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Fig. 2 | Molecular Neurodegeneration

Fig. 2

From: Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease

Fig. 2

A model for tau pathogenesis. a Tau is a microtubule-binding protein, which can undergo various types of post-translational modifications (PTMs), such as phosphorylation and truncation. Under disease conditions, aberrant PTMs induces tau dissociation from microtubules, leading to tau aggregation and oligomer formation. Tau oligomers can further aggregate to form PHFs and NFTs in neurons. Tau aggregates can induce mitochondria fragmentation, impair synaptic vesicle mobility and release, thereby leading to presynaptic dysfunction. In addition, pathological tau species such as truncated tau and tau oligomers can be released to the extracellular environment via exosomes or directly from the plasma membrane. b Tau is normally distributed to compartments other than postsynaptic densities. Hyperphosphorylated and truncated tau species may enter postsynaptic compartments to consequently impair LTP by modulating Fyn/NMDAR complexes. Extracellular pathogenic tau species may be internalized in neurons through a HSPGs-mediated pathway to induce the aggregation of intracellular tau. c Extracellular tau can bind CX3CR1 receptors, and subsequently internalized by microglia for degradation. Alternatively, tau released from neurons can enter microglia through unknown mechanisms. Internalized tau may be modified and re-released from microglia to the extracellular space via exosomes, and then taken up by adjacent neurons to induce tau propagation. In addition, pathological tau species can activate microglial NF-κB and NLRP3 inflammasome pathways, leading to pro-inflammatory cytokine release. Excessive pro-inflammatory cytokines can increase the activity of tau kinases such as CDK5 and P38, thereby exacerbating tau hyperphosphorylation

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