Abstract
Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule associated protein tau, a main component of neurofibrillary tangles. Alzheimer’s disease (AD) is the most common type of secondary tauopathy. While stabilizing microtubules is a well-established role for tau, tau is also localized at postsynaptic sites and can disrupt synaptic plasticity when knocked out or overexpressed. A major gap in understanding tau functions is identifying the intracellular mechanisms through which tau modulates synaptic function. Here, we found that overexpression of the 0N4R isoform of tau in HEK 293 cells decreased the stability of the activity-regulated cytoskeleton-associated protein (Arc), an immediate early gene that plays a key role in synaptic plasticity, learning and memory. Importantly, tau-induced Arc degradation was found to be isoform-specific in that overexpression of the 0N3R tau isoform had no effect. Tau-dependent reduction of Arc required proteasome activity, yet was independent of Arc ubiquitination. Surprisingly, tau-induced Arc removal required the endophilin-binding domain of Arc. Overexpression of 0N4R tau in primary hippocampal neurons led to Arc instability exclusively in neuronal dendrites, which was coupled to increases in the expression of dendritic and somatic surface GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Interestingly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. Our findings implicate isoform- and domain-specific effects of tau in regulating Arc stability and AMPA receptor targeting, which may in part explain the deficits in synaptic plasticity that are observed in select types of tauopathies.
Competing Interest Statement
The authors have declared no competing interest.
