| First Author | Park D | Year | 2017 |
| Journal | Sci Signal | Volume | 10 |
| Issue | 487 | PubMed ID | 28698220 |
| Mgi Jnum | J:330075 | Mgi Id | MGI:6832012 |
| Doi | 10.1126/scisignal.aam8661 | Citation | Park D, et al. (2017) Activation of CaMKIV by soluble amyloid-beta1-42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis. Sci Signal 10(487) |
| abstractText | The prefibrillar form of soluble amyloid-beta (sAbeta1-42) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sAbeta1-42 led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. We found that sAbeta1-42 prevented new synapse formation induced by chemical long-term potentiation (cLTP). In cultured rat hippocampal neurons, nanomolar amounts of sAbeta1-42 impaired Ca(2+) clearance from presynaptic terminals and increased the basal Ca(2+) concentration. This caused an increase in the phosphorylation of Ca(2+)/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 Abeta1-42, or by expression a phosphodeficient synapsin mutant. The CaMKK inhibitor also abolished the defects in activity-dependent synaptogenesis caused by sAbeta1-42 Our results suggest that by disrupting SV reallocation between synapses, sAbeta1-42 prevents neurons from forming new synapses or adjusting strength and activity among neighboring synapses. Targeting this mechanism might prevent synaptic dysfunction in AD patients. |
