Effects of secreted oligomers of amyloid β-protein on hippocampal synaptic plasticity: a potent role for trimers

Authors

  • Matthew Townsend,

    1. Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA
    Search for more papers by this author
  • Ganesh M. Shankar,

    1. Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA
    Search for more papers by this author
  • Tapan Mehta,

    1. Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA
    Search for more papers by this author
  • Dominic M. Walsh,

    1. Laboratory for Neurodegenerative Research, Conway Institute for Biomedical and Biomolecular Research, University College Dublin, Dublin 4, Ireland
    Search for more papers by this author
  • Dennis J. Selkoe

    1. Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA
    Search for more papers by this author

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@rics.bwh.harvard.edu

Abstract

The accumulation of amyloid β-protein (Aβ) 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 Aβ 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 Aβ 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 Aβ inhibits hippocampal synaptic plasticity in wild-type mice. To ascertain which Aβ assemblies contribute to the impairment of LTP, we fractionated oligomers by size-exclusion chromatography and found that Aβ trimers fully inhibit LTP, whereas dimers and tetramers have an intermediate potency. Natural Aβ 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 Aβ oligomers on presynaptic vesicle release. LTP in juvenile mice is resistant to the effects of Aβ oligomers, as is brain-derived-neurotrophic-factor-induced LTP in adult hippocampus. We conclude that specific assemblies, particularly timers, of naturally secreted Aβ oligomers are potent and selective inhibitors of certain forms of hippocampal LTP.

Ancillary