Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway.

Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Research Abstract Details 

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Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Abstract Text:

Ganesh M Shankar,Brenda L Bloodgood,Matthew Townsend,Dominic M Walsh,Dennis J Selkoe,Bernardo L Sabatini,

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.

Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Publishing Authors By Initials

GM Shankar,BL Bloodgood,M Townsend,DM Walsh,DJ Selkoe,BL Sabatini,

For similar nervous system: synapses research abstracts see: nervous system: synapses research

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Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of neuroscience : the official journal

VOLUME: 27

Page Numbers: 2866-75

Journal Abbreviation: J. Neurosci.

ISSN: 1529-2401

DAY: 14

MONTH: Mar

YEAR: 2007

Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Information

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LANGUAGE: eng

NlmUniqueID: 8102140

Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Keywords Mesh Terms:

KEYWORDS: Synapses

MESH TERMS: physiology

Chemical & Substance for Abstract: Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. Information

Substance Name: Receptors, N-Methyl-D-Aspartate

Registry Number: 0

Grant and Affiliation Information for Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway.

AFFILIATION: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Country: United States

AGENCY: United States NIA

GRANT: 1R01AG027443

ACRONYM: AG

MEDLINETA: J Neurosci

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