Arc/Arg3.1 Regulates an Endosomal Pathway Essential for Activity-Dependent β-Amyloid Generation

Jing Wu, Ronald S. Petralia, Hideaki Kurushima, Hiral Patel, Mi Young Jung, Lenora Volk, Shoaib Chowdhury, Jason D. Shepherd, Marlin Dehoff, Yueming Li, Dietmar Kuhl, Richard L. Huganir, Donald L. Price, Robert Scannevin, Juan C. Troncoso, Philip C. Wong, Paul F. Worley

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Assemblies of β-amyloid (Aβ) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase. The generation of Aβ is coupled to neuronal activity, but the molecular basis is unknown. Here, we report that the immediate early gene Arc is required for activity-dependent generation of Aβ. Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both Hebbian and non-Hebbian forms of plasticity. The Arc-endosome also traffics APP and BACE1, and Arc physically associates with presenilin1 (PS1) to regulate γ-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces Aβ load in a transgenic mouse model of AD. In concert with the finding that patients with AD can express anomalously high levels of Arc, we hypothesize that Arc participates in the pathogenesis of AD.

Original languageEnglish (US)
Pages (from-to)615-628
Number of pages14
JournalCell
Volume147
Issue number3
DOIs
StatePublished - Oct 28 2011

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Wu, J., Petralia, R. S., Kurushima, H., Patel, H., Jung, M. Y., Volk, L., Chowdhury, S., Shepherd, J. D., Dehoff, M., Li, Y., Kuhl, D., Huganir, R. L., Price, D. L., Scannevin, R., Troncoso, J. C., Wong, P. C., & Worley, P. F. (2011). Arc/Arg3.1 Regulates an Endosomal Pathway Essential for Activity-Dependent β-Amyloid Generation. Cell, 147(3), 615-628. https://doi.org/10.1016/j.cell.2011.09.036