Activation of CaMKIV by soluble amyloid-β1-42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis.

The prefibrillar form of soluble amyloid-β (sAβ1-42) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sAβ1-42 led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. We found that sAβ1-42 prevented new synapse formation induced by chemical long-term potentiation (cLTP). In cultured rat hippocampal neurons, nanomolar amounts of sAβ1-42 impaired Ca2+ clearance from presynaptic terminals and increased the basal Ca2+ concentration. This caused an increase in the phosphorylation of Ca2+/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 Aβ1-42, or by expression a phosphodeficient synapsin mutant. The CaMKK inhibitor also abolished the defects in activity-dependent synaptogenesis caused by sAβ1-42 Our results suggest that by disrupting SV reallocation between synapses, sAβ1-42 prevents neurons from forming new synapses or adjusting strength and activity among neighboring synapses. Targeting this mechanism might prevent synaptic dysfunction in AD patients.