Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation Journal Article
| Authors: | 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. |
| Article 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. © 2011 Elsevier Inc. |
| Keywords: | controlled study; gene deletion; nonhuman; mouse; animals; mice; mice, knockout; animal tissue; animal experiment; animal model; nerve tissue proteins; mus musculus; disease model; nerve cell plasticity; cell membrane; protein transport; c57bl 6 mouse; alzheimer disease; amyloid precursor protein; gamma secretase; presenilin 1; cytoskeletal proteins; endosome; genetic regulation; amyloid beta protein; amyloid beta-protein precursor; beta secretase 1; endosomes; activity regulated cytoskeleton associated protein; ampa receptor; dynamin; endophilin |
| Journal Title: | Cell |
| Volume: | 147 |
| Issue: | 3 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 2011-10-28 |
| Start Page: | 615 |
| End Page: | 628 |
| Language: | English |
| DOI: | 10.1016/j.cell.2011.09.036 |
| PROVIDER: | scopus |
| PMCID: | PMC3207263 |
| PUBMED: | 22036569 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 9 December 2011" - "CODEN: CELLB" - "Source: Scopus" |
