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The Journal of Neuroscience, January 23, 2008, 28(4):788-797; doi:10.1523/JNEUROSCI.4771-07.2008

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Neurobiology of Disease
Amyloid β Oligomers (Aβ_1–42 Globulomer) Suppress Spontaneous Synaptic Activity by Inhibition of P/Q-Type Calcium Currents

Volker Nimmrich,^1 * Christiane Grimm,^2 * Andreas Draguhn,² Stefan Barghorn,¹ Alexander Lehmann,² Hans Schoemaker,¹ Heinz Hillen,¹ Gerhard Gross,¹ Ulrich Ebert,¹ and Claus Bruehl²

¹Neuroscience Discovery, Global Pharmaceutical Research and Development, Abbott, D-67061 Ludwigshafen, Germany, and ²Department of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany

Correspondence should be addressed to Volker Nimmrich, Abbott, Knollstrasse, D-67061 Ludwigshafen, Germany. Email: volker.nimmrich{at}abbott.com

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 "Aβ_1–42 globulomer." Synthetically prepared Aβ_1–42 globulomer has been shown to localize to neurons and impairs long-term potentiation (Barghorn et al., 2005). Here, we demonstrate that Aβ_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 Aβ_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 Aβ_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 Aβ_1–42 globulomer may cause deficits in cellular mechanisms of information storage in brains of Alzheimer's disease patients. The inhibitory effect of Aβ_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.

Key words: Aβ globulomer; Aβ oligomers; P/Q-type calcium channel; amyloid; Alzheimer's disease; hippocampal neurons

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Received July 4, 2007; revised Nov. 27, 2007; accepted Dec. 4, 2007.

Correspondence should be addressed to Volker Nimmrich, Abbott, Knollstrasse, D-67061 Ludwigshafen, Germany. Email: volker.nimmrich{at}abbott.com

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