Alternations of central insulin‐like growth factor‐1 sensitivity in APP/PS1 transgenic mice and neuronal models

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 β‐amyloid (Aβ) and Aβ‐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 Aβ or Aβ‐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 Aβ, especially the oligomeric Aβ. 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. © 2013 Wiley Periodicals, Inc.