Author/Authors :
Jing Wu، نويسنده , , Ronald S. Petralia، نويسنده , , Hideaki Kurushima، نويسنده , , Hiral Patel، نويسنده , , Mi-Young Jung، نويسنده , , Lenora Volk، نويسنده , , Shoaib Chowdhury، نويسنده , , Jason D. Shepherd، نويسنده , , Marlin Dehoff، نويسنده , , Yueming Li، نويسنده , , Dietmar Kuhl، نويسنده , , Richard L. Huganir، نويسنده , , Donald L. Price، نويسنده , , Robert Scannevin، نويسنده , , Juan C. Troncoso، نويسنده , , Philip C. Wong، نويسنده , , Paul F. Worley، نويسنده ,
Abstract :
Assemblies of β-amyloid (Aβ) peptides are pathological mediators of Alzheimerʹs 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.
