Tau target identification reveals NSF‐dependent effects on AMPA receptor trafficking and memory formation

Abstract

Microtubule‐associated protein tau is a central factor in Alzheimer's disease and other tauopathies. However, the physiological functions of tau are unclear. Here, we used proximity‐labelling proteomics to chart tau interactomes in primary neurons and mouse brains in vivo. Tau interactors map onto pathways of cytoskeletal, synaptic vesicle and postsynaptic receptor regulation and show significant enrichment for Parkinson's, Alzheimer's and prion disease. We find that tau interacts with and dose‐dependently reduces the activity of N‐ethylmaleimide sensitive fusion protein (NSF), a vesicular ATPase essential for AMPA‐type glutamate receptor (AMPAR) trafficking. Tau‐deficient (tau−/−) neurons showed mislocalised expression of NSF and enhanced synaptic AMPAR surface levels, reversible through the expression of human tau or inhibition of NSF. Consequently, enhanced AMPAR‐mediated associative and object recognition memory in tau−/− mice is suppressed by both hippocampal tau and infusion with an NSF‐inhibiting peptide. Pathologic mutant tau from mouse models or Alzheimer's disease significantly enhances NSF inhibition. Our results map neuronal tau interactomes and delineate a functional link of tau with NSF in plasticity‐associated AMPAR‐trafficking and memory.

Tau regulates Arc stability in neuronal dendrites via a proteasome-sensitive but ubiquitin-independent pathway

“…Consistent with our findings, tau knockout cortical and hippocampal neurons show significantly lower surface GluA1 compared to wildtype cells (26). Tau interacts with several proteins that regulate AMPA receptor trafficking profiles such as NSF and PICK1 (26, 82), and tau knockout neurons show a rapid reduction in the number of GluA2 puncta after NMDA treatment (84). Additionally, tau plays a role in the postsynaptic targeting of the Src kinase Fyn, which regulates the activation of NMDA receptors (21), and consequently affects AMPA receptor trafficking (85).…”

“…Arc binds endophilin, dynamin, and AP-2 to mediate endocytosis of AMPA receptors (32, 33). Recent findings show that tau (2N4R) has an extensive network of interactions with proteins that regulate endocytosis, including endophilin, AP-2 and dynamin (26, 79). Interestingly, expression of human tau (0N4R) induces de novo assembly of microtubules which interferes with endocytosis through sequestration of dynamin (80).…”

“…Since surface GluA1 was also increased in the soma despite no detected change in Arc in that region, we propose that tau overexpression mistargets GluA1-containing AMPA receptors to the soma due to altered trafficking. The physiological interactions of dendritic tau with synaptic proteins that regulate postsynaptic receptor trafficking and synaptic plasticity have been described (21,26,81–83). Consistent with our findings, tau knockout cortical and hippocampal neurons show significantly lower surface GluA1 compared to wildtype cells (26).…”

“…The physiological interactions of dendritic tau with synaptic proteins that regulate postsynaptic receptor trafficking and synaptic plasticity have been described (21,26,81–83). Consistent with our findings, tau knockout cortical and hippocampal neurons show significantly lower surface GluA1 compared to wildtype cells (26). Tau interacts with several proteins that regulate AMPA receptor trafficking profiles such as NSF and PICK1 (26, 82), and tau knockout neurons show a rapid reduction in the number of GluA2 puncta after NMDA treatment (84).…”

“…Other mutations, like the missense P301L mutation found within the 2R region, increase tau phosphorylation, decrease its binding to microtubules resulting in increased levels of free tau, which is thought to promote its aggregation (19). While tau has been well established in its role in stabilizing microtubules (20), more recent studies show that tau has a postsynaptic role that may have effects on synaptic plasticity (21)(22)(23)(24)(25)(26).…”