The pro-domains of neurotrophins, including BDNF, are linked to Alzheimer's disease through a toxic synergy with Aß.
Hum Mol Genet
; 24(14): 3929-38, 2015 Jul 15.
Article
em En
| MEDLINE
| ID: mdl-25954034
ABSTRACT
Brain-derived neurotrophic factor (BDNF) has a crucial role in learning and memory by promoting neuronal survival and modulating synaptic connectivity. BDNF levels are lower in the brains of individuals with Alzheimer's disease (AD), suggesting a pathogenic involvement. The Drosophila orthologue of BDNF is the highly conserved Neurotrophin 1 (DNT1). BDNF and DNT1 have the same overall protein structure and can be cleaved, resulting in the conversion of a full-length polypeptide into separate pro- and mature-domains. While the BDNF mature-domain is neuroprotective, the role of the pro-domain is less clear. In flies and mammalian cells, we have identified a synergistic toxic interaction between the amyloid-ß peptide (Aß1-42) and the pro-domains of both DNT1 and BDNF. Specifically, we show that DNT1 pro-domain acquires a neurotoxic activity in the presence of Aß1-42. In contrast, DNT1 mature-domain is protective against Aß1-42 toxicity. Likewise, in SH-SY5Y cell culture, BDNF pro-domain is toxic only in the presence of Aß1-42. Western blots indicate that this synergistic interaction likely results from the Aß1-42-induced upregulation of the BDNF pro-domain receptor p75(NTR). The clinical relevance of these findings is underlined by a greater than thirty fold increase in the ratio of BDNF pro- to mature-domains in the brains of individuals with AD. This unbalanced BDNF promature-domain ratio in patients represents a possible biomarker of AD and may offer a target for therapeutic intervention.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Fator Neurotrófico Derivado do Encéfalo
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Proteínas de Drosophila
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Drosophila
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Doença de Alzheimer
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Fatores de Crescimento Neural
Tipo de estudo:
Prognostic_studies
Limite:
Aged
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Aged80
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article