Amyloid β oligomers (Aβ1-42 globulomer) suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents

Abnormal accumulation of soluble oligomers of amyloid beta(A beta) is believed to cause malfunctioning of neurons in Alzheimer's disease. It has been shown that A beta oligomers impair synaptic plasticity, thereby altering the ability of the neuron to store information. We examined the underlying cellular mechanism of A beta oligomer-induced synaptic modifications by using a recently described stable oligomeric A beta preparation called "A beta(1-42) globulomer." Synthetically prepared A beta(1-42) globulomer has been shown to localize to neurons and impairs long-term potentiation (Barghorn et al., 2005). Here, we demonstrate that A beta(1-42) globulomer does not affect intrinsic neuronal properties, as assessed by measuring input resistance and discharge characteristics, excluding an unspecific alteration of membrane properties. We provide evidence that A beta(1-42) globulomer, at concentrations as low as 8 nM, specifically suppresses spontaneous synaptic activity resulting from a reduction of vesicular release at terminals of both GABAergic and glutamatergic synapses. EPSCs and IPSCs were primarily unaffected. A detailed search for the precise molecular target of A beta(1-42) globulomer revealed a specific inhibition of presynaptic P/Q calcium currents, whereas other voltage-activated calcium currents remained unaltered. Because intact P/Q calcium currents are needed for synaptic plasticity, the disruption of such currents by A beta(1-42) globulomer may cause deficits in cellular mechanisms of information storage in brains of Alzheimer's disease patients. The inhibitory effect of A beta(1-42) globulomer on synaptic vesicle release could be reversed by roscovitine, a specific enhancer of P/Q currents. Selective enhancement of the P/Q calcium current may provide a promising strategy in the treatment of Alzheimer's disease.