase is also involved in tau-induced neurotoxicity since neuronal loss was abolished by its pharmacological inhibitor. Overall, our data indicate that extracellular tau protein stimulates microglia to phagocytose live neurons via Toll-like 4 receptor–NLRP3 inflammasome–caspase-1 axis and NADPH oxidase, each of which may serve as a potential molecular target for pharmacological treatment of tauopathies.

Pilot Study of the Total and Phosphorylated Tau Proteins in Early-Stage Multiple Sclerosis

“…Our previous research has demonstrated that extracellular tau protein can cause microglia-dependent phosphatidylserine exposure on the external plasma membrane leaflet of living neurons, which serves as an “eat-me” signal for phagocytes, leading to phagocytosis [ 59 ]. Moreover, we found that extracellular tau can activate microglia via Toll-like 4 receptors and promote neuronal phagocytosis through phagocytic phosphatidylserine recognizing MerTK receptors and purinergic P2Y6 receptors [ 59 , 60 , 61 ]. Other studies have shown that microglial engulfment of complement-labelled synapses leads to synaptic pathology in a murine tauopathy model [ 62 ].…”

Sesamin ameliorates nonalcoholic steatohepatitis through inhibiting hepatocyte pyroptosis in vivo and in vitro

“…The activity of caspase-1 in mouse liver tissue and primary hepatocytes was assessed using two different assays. The FAM-FLICA ® caspase-1 assay kit, with staining performed using the FAM-YVAD-FMK probe, was applied to frozen liver tissue slides and primary hepatocytes ( Pampuscenko et al, 2023 ). The number of hepatic cells with active caspase-1 was calculated using ImageJ software.…”

Minding the Gap: Exploring Neuroinflammatory and Microglial Sex Differences in Alzheimer’s Disease

“…Despite tau being a structural neuronal protein and contributing to intraneuronal neurofibrillary tangles, it propagates from neuron to neuron, where it can activate microglia (reviewed in [290]). Tau activates a variety of signaling cascades in microglia, including the Toll-like Receptor 4 (TLR4)-NOD-, LRR-and pyrin domain-containing 3 (NLRP3)-caspase 1 cascade for phagocytosis of living neurons [291]. Additionally, the cyclic GMP-AMP synthase (cGAS)-IFN signaling pathway suppresses MEF2C neuronal transcriptional networks to attenuate cognitive resilience [292].…”