Abstract
Abnormal accumulation of soluble oligomers of amyloid β (Aβ) is believed to cause malfunctioning of neurons in Alzheimer's disease. It has been shown that Aβ oligomers impair synaptic plasticity, thereby altering the ability of the neuron to store information. We examined the underlying cellular mechanism of Aβ oligomer-induced synaptic modifications by using a recently described stable oligomeric Aβ preparation called “Aβ1–42 globulomer.” Synthetically prepared Aβ1–42 globulomer has been shown to localize to neurons and impairs long-term potentiation (Barghorn et al., 2005). Here, we demonstrate that Aβ1–42 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 Aβ1–42 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 Aβ1–42 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 Aβ1–42 globulomer may cause deficits in cellular mechanisms of information storage in brains of Alzheimer's disease patients. The inhibitory effect of Aβ1–42 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.
