Activation of CaMKIV by Soluble Amyloid-β Impedes Trafficking of Axonal Vesicles and Impairs Activity-dependent Synaptogenesis

The prefibrillar form of soluble amyloid-β (sAβ) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sAβ led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. We found that sAβ prevented new synapse formation induced by chemical long-term potentiation (cLTP). In cultured rat hippocampal neurons, nanomolar amounts of sAβ impaired Ca clearance from presynaptic terminals and increased the basal Ca concentration. This caused an increase in the phosphorylation of Ca/calmodulin-dependent protein kinase IV (CaMKIV) and its substrate synapsin, which markedly inhibited SV trafficking along axons between synapses. Neurons derived from a transgenic AD mouse model had similar defects, which were prevented by an inhibitor of CaMK kinase (CaMKK; which activates CaMKIV), by antibodies against Aβ, or by expression a phosphodeficient synapsin mutant. The CaMKK inhibitor also abolished the defects in activity-dependent synaptogenesis caused by sAβ Our results suggest that by disrupting SV reallocation between synapses, sAβ prevents neurons from forming new synapses or adjusting strength and activity among neighboring synapses. Targeting this mechanism might prevent synaptic dysfunction in AD patients.