Alternations of central insulin-like growth factor-1 sensitivity in APP/PS1 transgenic mice and neuronal models.
J Neurosci Res
; 91(5): 717-25, 2013 May.
Article
en En
| MEDLINE
| ID: mdl-23401344
ABSTRACT
Although many post-mortem studies have found evidence of central insulin resistance in Alzheimer's disease (AD) patients, results on changes of central insulin-like growth factor-1 (IGF-1) signaling in the pathological process of AD remain controversial. In the present study, we observed the activation states of IGF-1 downstream signaling in brain slices of transgenic mice carrying APPswe/PS1dE9 mutations (APP/PS1 mice) at both early and late stages (ex vivo) and further investigated the involvement of oligomeric ß-amyloid (Aß) and Aß-enriched culture medium (CM) on IGF-1 sensitivity employing neuronal models (in vitro). In 6- and 18-month-old APP/PS1 mice, the phosphorylations of IGF-1 receptor (IGF-1R) and Akt in response to IGF-1 stimulation were significantly reduced in the hippocampal and cortical slices, whereas IGF-1R protein expression and mRNA levels of IGF-1 and IGF-1R in the hippocampal slices were significantly higher than that in wild-type mice. In agreement with these results, reduced IGF-1 sensitivity was verified in APP and PS1 double stably transfected CHO cells; moreover, IGF-1 stimulated phosphorylations of IGF-1R and Akt were also markedly weakened by oligomeric Aß or Aß-enriched CM posttreatment in CHO cells without APP/PS1-transfected (K1 cells) and primary hippocampal neurons. These observations indicate that the impaired central IGF-1 sensitivity at early and late stages of APP/PS1 transgenic mice might be attributable, at least partially, to the overproduced Aß, especially the oligomeric Aß. These findings may shed new light on the mechanisms underlying the defective IGF-1 signaling in AD pathogenesis and provide important clues for AD drug discovery.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Encéfalo
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Factor I del Crecimiento Similar a la Insulina
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Regulación de la Expresión Génica
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Receptor IGF Tipo 1
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Enfermedad de Alzheimer
Tipo de estudio:
Diagnostic_studies
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Prognostic_studies
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Neurosci Res
Año:
2013
Tipo del documento:
Article
País de afiliación:
China