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

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-Ca _V 2.3-PKC-GSK-3β signal transduction pathway that is engaged by oligomeric amyloid β (Aβ _o ) _{to enhance presynaptic Ca V 2.1 voltage-gated Ca ²⁺ channel activity, resulting in pathological potentiation of action potential-evoked synaptic vesicle exocytosis. Normalization of presynaptic function by pharmacological Ca V 2.1 inhibition or genetic Ca V 2.1 haploinsufficiency rescues Aβ o -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 Ca V 2.1-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.}