Amyloid beta oligomers (A beta(1-42) globulomer) suppress spontaneous synaptic activity by inhibition of P/Q-type calcium currents.
Abnormal accumulation of soluble oligomers of amyloid beta (Abeta) is believed to cause malfunctioning of neurons in Alzheimer's disease. It has been shown that Abeta oligomers impair synaptic plasticity, thereby altering the ability of the neuron to store information. We examined the underlying cellular mechanism of Abeta oligomer-induced synaptic modifications by using a recently described stable oligomeric Abeta preparation called "Abeta(1-42) globulomer." Synthetically prepared Abeta(1-42) globulomer has been shown to localize to neurons and impairs long-term potentiation (Barghorn et al., 2005). Here, we demonstrate that Abeta(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 Abeta(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 Abeta(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 Abeta(1-42) globulomer may cause deficits in cellular mechanisms of information storage in brains of Alzheimer's disease patients. The inhibitory effect of Abeta(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.
Nimmrich
Volker
V
Neuroscience Discovery, Global Pharmaceutical Research and Development, Abbott, D-67061 Ludwigshafen, Germany. volker.nimmrich@abbott.com
Grimm
Christiane
C
Draguhn
Andreas
A
Barghorn
Stefan
S
Lehmann
Alexander
A
Schoemaker
Hans
H
Hillen
Heinz
H
Gross
Gerhard
G
Ebert
Ulrich
U
Bruehl
Claus
C
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000502:physiology; D000818:Animals; D002121:Calcium Channel Blockers / Q000737:chemistry*; D020865:Calcium Channels, P-Type / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000378:metabolism*; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid