Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway.
Alzheimer's disease (AD) is characterized by decreased synapse density in hippocampus and neocortex, and synapse loss is the strongest anatomical correlate of the degree of clinical impairment. Although considerable evidence supports a causal role for the amyloid-beta protein (Abeta) in AD, a direct link between a specific form of Abeta and synapse loss has not been established. We demonstrate that physiological concentrations of naturally secreted Abeta dimers and trimers, but not monomers, induce progressive loss of hippocampal synapses. Pyramidal neurons in rat organotypic slices had markedly decreased density of dendritic spines and numbers of electrophysiologically active synapses after exposure to picomolar levels of soluble oligomers. Spine loss was reversible and was prevented by Abeta-specific antibodies or a small-molecule modulator of Abeta aggregation. Mechanistically, Abeta-mediated spine loss required activity of NMDA-type glutamate receptors (NMDARs) and occurred through a pathway involving cofilin and calcineurin. Furthermore, NMDAR-mediated calcium influx into active spines was reduced by Abeta oligomers. Partial blockade of NMDARs by pharmacological antagonists was sufficient to trigger spine loss. We conclude that soluble, low-n oligomers of human Abeta trigger synapse loss that can be reversed by therapeutic agents. Our approach provides a quantitative cellular model for elucidating the molecular basis of Abeta-induced neuronal dysfunction.
Shankar
Ganesh M
GM
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bloodgood
Brenda L
BL
Townsend
Matthew
M
Walsh
Dominic M
DM
Selkoe
Dennis J
DJ
Sabatini
Bernardo L
BL
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000473:pathology* / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016194:Receptors, N-Methyl-D-Aspartate