Date of Award
Doctor of Philosophy (PhD)
Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule-associated protein tau. Alzheimer’s disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Tau 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 (Ab). Given that high levels of Arc have been detected in an Ab mouse model and post-mortum cortical tissue from AD patients, we hypothesized that disruption of Arc turnover can participate in AD pathogenesis. We investigated the role of Arc turnover mediated by ubiquitination at lysines 268/269 in a middle-aged ArcKR mouse model where these sites are mutated to Arginine. In this model, we did not find abnormal accumulation of tau, Ab or b-amyloid plaques and no disruption in spatial learning. However, we did identify a relationship between tau overexpression and Arc stability, where overexpression of the 0N4R isoform of tau in primary hippocampal neurons led to Arc instability exclusively in neuronal dendrites. 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, which is a domain that is essential for promoting the endocytosis of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors. This was coupled to increases in the expression of dendritic and somatic surface GluA1-containing AMPA receptors. Interestingly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. We also show that endogenous tau has a physiological role in regulating Arc, where Arc levels are upregulated in the hippocampus of tau knockout (Tau KO) mice and in dendrites of primary hippocampal neurons. Our findings implicate specific variants of tau in regulating Arc stability and AMPA receptor targeting, which may in part explain deficits in synaptic plasticity that are observed in select types of tauopathies.
Yakout, Dina, "Role of Arc Turnover in Tauopathies." Dissertation, Georgia State University, 2023.
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