Ca2.1 mediates presynaptic dysfunction induced by amyloid β oligomers.

Synaptic dysfunction is an early pathological phenotype of Alzheimer's disease (AD) that is initiated by oligomers of amyloid β peptide (Aβs). Treatments aimed at correcting synaptic dysfunction could be beneficial in preventing disease progression, but mechanisms underlying Aβ-induced synaptic defects remain incompletely understood. Here, we uncover an epithelial sodium channel (ENaC) - Ca2.3 - protein kinase C (PKC) - glycogen synthase kinase-3β (GSK-3β) signal transduction pathway that is engaged by Aβs to enhance presynaptic Ca2.1 voltage-gated Ca channel activity, resulting in pathological potentiation of action-potential-evoked synaptic vesicle exocytosis. We present evidence that the pathway is active in human APP transgenic mice in vivo and in human AD brains, and we show that either pharmacological Ca2.1 inhibition or genetic Ca2.1 haploinsufficiency is sufficient to restore normal neurotransmitter release. These findings reveal a previously unrecognized mechanism driving synaptic dysfunction in AD and identify multiple potentially tractable therapeutic targets.