Amyloid-Beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
Item Type:Journal Article
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-? protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory., Nature Medicine, 14, 8, 2008, 837-842
Amyloid ?-Protein Dimers Isolated Directly from Alzheimer Brains Impair Synaptic Plasticity and Memory.pdf (Published (publisher's copy) - Peer Reviewed) 1.766Mb
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 ??protein (A?) 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 A? from AD brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to A? dimers. Mechanistically, metabotropic glutamate receptors (mGluR) were required for LTD enhancement and NMDA receptors (NMDAR) for spine loss. Co-administering antibodies to the A? 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 A? dimers, suggesting that plaque cores are largely inactive but sequester A? dimers that are synaptotoxic. We conclude that soluble A? oligomers extracted from AD brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.
Science Foundation Ireland
Author: ROWAN, MICHAEL JOSEPH
Type of material:Journal Article
Series/Report no:Nature Medicine
Availability:Full text available