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Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent beta-amyloid generation.

Authors: Wu, J  Petralia, RS  Kurushima, H  Patel, H  Jung, MY  Volk, L  Chowdhury, S  Shepherd, JD  Dehoff, M  Li, Y  Kuhl, D  Huganir, RL  Price, DL  Scannevin, R  Troncoso, JC  Wong, PC  Worley, PF 
Citation: Wu J, etal., Cell. 2011 Oct 28;147(3):615-28. doi: 10.1016/j.cell.2011.09.036.
Pubmed: (View Article at PubMed) PMID:22036569
DOI: Full-text: DOI:10.1016/j.cell.2011.09.036

Assemblies of beta-amyloid (Abeta) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by beta-secretase (BACE1) and gamma-secretase. The generation of Abeta 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 Abeta. 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 gamma-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces Abeta 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.


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RGD Object Information
RGD ID: 8554064
Created: 2014-05-08
Species: All species
Last Modified: 2014-05-08
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.