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Fig. 2 | Acta Neuropathologica Communications

Fig. 2

From: Intersection of pathological tau and microglia at the synapse

Fig. 2

a Several cell types are involved in tau-induced neuroinflammation. Neurons with tau pathology exposing phosphatidylserines can be live phagocytosed by microglia. Neuronal tau pathology also induces neuroinflammation by shedding myelin fragments, secreting stress factors, tau oligomers, or via other unknown pathways. In Alzheimer’s disease – the most common tauopathy – extracellular amyloid plaques also induce neuroinflammation. Tau oligomers can damage the vasculature directly, or indirectly via microglia-induced neuroinflammation or alterations of astrocytic functions at the vasculature. All these events can potentially lead to exacerbation of the neuroinflammatory state, which in turn can aggravate tau pathology via proinflammatory cytokines. Microglia can also induce a neurotoxic “A1” phenotype in astrocytes which directly leads to neurodegeneration. Astrocytes in primary tauopathies can also accumulate tau, which can lead to mild changes in the vasculature and possibly impact microglia and synaptic function. b Microglia and astrocytes play an important role in tau-induced synaptic dysfunction. Microglia can phagocytose synapses from neurons with tau pathology via the classical complement pathway. Microglia can also phagocytose secreted tau oligomers and spread them to healthy neuron in exosomes. Microglia in the healthy brain also play an important role in synapse homeostasis, for example via the secretion of cytokines or secretion of growth factors. Tau pathology could alter these homeostatic functions and lead to possible toxic gain-of-function. Astrocytes also play a critical role in synaptic function, for example by taking up extracellular glutamate, release of gliotransmitters that act on synaptic receptors, and secretion of factors that promote synapse assembly. Microglia in tauopathies can also alter the homeostatic functions of astrocytes, possibly leading to synaptic toxicity. Astrocytes with tau pathology can potentially also have deleterious effects on synaptic functions, but this is not yet studied and the role of microglia is therefore unclear

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