Deficiency in LRP6-mediated Wnt signaling contributes to synaptic abnormalities and amyloid pathology in Alzheimer's disease.
Neuron
; 84(1): 63-77, 2014 Oct 01.
Article
em En
| MEDLINE
| ID: mdl-25242217
ABSTRACT
Alzheimer's disease (AD) is an age-related neurological disorder characterized by synaptic loss and dementia. The low-density lipoprotein receptor-related protein 6 (LRP6) is an essential coreceptor for Wnt signaling, and its genetic variants have been linked to AD risk. Here we report that neuronal LRP6-mediated Wnt signaling is critical for synaptic function and cognition. Conditional deletion of Lrp6 gene in mouse forebrain neurons leads to age-dependent deficits in synaptic integrity and memory. Neuronal LRP6 deficiency in an amyloid mouse model also leads to exacerbated amyloid pathology due to increased APP processing to amyloid-ß. In humans, LRP6 and Wnt signaling are significantly downregulated in AD brains, likely by a mechanism that depends on amyloid-ß. Our results define a critical pathway in which decreased LRP6-mediated Wnt signaling, synaptic dysfunction, and elevated Aß synergistically accelerate AD progression and suggest that restoring LRP6-mediated Wnt signaling can be explored as a viable strategy for AD therapy.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sinapses
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Peptídeos beta-Amiloides
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Doença de Alzheimer
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Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade
/
Via de Sinalização Wnt
Tipo de estudo:
Guideline
Limite:
Aged
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Aged80
/
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Neuron
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
China