Article

Physiological release of endogenous tau is stimulated by neuronal activity

Department of Neuroscience (PO37), King's College London, Institute of Psychiatry, London SE5 8AF, UK.
EMBO Reports (Impact Factor: 9.06). 02/2013; 14(4). DOI: 10.1038/embor.2013.15
Source: PubMed

ABSTRACT

Propagation of tau pathology is linked with progressive neurodegeneration, but the mechanism underlying trans-synaptic spread of tau is unknown. We show that stimulation of neuronal activity, or AMPA receptor activation, induces tau release from healthy, mature cortical neurons. Notably, phosphorylation of extracellular tau appears reduced in comparison with intracellular tau. We also find that AMPA-induced release of tau is calcium-dependent. Blocking pre-synaptic vesicle release by tetanus toxin and inhibiting neuronal activity with tetrodotoxin both significantly impair AMPA-mediated tau release. Tau secretion is therefore a regulatable process, dysregulation of which could lead to the spread of tau pathology in disease.

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    • "Once extracellular tau is bound to muscarinic receptors, it can be endocytosed in a clathrin-dependent process. This uptake mechanism could facilitate the spreading of tau from neuron to neuron, perhaps through synaptic transmission (De Calignon et al., 2012; Liu et al., 2012; Pooler et al., 2013). For aggregated tau, endocytosis is mediated by macropinocytosis (Holmes et al., 2014), in which components of the extracellular matrix, such as heparin sulfate, seem to play a role. "
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    ABSTRACT: Development of tau pathology is associated with progressive neuronal loss and cognitive decline. In the brains of Alzheimer's disease (AD) patients, tau pathology propagates according to an anatomically defined pattern with relatively uniform distribution, and contributes to cognitive decline in age-associated tauopathy (Itraak and Braak, 1991; Saito et ad, 2004). Recently, it has been revealed that tau, which is an intracellular protein, can appear in the extracellular space, likely due to an exocytosis mechanism. Such extracellular tau could then be internalized into neighboring cells in at least two different ways depending on its aggregation state. In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin dependent (reviewed in, 2006). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis (I I olmes et ad, 2014). As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. In this opinion article we have focused on the endocytosis mechanism. Several genetic risk factors have been associated with a higher probability of developing sporadic Alzheimer's disease (SAD). The Alzheimer Association (http://www.alzforum.org/) has ranked the top six risk genes, shown in Table 1, based on genome-wide association studies (GWAS).
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    • "Tau proteins are involved in promoting microtubule nucleation, growth, and bundling, and it has been hypothesized that the phosphorylation of Tau proteins is an important factor in the regulation of Tau-microtubule interactions (reviewed in [38]). On the other hand, recent reports suggest also pathophysiologic roles of the extracellular Tau molecules [39] [40]. Interestingly, the spatial spread of the Tau pathology in the brain tissue of AD patients correlates with the pattern of the cognitive dysfunctions observed clinically [41]. "
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    • "Interestingly, the pool of tau found in exosomes produced by M1C cells overexpressing human tau was phosphorylated at several epitopes (AT180, AT100, AT270, AT8 and PHF-1) detected in AD brain, tau phosphorylated at T181 being enriched in exosomes18. In the case of tau secreted by primary cortical neurons, one study reported that it was phosphorylated at T181 and two studies showed that it was dephosphorylated at the epitope recognized by the Tau-1 antibody1625. "
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    ABSTRACT: Recent studies have demonstrated that human tau can be secreted by neurons and non-neuronal cells, an event linked to the propagation of tau pathology in the brain. In the present study, we confirmed that under physiological conditions, one tau-positive band was detected in the culture medium with an anti-tau antibody recognizing total tau and the Tau-1 antibody directed against unphosphorylated tau. We then examined whether tau secretion was modified upon insults. Tau secretion was increased by starvation [Earle's Balanced Salt Solution (EBSS)], inhibition of lysosomal function (leupeptin) and when both of these conditions were superimposed, this combined treatment having the most important effects on tau secretion. Interestingly, the pattern of tau secretion was distinct from that of control neurons when neurons were treated either with EBSS alone or EBSS + leupeptin. In these conditions, three tau-positive bands were detected in the culture medium. Two of these three bands were immunoreactive to Tau-1 antibody revealing that at least two tau species were released upon these treatments. Collectively, our results indicate that insults such as nutrient deprivation and lysosomal dysfunction observed in neurodegenerative diseases could result in an increase of tau secretion and propagation of tau pathology in the brain.
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