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Please use this identifier to cite or link to this item: http://hdl.handle.net/2262/60917

Title: Amyloid-Beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
Author: ROWAN, MICHAEL JOSEPH
Sponsor: 
Name Grant Number
03/IN3/B403C

Author's Homepage: http://people.tcd.ie/mrowan
Keywords: Neuroscience
Alzheimer’s disease (AD)
Issue Date: 2008
Citation: Shankar, GM, Li, S, Mehta, TH, Garcia-Munoz, A, Shepardson, NE, Smith, I, Brett, FM, Farrell, MA, Rowan, MJ, Lemere, CA, Regan, CM, Walsh, DM, Sabatini, BL, Selkoe, DJ, Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory., Nature Medicine, 14, 8, 2008, 837-842
Series/Report no.: Nature Medicine
14
8
Abstract: Alzheimer’s disease (AD) constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of AD have not been achieved. We extracted soluble amyloid β–protein (Aβ) oligomers directly from the cerebral cortex of typical AD subjects. The oligomers potently inhibited long term potentiation (LTP), enhanced long term depression (LTD), and reduced dendritic spine density in normal rodent hippocampus. Soluble Aβ from AD brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Aβ dimers. Mechanistically, metabotropic glutamate receptors (mGluR) were required for LTD enhancement and NMDA receptors (NMDAR) for spine loss. Co-administering antibodies to the Aβ N-terminus prevented the LTP and LTD deficits, whereas antibodies to the mid-region or C-terminus were less effective. Insoluble amyloid plaque cores from AD cortex did not impair LTP unless they were first solubilized to release Aβ dimers, suggesting that plaque cores are largely inactive but sequester Aβ dimers that are synaptotoxic. We conclude that soluble Aβ oligomers extracted from AD brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.
Description: PUBLISHED
URI: http://hdl.handle.net/2262/60917
Related links: http://dx.doi.org/10.1038/nm1782
Appears in Collections:Pharmacology & Therapeutics (Scholarly Publications)

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