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

Abstract

Abnormal accumulation of soluble oligomers of amyloid ␤ (A␤) is believed to cause malfunctioning of neurons in Alzheimer's disease. It has been shown that A␤ oligomers impair synaptic plasticity, thereby altering the ability of the neuron to store information. We examined the underlying cellular mechanism of A␤ oligomer-induced synaptic modifications by using a recently described stable oligomeric A␤ preparation called "A␤ 1-42 globulomer." Synthetically prepared A␤ 1-42 globulomer has been shown to localize to neurons and impairs long-term potentiation (Barghorn et al., 2005). Here, we demonstrate that A␤ 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 A␤ 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 A␤ 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 A␤ 1-42 globulomer may cause deficits in cellular mechanisms of information storage in brains of Alzheimer's disease patients. The inhibitory effect of A␤ 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.

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

“…Aβ was also shown to inhibit presynaptic P/Q Ca 2+ channels, suppressing spontaneous synaptic activity (Mezler et al, 2012;Nimmrich et al, 2008), along with the activation of presynaptic α7-nicotinic acetylcholine (ACh) receptors (Dougherty et al, 2003). More recently, Aβ was reported to directly modulate recombinant P/Q-type and also N-type Ca 2+ channels in HEK293 cells and blockade of presynaptic Ca 2+ channels reversed…”

Generation and Therapeutic Efficacy of Highly Oligomer-Specific β-Amyloid Antibodies

“…Finally, the improved spine density and cognitive function in APP transgenic mice after A-887755 treatment raises the hope that selective A␤ oligomer immunotherapy is a promising therapeutic approach without side effects associated with general anti-A␤ therapy. In addition, the globulomer concept will assist in reaching a clearer understanding of the molecular mechanisms of A␤ oligomer pathology, like a recently described interference with the presynaptic P/Q-type calcium current (Nimmrich et al, 2008).…”

Ca2+ channel currents of cortical neurons from pure and mixed cultures

“…Many studies have reported the roles of VGCCs in CNS injuries and diseases. For instance, N-type VGCC is a key component in controlling the transmission of nociceptive signals (Altier et al 2006), and the inhibition of P/Q-type VGCCs mediates the suppression of spontaneous synaptic activity by amyloid b oligomers (Nimmrich et al 2008). In addition, the entry of L-type VGCCs has been associated with neuronal death in Alzheimer's disease (Yagami et al 2004), ischemia (Li et al 2007), and glutamate toxicity (Sribnick et al 2009).…”