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

Assemblies of beta-amyloid (A beta) 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 A beta 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 A beta. 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 A beta 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.