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Neuroscience |
1 Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA
2 Laboratory for Neurodegenerative Research, Conway Institute for Biomedical and Biomolecular Research, University College Dublin, Dublin 4, Ireland
The accumulation of amyloid ß-protein (Aß) in brain regions serving memory and cognition is a central pathogenic feature of Alzheimer's disease (AD). We have shown that small soluble oligomers of human Aß that are naturally secreted by cultured cells inhibit hippocampal long-term potentiation (LTP) in vitro and in vivo and transiently impair the recall of a complex learned behaviour in rats. These results support the hypothesis that diffusible oligomers of Aß initiate a synaptic dysfunction that may be an early event in AD. We now report detailed electrophysiological analyses that define conditions under which acute application of soluble Aß inhibits hippocampal synaptic plasticity in wild-type mice. To ascertain which Aß assemblies contribute to the impairment of LTP, we fractionated oligomers by size-exclusion chromatography and found that Aß trimers fully inhibit LTP, whereas dimers and tetramers have an intermediate potency. Natural Aß oligomers are sensitive to heat denaturation, primarily inhibit the induction phase of LTP, and cause a sustained impairment of LTP even after extensive washout. We observed no effects of Aß oligomers on presynaptic vesicle release. LTP in juvenile mice is resistant to the effects of Aß oligomers, as is brain-derived-neurotrophic-factor-induced LTP in adult hippocampus. We conclude that specific assemblies, particularly timers, of naturally secreted Aß oligomers are potent and selective inhibitors of certain forms of hippocampal LTP.
(Received 16 December 2005;
accepted after revision 7 February 2006;
first published online 9 February 2006)
Corresponding author D. J. Selkoe: Center for Neurologic Diseases, Harvard Institutes of Medicine, 77 Ave Louis Pasteur, Room 730, Boston, MA 02115-5716, USA. Email: dselkoe{at}rics.bwh.harvard.edu
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