A β‐amyloid oligomer directly modulates P/Q‐type calcium currents in Xenopus oocytes

Abstract

BACKGROUND AND PURPOSEb-amyloid (Ab) oligomers have been implicated in the early pathophysiology of Alzheimer's disease (AD). While the precise nature of the molecular target has not been fully revealed, a number of studies have indicated that Ab oligomers modulate neuron-specific ion channels. We recently provided evidence that Ab oligomers suppress isolated P/Q-type calcium currents in cultured nerve cells. Using a heterologous expression system, we aimed to prove a direct effect on the membrane channel mediating such current. EXPERIMENTAL APPROACHThe effects of a synthetically generated Ab oligomer, Ab globulomer, were investigated on P/Q-type currents recorded from Xenopus laevis oocytes expressing the full P/Q-type calcium channel or the pore-forming subunit only. We also examined the effects of Ab globulomer on recombinant NMDA receptor currents. Finally, we compared the modulation by Ab globulomer with that induced by a synthetic monomeric Ab. KEY RESULTSAb globulomer directly and dose-dependently modulated P/Q-type calcium channels. A leftward shift of the current-voltage curve indicated that the threshold for channel opening was reduced. The effect of Ab globulomer was also present when only the a1A subunit of the normally tripartite channel was expressed. In contrast, the monomeric Ab had no effect on P/Q current. Also globulomer Ab had no effect on glutamate-induced NMDA currents. CONCLUSIONS AND IMPLICATIONSThe a1A subunit of the P/Q-type calcium channel is directly modulated by oligomeric Ab. Threshold reduction as well as an increase in current at synaptic terminals may facilitate vesicle release and could trigger excitotoxic events in the brains of patients with AD.

Calcium channel blockers and dementia

“…We then expressed the P/Q-type channel recombinantly in Xenopus laevis oocytes and observed a current increase after Aβ1-42 globulomer application (Mezler et al, 2012). This effect also occurred in the absence of accessory subunits, suggesting a direct effect of Aβ on the pore forming α1A subunit.…”

Alzheimer's disease, β‐amyloid, glutamate, NMDA receptors and memantine – searching for the connections

“…Similar increases in the cytosolic concentration of Ca 2+ induced by Aβ oligomers in cortical neurons were only slightly attenuated by the NR2B preferring NMDA receptor antagonist ifenprodil, indicating that Aβ oligomers directly activate NMDA receptors, particularly those with the NR2A subunit (Texido et al ., 2011). In contrast, others found no effect of oligomeric Aβ on glutamate‐induced currents in Xenopus oocytes expressing NMDA receptors under conditions where clear effects of voltage‐gated P/Q‐type calcium channels were seen (Mezler et al ., 2011).…”

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…Normal P/Q- or N-type Ca 2+ channels are high-voltage-gated calcium channels contributing to vesicle release at synaptic terminals and therefore are critical for synaptic stability; increasing N- and P/Q-type calcium currents triggers synaptic vesicle release. A recent study reported that as low as 8 nM of A β42 globulomer (a highly stable globular oligomeric Aβ) can impair LTP by directly reducing the threshold for channel opening of presynaptic P/Q- or N-type Ca 2+ channels (Hermann et al, 2013; Mezler et al, 2012; Nimmrich et al, 2008). Specifically blocking P/Q-type or N-type calcium channels with peptide toxins completely reversed Aβ globulomer-induced deficits in glutamatergic neurotransmission.…”