@article{5626986d92cb45cbab66b3fdeadafb89,
title = "Arc/Arg3.1 Regulates an Endosomal Pathway Essential for Activity-Dependent β-Amyloid Generation",
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.",
author = "Jing Wu and Petralia, {Ronald S.} and Hideaki Kurushima and Hiral Patel and Jung, {Mi Young} and Lenora Volk and Shoaib Chowdhury and Shepherd, {Jason D.} and Marlin Dehoff and Yueming Li and Dietmar Kuhl and Huganir, {Richard L.} and Price, {Donald L.} and Robert Scannevin and Troncoso, {Juan C.} and Wong, {Philip C.} and Worley, {Paul F.}",
note = "Funding Information: We would like to thank Gopal Thinakaran, Sangram Sisodia (University of Chicago), and Tong Li for critical reagents and helpful discussions. Thanks to Gay Rudow for helping with unbiased stereology. Thanks to Desheng Xu and Shi Yang for help with lentivirus packaging. Many thanks to Robert Ardiuni, Melissa Levesque, Darren Baker, and Stephan Miller from Biogen Idec for their excellent technical support on in vitro binding assay. We thank Ya-Xian Wang for help with the EM studies. We also thank Robert Malinow (University of California at San Diego) and Mike Ehlers (Duke University) for APP Sindbis virus constructs and GFP-Rab constructs. This work was supported by NIMH grant RO1 MH053608 (P.F.W.), the Johns Hopkins Alzheimer's Disease Research Center (NIH grant P50AG005146) and in part by the NIDCD Intramural Program (R. S. P.) and NIH grant MH084020. ",
year = "2011",
month = oct,
day = "28",
doi = "10.1016/j.cell.2011.09.036",
language = "English (US)",
volume = "147",
pages = "615--628",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}