Abstract
In different clinical studies, an association of type 2 diabetes and Alzheimers disease (AD) has been described. However, the underlying mechanisms are still unclear. One explanation could be that vascular complications of diabetes result in neurodegeneration. Alternatively, the mechanism might be directly related to insulin and insulin-like growth factor( IGF)-1 signaling, leading to the proposal that AD is a “brain-type diabetes”. Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration. These findings raise the question, whether this phenomenon is cause or consequence of neurodegeneration. Recently, Cohen and coworkers have show that knocking down DAF-2 in C. elegans, the homolog of the mammalian IR/IGF-1R, reduces β-amyloid(Aβ)1-42 toxicity. Cell based experiments suggest a specific role for the IGF-1/IRS-2 signaling pathway in regulating α-/β-secretase activity. Moreover circulating IGF-1 might influence Aβ clearance from the brain by promoting Aβ transport over the blood brain barrier. Interestingly, brain specific deletion of IRS-2 increases life span, suggesting that long term neuronal IGF-1R signaling might be harmful. Taken together, the data from humans and different model organisms indicate a role of IR/IGF-1R signaling in Aβ metabolism, and clearance as well as longevity. Since more studies are needed to elucidate the impact of insulin and/or IGF-1 treatment in AD, the time to propose these hormones as a potential treatment option for AD has not come yet.
Keywords: Insulin receptor, IGF-1 receptor, Alzheimer's disease
Current Alzheimer Research
Title: The Role of IGF-1 Receptor and Insulin Receptor Signaling for the Pathogenesis of Alzheimers Disease: From Model Organisms to Human Disease
Volume: 6 Issue: 3
Author(s): S. Freude, K. Schilbach and M. Schubert
Affiliation:
Keywords: Insulin receptor, IGF-1 receptor, Alzheimer's disease
Abstract: In different clinical studies, an association of type 2 diabetes and Alzheimers disease (AD) has been described. However, the underlying mechanisms are still unclear. One explanation could be that vascular complications of diabetes result in neurodegeneration. Alternatively, the mechanism might be directly related to insulin and insulin-like growth factor( IGF)-1 signaling, leading to the proposal that AD is a “brain-type diabetes”. Furthermore, postmortem analyses of brains from patients with AD revealed a markedly downregulated expression of insulin receptor (IR), IGF-1 receptor (IGF-1R), insulin receptor substrate (IRS)-1 and IRS-2, and these changes progress with severity of neurodegeneration. These findings raise the question, whether this phenomenon is cause or consequence of neurodegeneration. Recently, Cohen and coworkers have show that knocking down DAF-2 in C. elegans, the homolog of the mammalian IR/IGF-1R, reduces β-amyloid(Aβ)1-42 toxicity. Cell based experiments suggest a specific role for the IGF-1/IRS-2 signaling pathway in regulating α-/β-secretase activity. Moreover circulating IGF-1 might influence Aβ clearance from the brain by promoting Aβ transport over the blood brain barrier. Interestingly, brain specific deletion of IRS-2 increases life span, suggesting that long term neuronal IGF-1R signaling might be harmful. Taken together, the data from humans and different model organisms indicate a role of IR/IGF-1R signaling in Aβ metabolism, and clearance as well as longevity. Since more studies are needed to elucidate the impact of insulin and/or IGF-1 treatment in AD, the time to propose these hormones as a potential treatment option for AD has not come yet.
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Freude S., Schilbach K. and Schubert M., The Role of IGF-1 Receptor and Insulin Receptor Signaling for the Pathogenesis of Alzheimers Disease: From Model Organisms to Human Disease, Current Alzheimer Research 2009; 6 (3) . https://dx.doi.org/10.2174/156720509788486527
DOI https://dx.doi.org/10.2174/156720509788486527 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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