Synaptic dysfunction is an early pathological phenotype of Alzheimer’s disease (AD) that is initiated by oligomers of amyloid β peptide (Aβos). Treatments aimed at correcting synaptic dysfunction could be beneficial in preventing disease progression, but mechanisms underlying Aβo-induced synaptic defects remain incompletely understood. Alexander Jeans and co-workers uncover an epithelial sodium channel (ENaC) - CaV2.3 - protein kinase C (PKC) - glycogen synthase kinase-3β (GSK-3β) signal transduction pathway that is engaged by Aβos to enhance presynaptic CaV2.1 voltage-gated Ca2+ channel activity, resulting in pathological potentiation of action-potential-evoked synaptic vesicle exocytosis. The authors present evidence that the pathway is active in human APP transgenic mice in vivo and in human AD brains, and they show that either pharmacological CaV2.1 inhibition or genetic CaV2.1 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.
Presynaptic dysfunction can be rescued in vivo by lowering CaV2.1 expression
27 March 2025
Oxford study finds a new mechanism underlying synaptic dysfunction in Alzheimer's Disease