AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.
Beta amyloid (Abeta), a peptide generated from the amyloid precursor protein (APP) by neurons, is widely believed to underlie the pathophysiology of Alzheimer's disease. Recent studies indicate that this peptide can drive loss of surface AMPA and NMDA type glutamate receptors. We now show that Abeta employs signaling pathways of long-term depression (LTD) to drive endocytosis of synaptic AMPA receptors. Synaptic removal of AMPA receptors is necessary and sufficient to produce loss of dendritic spines and synaptic NMDA responses. Our studies indicate the central role played by AMPA receptor trafficking in Abeta-induced modification of synaptic structure and function.
Hsieh
Helen
H
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Boehm
Jannic
J
Sato
Chihiro
C
Iwatsubo
Takeshi
T
Tomita
Taisuke
T
Sisodia
Sangram
S
Malinow
Roberto
R
D018354:Alphavirus Infections / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D004594:Electrophysiology; D004705:Endocytosis / Q000235:genetics / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D009154:Mutation / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000096:biosynthesis / Q000235:genetics; D012845:Sindbis Virus / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000502:physiology
D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D004247:DNA; D048051:p38 Mitogen-Activated Protein Kinases