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

J Biol Chem. 2024 May;300(5):107237. doi: 10.1016/j.jbc.2024.107237. Epub 2024 Mar 27.

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 tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides its role in stabilizing microtubules, tau is localized at postsynaptic sites and can regulate synaptic plasticity. 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 and regulates the release of amyloid-beta. We found that decreased Arc levels correlate with AD status and disease severity. Importantly, Arc protein was upregulated in the hippocampus of Tau KO mice and dendrites of Tau KO primary hippocampal neurons. Overexpression of tau decreased Arc stability in an activity-dependent manner, exclusively in neuronal dendrites, which was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. The tau-dependent decrease in Arc was found to be proteasome-sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. These observations provide a potential molecular basis for synaptic dysfunction mediated through the accumulation of tau in dendrites. Our findings confirm that Arc is misregulated in AD and further show a physiological role for tau in regulating Arc stability and AMPA receptor targeting.

Keywords: AMPA receptors; Alzheimer’s disease; arc; proteasome; tau; ubiquitination.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Cytoskeletal Proteins* / genetics
  • Cytoskeletal Proteins* / metabolism
  • Dendrites* / metabolism
  • Dendrites* / pathology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / metabolism
  • Neurons / metabolism
  • Neurons / pathology
  • Proteasome Endopeptidase Complex* / metabolism
  • Protein Stability
  • Ubiquitin / metabolism
  • Ubiquitination
  • tau Proteins* / genetics
  • tau Proteins* / metabolism

Substances

  • activity regulated cytoskeletal-associated protein
  • Cytoskeletal Proteins
  • Mapt protein, mouse
  • Nerve Tissue Proteins
  • Proteasome Endopeptidase Complex
  • tau Proteins
  • Ubiquitin
  • glutamate receptor ionotropic, AMPA 1