Activation of CaMKIV by soluble amyloid-ß1-42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis.
Sci Signal
; 10(487)2017 Jul 11.
Article
em En
| MEDLINE
| ID: mdl-28698220
ABSTRACT
The prefibrillar form of soluble amyloid-ß (sAß1-42) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sAß1-42 led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. We found that sAß1-42 prevented new synapse formation induced by chemical long-term potentiation (cLTP). In cultured rat hippocampal neurons, nanomolar amounts of sAß1-42 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 Aß1-42, or by expression a phosphodeficient synapsin mutant. The CaMKK inhibitor also abolished the defects in activity-dependent synaptogenesis caused by sAß1-42 Our results suggest that by disrupting SV reallocation between synapses, sAß1-42 prevents neurons from forming new synapses or adjusting strength and activity among neighboring synapses. Targeting this mechanism might prevent synaptic dysfunction in AD patients.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Transporte Axonal
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Sinapses
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Peptídeos beta-Amiloides
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Vesículas Citoplasmáticas
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Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina
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Doença de Alzheimer
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Sci Signal
Assunto da revista:
CIENCIA
/
FISIOLOGIA
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Coréia do Sul