Synthetic Aβ oligomers (Aβ1-42 globulomer) modulate presynaptic calcium currents: Prevention of Aβ-induced synaptic deficits by calcium channel blockers

Alzheimer's disease is accompanied by increased brain levels of soluble amyloid-beta (A beta) oligomers. It has been suggested that oligomers directly impair synaptic function, thereby causing cognitive deficits in Alzheimer's disease patients. Recently, it has been shown that synthetic A beta oligomers directly modulate P/Q-type calcium channels, possibly leading to excitotoxic cascades and subsequent synaptic decline. Using whole-cell recordings we studied the modulation of recombinant presynaptic calcium channels in HEK293 cells after application of a stable A beta oligomer preparation (A beta(1-42) globulomer). A beta globulomer shifted the half-activation voltage of P/Q-type and N-type calcium channels to more hyperpolarized values (by 11.5 and 7.5 mV). Application of non-aggregated A beta peptides had no effect. We then analyzed the potential of calcium channel blockers to prevent A beta globulomer-induced synaptic decline in hippocampal slice cultures. Specific block of P/Q-type or N-type calcium channels with peptide toxins completely reversed A beta globulomer-induced deficits in glutamatergic neurotransmission. Two state-dependent low molecular weight P/Q-type and N-type calcium channel blockers also protected neurons from A beta-induced alterations. On the contrary, inhibition of L-type calcium channels failed to reverse the deficit. Our data show that A beta globulomer directly modulates recombinant P/Q-type and N-type calcium channels in HEK293 cells. Block of presynaptic calcium channels with both state-dependent and state-independent modulators can reverse A beta-induced functional deficits in synaptic transmission. These findings indicate that presynaptic calcium channel blockers may be a therapeutic strategy for the treatment of Alzheimer's disease. (C) 2013 Elsevier B.V. All rights reserved.