Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation.
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Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation. / Wu, Jing; Petralia, Ronald S; Kurushima, Hideaki; Patel, Hiral; Jung, Mi-young; Volk, Lenora; Chowdhury, Shoaib; Shepherd, Jason D; Dehoff, Marlin; Li, Yueming; Kuhl, Dietmar; Huganir, Richard L; Price, Donald L; Scannevin, Robert; Troncoso, Juan C; Wong, Philip C; Worley, Paul F.
In: CELL, Vol. 147, No. 3, 3, 2011, p. 615-628.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation.
AU - Wu, Jing
AU - Petralia, Ronald S
AU - Kurushima, Hideaki
AU - Patel, Hiral
AU - Jung, Mi-young
AU - Volk, Lenora
AU - Chowdhury, Shoaib
AU - Shepherd, Jason D
AU - Dehoff, Marlin
AU - Li, Yueming
AU - Kuhl, Dietmar
AU - Huganir, Richard L
AU - Price, Donald L
AU - Scannevin, Robert
AU - Troncoso, Juan C
AU - Wong, Philip C
AU - Worley, Paul F
PY - 2011
Y1 - 2011
N2 - Assemblies of ?-amyloid (A?) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by ?-secretase (BACE1) and ?-secretase. The generation of A? 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?. 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 ?-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces A? 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.
AB - Assemblies of ?-amyloid (A?) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by ?-secretase (BACE1) and ?-secretase. The generation of A? 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?. 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 ?-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces A? 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.
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Nerve Tissue Proteins/metabolism
KW - Endosomes/metabolism
KW - Alzheimer Disease/metabolism
KW - Amyloid beta-Protein Precursor/metabolism
KW - Cell Membrane/metabolism
KW - Cytoskeletal Proteins/metabolism
KW - Protein Transport
KW - Animals
KW - Humans
KW - Mice
KW - Mice, Knockout
KW - Nerve Tissue Proteins/metabolism
KW - Endosomes/metabolism
KW - Alzheimer Disease/metabolism
KW - Amyloid beta-Protein Precursor/metabolism
KW - Cell Membrane/metabolism
KW - Cytoskeletal Proteins/metabolism
KW - Protein Transport
M3 - SCORING: Journal article
VL - 147
SP - 615
EP - 628
JO - CELL
JF - CELL
SN - 0092-8674
IS - 3
M1 - 3
ER -