Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers

Abstract

Tau is a microtubule-associated protein well known for its stabilization of microtubules in axons. Recently, it has emerged that tau participates in synaptic function as part of the molecular pathway leading to amyloid-beta (A␤)-driven synaptotoxicity in the context of Alzheimer's disease. Here, we report the implication of tau in the profound functional synaptic modification associated with synaptic plasticity. By exposing murine cultured cortical neurons to a pharmacological synaptic activation, we induced translocation of endogenous tau from the dendritic to the postsynaptic compartment. We observed similar tau translocation to the postsynaptic fraction in acute hippocampal slices subjected to long-term potentiation. When we performed live confocal microscopy on cortical neurons transfected with human-tau-GFP, we visualized an activity-dependent accumulation of tau in the postsynaptic density. Coprecipitation using phalloidin revealed that tau interacts with the most predominant cytoskeletal component present, filamentous actin. Finally, when we exposed cortical cultures to 100 nM human synthetic A␤ oligomers (A␤o's) for 15 min, we induced mislocalization of tau into the spines under resting conditions and abrogated subsequent activity-dependent synaptic tau translocation. These changes in synaptic tau dynamics may rely on a difference between physiological and pathological phosphorylation of tau. Together, these results suggest that intense synaptic activity drives tau to the postsynaptic density of excitatory synapses and that A␤o-driven tau translocation to the spine deserves further investigation as a key event toward synaptotoxicity in neurodegenerative diseases.

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).…”

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits

“…As discussed above, there is clear evidence for a physiological role of tau in synaptic plasticity (Frandemiche et al., 2014; Hu et al., 2011). Conversely, hyperphosphorylated tau accumulates in synaptic spines and alters synaptic function in a mouse model of AD (Hoover et al., 2010).…”

“…Conversely, hyperphosphorylated tau accumulates in synaptic spines and alters synaptic function in a mouse model of AD (Hoover et al., 2010). Consistent with this observation, tau translocates to synaptic spines in an activity‐dependent manner, an event blocked by Aβ (Frandemiche et al., 2014). Taken together, these data clearly indicate that tau can contribute to cognitive deficits both by toxic gain‐of‐function and by loss‐of‐function.…”

“…For example, tau can directly interact with the plasma membrane and with several tyrosine kinases, thereby regulating selective intracellular pathways (Fulga et al., 2007). Additionally, intense synaptic activity drives tau into dendritic spines, suggesting that tau may participate in spine remodeling that underlies synaptic plasticity (Frandemiche et al., 2014). …”