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bioRxiv · 10.1101/2022.12.15.520620

A differential effect for tau isoforms and mutants in decreasing the stability of Arc

Yakout, D. W.·Shroff, A.·Allen, Z. D.·Nazarko, T. Y.·Mabb, A. M.
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Abstract

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule associated protein tau, a main component of neurofibrillary tangles. Alzheimers disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides the role of tau in stabilizing microtubules, it is localized at postsynaptic sites and can disrupt synaptic plasticity when knocked out or overexpressed. The activity-regulated cytoskeleton-associated protein (Arc), is an immediate early gene that plays a key role in synaptic plasticity, learning and memory. Arc has been implicated in AD pathogenesis, where it was found to regulate activity-dependent release of amyloid-beta (A{beta}). Here we show that Arc protein is upregulated in the hippocampus of tau knockout (Tau KO) mice and in dendrites of Tau KO primary hippocampal neurons. Conversely, overexpression of tau decreased Arc stability exclusively in neuronal dendrites and was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The Tau-dependent decrease in Arc was proteasome sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc, which is essential for promoting the endocytosis of AMPA receptors. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. Our findings show a physiological role for tau in regulating Arc and implicate specific variants of tau in regulating Arc stability and AMPA receptor targeting, which may in part explain observed deficits in synaptic plasticity in select types of tauopathies.

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Yakout, D. W., Shroff, A., Allen, Z. D., Nazarko, T. Y., Mabb, A. M.. 2022-12-15. A differential effect for tau isoforms and mutants in decreasing the stability of Arc. https://doi.org/10.1101/2022.12.15.520620

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