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

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 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.

Loss of serum IGF-I input to the brain as an early biomarker of disease onset in Alzheimer mice

“…14 Indeed, new evidence indicates that in postmortem AD brains there is a profound resistance to IGF-I, 15 a finding recently replicated in AD mice. 16 This is in agreement with a recently reported reduction of the cerebrospinal fluid (CSF)/plasma IGF-I ratio in AD patients. 17 Hence, we now tested this hypothesis by introducing the notion that this impairment could be detected through clinically amenable tools such as the electroencephalogram (EEG).…”

“…As recently confirmed in AD mice, 16 Aβ interferes with insulin and IGF-I signaling. 30 Accordingly, we observed that Aβ interferes with IGF-I uptake by brain endothelium, a process that requires the interaction of IGF-I with its receptor.…”

“…11 Others reported increases in various indicators of IGF-I resistance in the brain of AD patients 15,27,28 and more recently, in APP/PS1 mice. 16 Changes in systemic IGF components have also been proposed as biomarkers of AD. 17,29 Indeed, we confirmed the existence of reduced traffic of serum-to-CSF IGF-I in AD patients, 17 a reduction replicated in AD mice.…”

The Ames dwarf mutation attenuates Alzheimer's disease phenotype of APP/PS1 mice

“…The idea of attenuated IGF-1R mediated signaling in spite of elevated IGF-1 levels is supported by our inability to observe any change in IGF-1R phosphorylation in any brain region in these mice in spite of increased pAkt and pGSK3β levels in the hippocampus of APP/PS1 mice. Several studies have reached a similar conclusion of IGF-1 dysfunction in both mouse models and human AD brains either due to lower levels of brain or serum IGF-1 or attenuated receptor signaling (Alvarez, et al, 2007,Carro, et al, 2002,Cohen, et al, 2010,Duron, et al, 2012,Moloney, et al, 2010,Talbot, et al, 2012,Watanabe, et al, 2005,Westwood, et al, 2014,Zhang, et al, 2013). Moreover, rodent and human data support the fact that attenuated IGF-1R signaling is early in disease course correlating with stages of disease and even appearing first during mild cognitive impairment (Rivera, et al, 2005,Steen, et al, 2005,Talbot, et al, 2012,Trueba-Saiz, et al, 2013,Watanabe, et al, 2005).…”

Irreversible destruction of amyloid fibril plaques by conjugated polymer based fluorogenic nanogrenades

“…We also tested the response of DCM1 alone or the nanogranade to BSA (bovine serum albumin) and HSA (human serum albumin), two serum proteins that strongly interact with small-molecular hydrophobic dyes (Fig. 29 The ex vivo imaging assay showed that the nanogranade could image the small amyloid fibril plaques deposited on the hippocampus of the brain (Fig. While DCM1 alone showed strong fluorescence enhancement with both BSA and HSA (Fig.…”