Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein.
In Alzheimer's disease increasing evidence attributes synaptic and cognitive deficits to soluble oligomers of amyloid beta protein (Abeta), even prior to the accumulation of amyloid plaques, neurofibrillary tangles, and neuronal cell death. Here we show that within 1-2 h picomolar concentrations of cell-derived, soluble Abeta induce specific alterations in pre- and postsynaptic morphology and connectivity in cultured hippocampal neurons. Clusters of presynaptic vesicle markers decreased in size and number at glutamatergic but not GABAergic terminals. Dendritic spines also decreased in number and became dysmorphic, as spine heads collapsed and/or extended long protrusions. Simultaneous time-lapse imaging of axon-dendrite pairs revealed that shrinking spines sometimes became disconnected from their presynaptic varicosity. Concomitantly, miniature synaptic potentials decreased in amplitude and frequency. Spine changes were prevented by blockers of nAChRs and NMDARs. Washout of Abeta within the first day reversed these spine changes. Further, spine changes reversed spontaneously by 2 days, because neurons acutely developed resistance to continuous Abeta exposure. Thus, rapid Abeta-induced synapse destabilization may underlie transient behavioral impairments in animal models, and early cognitive deficits in Alzheimer's patients.
Calabrese
Barbara
B
Department of Cell Biology and Institute for Childhood and Neglected Diseases, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA.
Shaked
Gideon M
GM
Tabarean
Iustin V
IV
Braga
Julia
J
Koo
Edward H
EH
Halpain
Shelley
S
D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D002478:Cells, Cultured; D018680:Cholinergic Antagonists / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D003712:Dendrites / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000096:biosynthesis; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D013569:Synapses / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D018680:Cholinergic Antagonists; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins