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The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: From model organisms to human disease

Department of Internal Medicine II, Center for Molecular Medicine Cologne (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Köln, Kerpener Str. 62, 50937 Köln, Germany.
Current Alzheimer research (Impact Factor: 3.8). 07/2009; 6(3):213-23. DOI: 10.2174/156720509788486527
Source: PubMed

ABSTRACT In different clinical studies, an association of type 2 diabetes and Alzheimer's 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 beta-amyloid(Abeta)(1-42) toxicity. Cell based experiments suggest a specific role for the IGF 1/IRS-2 signaling pathway in regulating alpha-/beta-secretase activity. Moreover circulating IGF-1 might influence Abeta clearance from the brain by promoting Abeta 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 Abeta 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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    • "Several candidate proteins have been proposed to bridge the pathophysiological link between the two conditions. The major mechanism through which T2DM may influence AD includes central insulin resistance, which leads to reduced sensitivity to insulin in the brain, resulting in hyperinsulinemia , impaired insulin receptor (IR) signaling, and glucose toxicity (Freude et al., 2009; Han and Li, 2010). T2DM mediated hyperinsulinemic/hypoglycemic episodes may produce long-term changes in brain vasculature, cellular toxicity including inflammation and oxidative stress, alternations in Aβ levels, tau phosphorylation , neurodegeneration, and cognitive impairment, thus facilitating AD onset. "
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    • "Previous studies showed that serum IGF1 levels are significantly still lower in AD patients than in patients with vascular dementia or age-matched non-demented elderly subjects [2] [23] [29]. IGF1 mediated signals might be involved in regulation of tau phosphorylation, amyloid precursor protein (APP) cleavage, ␤-amyloid (A␤) transport, and degradation as well as memory formation, aging and longevity [13]. Compelling biological data reveals effects of IGF1 on molecular and cellular mechanisms underlying the pathology of AD. "
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    • "An interesting recent study looked at the role of protein homeostasis in longevity (Alavez et al., 2011). C. elegans is a preferred system to study ageing and genetic determinants in longevity which again informs on susceptibility to neurodegeneration (Freude et al., 2009; Reis-Rodrigues et al., 2012). It was found that small molecules such as thioflavin T (ThT), a dye traditionally used in histopathology to stain amyloid in tissues, not only slowed protein aggregation in vitro and in cell culture, but also profoundly extended the lifespan and slowed ageing in C. elegans via regulators of protein homeostasis (Alavez et al., 2011). "
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