Interaction of Endogenous Tau Protein with Synaptic Proteins Is Regulated by N-Methyl-d-aspartate Receptor-dependent Tau Phosphorylation

Abstract

Background: Tau phosphorylation affects synaptic transmission, but the underlying mechanism remains elusive. Results: NMDA receptor activation leads to phosphorylation of endogenous tau, thereby regulating the interaction of tau with Fyn and postsynaptic scaffolding protein PSD95. Conclusion: Phosphorylation of tau controls the interaction of tau with the postsynaptic PSD95-Fyn-NMDA receptor complex leading to changes in synaptic activity. Significance: The here described physiological mechanism could go awry during the development of Alzheimer disease.

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…The molecular basis for these alterations is unclear, but they are indicative of a redistribution of synaptic weights, which is consistent with the bidirectional effect of PSD size that we also observed in these neurons. In fact, Tau is present in dendritic spines (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Frandemiche et al , 2014). In these structures, it has been shown that activation of NMDA glutamate receptor triggers Tau phosphorylation, thus regulating the interaction of Tau with the actin cytoskeleton, PSD95, and Fyn kinase (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Frandemiche et al , 2014).…”

“…In fact, Tau is present in dendritic spines (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Frandemiche et al , 2014). In these structures, it has been shown that activation of NMDA glutamate receptor triggers Tau phosphorylation, thus regulating the interaction of Tau with the actin cytoskeleton, PSD95, and Fyn kinase (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Frandemiche et al , 2014). Interestingly, the basal subtle electrophysiological alterations described in this work seem to occur specifically in granule neurons, as it has been demonstrated that Tau deficiency does not affect basic synaptic currents in other regions of the brain (Ittner et al , 2010).…”

“…Tau is translocated to the postsynaptic compartment of dendrites in response to synaptic stimulation (Mondragon‐Rodriguez et al , 2012; Frandemiche et al , 2014). Moreover, it has been suggested that the presence and interaction of microtubules at synaptic spines is crucial for the BDNF‐triggered addition of new synaptic contacts during development (Gu et al , 2008) and that microtubule dynamics control the shape and maturation of synaptic spines (Hu et al , 2008; Jaworski et al , 2009).…”

“…It plays key roles in the establishment of neuronal polarity and migration during embryonic development (Caceres & Kosik, 1990; Dawson et al , 2001; Sapir et al , 2012; Sayas et al , 2015), in axonal transport (Ballatore et al , 2007; Hernandez & Avila, 2010) and in intracellular trafficking (Hernandez & Avila, 2010). Under physiological conditions, Tau is located mainly in axonal microtubules (Hirokawa et al , 1996; Aronov et al , 2001), although increasing evidence supports its presence also in dendrites (Ittner et al , 2010) and dendritic spines (Ittner et al , 2010; Mondragon‐Rodriguez et al , 2012; Kimura et al , 2014). The affinity of Tau to bind microtubules is finely regulated, depending mainly on the selective expression of various isoforms and post‐translational modifications.…”

The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease

“…However, more recent evidence suggests physiological tau does localize to dendritic spines [14,164] where it binds not only Fyn but also the PSD95-NMDA receptor complex [164]. This binding, however, is phosphorylation dependent; NMDA receptor activation increases tau phosphorylation of tau, at GSK3β-dependent sites -PHF-1, AT8, and AT180 -leading to a decrease in tau's affinity for PSD95 and an increase in tau's interaction with Fyn.…”