Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation.
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.
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Jing
J
Wu
Ronald S
RS
Petralia
Hideaki
H
Kurushima
Hiral
H
Patel
Mi-young
MY
Jung
Lenora
L
Volk
Shoaib
S
Chowdhury
Jason D
JD
Shepherd
Marlin
M
Dehoff
Yueming
Y
Li
Dietmar
D
Kuhl
Richard L
RL
Huganir
Donald L
DL
Price
Robert
R
Scannevin
Juan C
JC
Troncoso
Philip C
PC
Wong
Paul F
PF
Worley
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D021381:Protein Transport
D016564:Amyloid beta-Protein Precursor; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein