Microtubule-associated tau contributes to intra-dendritic trafficking of AMPA receptors in multiple ways

Abstract

Microtubule-associated protein tau has crucial roles not only in the formation of some neurodegenerative disorders but also in normal synaptic functions, although its contributions to these are still unclear. Here, to reveal the influence of tau deletion on trafficking of synaptic receptors, we investigated the distribution of GluA2-containing AMPA-type glutamate receptors (AMPARs) within neuronal dendrites in wild-type and tau-deficient neurons using biochemical and laser-confocal imaging techniques. Under basal conditions, expression of GluA2 at tau-deficient synapses was almost normal; however, its level within dendrites in tau-deficient neurons was greater than that in wild-type neurons. After NMDA treatment, a decrease in GluA2-containing AMPARs at synapses was observed in wild-type neurons, but not in tau-deficient neurons. Single-cell imaging of GluA2 within dendrites demonstrated that wild-type neurons, but not tau-deficient neurons, showed enlargement of GluA2 puncta. Interestingly, we also found that NMDA rapidly reduced the number of GluA2 puncta without changing their size in tau-deficient neurons but not wild-type neurons. These results demonstrate the multiple contributions of tau to the maintenance of dynamic AMPAR trafficking within dendrites during both stimulated and unstimulated conditions.

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

“…Given that the extended absence of functional glutamatergic receptors can threaten spine stability, disruptions in the targeting and/or anchoring of these receptors may also contribute to spine loss (Cingolani & Goda, 2008;Matus, 2000). It is feasible that pS214-tau participates in glutamate receptor localization to the synapse here, as reported by others, a possibility worth exploring in future work (L. M. Ittner et al, 2010;Lau et al, 2016;Miller et al, 2014;Mondragon-Rodriguez et al, 2012;Suzuki & Kimura, 2017).…”

Synaptic tau: A pathological or physiological phenomenon?

“…summarises how the effects of Tau on electrophysiological measurements have a large degree of variability depending upon the methods applied. The most consistent finding appears to be that exogenous oligomeric Tau impairs LTP, with monomeric Tau having no effect [123,251,352,360,434]. Fá et al [123] showed that a 20 min treatment of CA3-CA1 hippocampal neurons with oligomeric 4R2N Tau before induction of LTP caused a marked reduction in LTP expression without affecting basal synaptic transmission.…”

“…Tau is not known to directly bind PICK1, GluA2, though there is an NMDA-dependent interaction of this complex with phospho-Tau [370]. These proteins are therefore added to the figure in order to highlight specific pathways that have been previously mentioned in the literature [434] the earliest stages of CME to occur [275,277]. Transferrin receptors are therefore also important for activitydependent AMPAR internalisation that is dependent on CME and required for LTD as they recruit AP2 (adaptor protein 2).…”

“…As well as its involvement in the GluA2-PICK1 interaction, Tau has also been shown capable of binding to NSF and AP2 by co-immunoprecipitation studies [276]. The function of this binding may be related to NMDA-induced trafficking of AMPARs from synapses, whereby Tau deficiency results in reduced GluA2 subunits in the postsynaptic density during chemical LTD [434]. GluA2 also regulates metabotropic glutamate receptor-dependent LTD (mGluR-LTD) through a pathway involving cofilin-mediated actin reorganisation [506].…”

The Link Between Tau and Insulin Signaling: Implications for Alzheimer’s Disease and Other Tauopathies

“…A proper balance in the number of phosphorylated and dephosphorylated residues of Tau favors its classical physiological role in neurite outgrowth, axonal transport and microtubule dynamics. In addition, due to its scaffolding property, Tau can bind to a variety of proteins, therefore impacting multiple physiological functions (Meier et al, 2015; Suzuki and Kimura, 2017; Zhou et al, 2017; Stefanoska et al, 2018). Many of these interactions still remain to be uncovered.…”