Amyloid β oligomers enhance presynaptic exocytosis via CaV2.1 to drive disease progression in Alzheimer’s models

Abstract Mixed outcomes in clinical trials of amyloid β-lowering agents for Alzheimer’s disease (AD) make the identification of alternative candidate molecular targets for therapy a priority. However, limited understanding of molecular pathways mediating the effects of amyloid β on synaptic and cognitive function hampers these efforts. Here, we uncover an ENaC-CaV2.3-PKC-GSK-3β signal transduction pathway that is engaged by oligomeric amyloid β (Aβo)to enhance presynaptic CaV2.1 voltage-gated Ca²⁺ channel activity, resulting in pathological potentiation of action potential-evoked synaptic vesicle exocytosis. Normalization of presynaptic function by pharmacological CaV2.1 inhibition or genetic CaV2.1 haploinsufficiency rescues Aβo-induced loss of dendritic spines and synaptic long-term potentiation ex vivo, and prevents spine loss, memory deficits and premature mortality in vivo, demonstrating a critical role for enhanced CaV2.1-driven presynaptic exocytosis in synaptic and cognitive decline. These findings reveal a previously unrecognized mechanism driving disease progression in AD, and identify multiple tractable potential therapeutic targets.