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

The accumulation of amyloid beta-protein (A beta) 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 A beta 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 A beta 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 A beta inhibits hippocampal synaptic plasticity in wild-type mice. To ascertain which A beta assemblies contribute to the impairment of LTP, we fractionated oligomers; by size-exclusion chromatography and found that A beta trimers fully inhibit LTP, whereas dimers and tetramers have an intermediate potency. Natural A beta oligomers are sensitive to heat denaturation, primarily inhibit the induction phase of LTP, and cause a sustained impairment of UP even after extensive washout. We observed no effects of A beta oligomers on presynaptic vesicle release. LTP in juvenile mice is resistant to the effects of A beta oligomers, as is brain-derived-neurotrophic-factor-induced UP in adult hippocampus. We conclude that specific assemblies, particularly timers, of naturally secreted A beta oligomers are potent and selective inhibitors of certain forms of hippocampal LTP.