Letter abstract
Nature Medicine 14, 837 - 842 (2008)
Published online: 22 June 2008 | Corrected online: 15 July 2008 | doi:10.1038/nm1782
Amyloid-
protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
Ganesh M Shankar1,2, Shaomin Li1, Tapan H Mehta1, Amaya Garcia-Munoz3, Nina E Shepardson1, Imelda Smith4, Francesca M Brett5, Michael A Farrell5, Michael J Rowan6, Cynthia A Lemere1, Ciaran M Regan3, Dominic M Walsh4, Bernardo L Sabatini2 & Dennis J Selkoe1
Alzheimer's disease 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 Alzheimer's disease has not been achieved. We extracted soluble amyloid-
protein (A) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. 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 Alzheimer's disease 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 were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the A N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease 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 Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.
- Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.
- School of Biomolecular and Biomedical Science, University College Dublin, Dublin 4, Ireland.
- Laboratory for Neurodegenerative Research, University College Dublin, Dublin 4, Ireland.
- Department of Pathology, Beaumont Hospital and Royal College of Surgeons Ireland, Dublin 9, Ireland.
- Trinity College Institute of Neuroscience and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland.
Correspondence to: Dennis J Selkoe1 e-mail: dselkoe@rics.bwh.harvard.edu
