Synapto-depressive effects of amyloid beta require PICK1.
Amyloid beta (Aβ), a key component in the pathophysiology of Alzheimer's disease, is thought to target excitatory synapses early in the disease. However, the mechanism by which Aβ weakens synapses is not well understood. Here we showed that the PDZ domain protein, protein interacting with C kinase 1 (PICK1), was required for Aβ to weaken synapses. In mice lacking PICK1, elevations of Aβ failed to depress synaptic transmission in cultured brain slices. In dissociated cultured neurons, Aβ failed to reduce surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 2, a subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that binds with PICK1 through a PDZ ligand-domain interaction. Lastly, a novel small molecule (BIO922) discovered through structure-based drug design that targets the specific interactions between GluA2 and PICK1 blocked the effects of Aβ on synapses and surface receptors. We concluded that GluA2-PICK1 interactions are a key component of the effects of Aβ on synapses.
Center for Neural Circuits and Behavior, Departments of Neuroscience and Biology, University of California at San Diego, La Jolla, CA, 92093, USA.
Stephanie
S
Alfonso
Helmut W
HW
Kessels
Charles C
CC
Banos
Timothy R
TR
Chan
Edward T
ET
Lin
Gnanasambandam
G
Kumaravel
Robert H
RH
Scannevin
Kenneth J
KJ
Rhodes
Richard
R
Huganir
Kevin M
KM
Guckian
Anthone W
AW
Dunah
Roberto
R
Malinow
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000633:toxicity*; D011485:Protein Binding; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D018091:Receptors, AMPA; C091822:Prkcabp protein, mouse; C075222:amyloid beta-protein (1-42); C104722:glutamate receptor ionotropic, AMPA 2
Alzheimer's disease; mouse; rat; synapse