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View Full TextAmyloid-β and intersynaptic trafficking
Synaptic loss and dysfunction as well as neuronal accumulation of amyloid-β (Aβ) are classic features of Alzheimer’s disease (AD). Synaptic components are transported along axons in actin- and synapsin-associated vesicles to adjust synaptic strength in response to activity and to promote the formation of new synapses. Using hippocampal neurons isolated from rats and mouse models of AD, Park et al. found that a soluble form of Aβ impedes Ca2+ clearance from neurons, which led to activation of the kinase CaMKIV. CaMKIV-mediated phosphorylation of synapsin caused its dissociation from synaptic vesicles and actin, thereby impairing vesicular transport. Targeting this pathway might suppress the pathological effects of Aβ in patients with AD.
Abstract
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.
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