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: 3.89).
07/2009; 6(3):213-23. DOI: 10.2174/156720509788486527
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.
- "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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ABSTRACT: Amylin (islet amyloid polypeptide) and amyloid-beta (Aβ) protein, which are deposited within pancreatic islets of diabetics and brains of Alzheimer's patients respectively, share many biophysical and physiological properties. Emerging evidence indicates that the amylin receptor is a putative target receptor for the actions of human amylin and Aβ in the brain. The amylin receptor consists of the calcitonin receptor dimerized with a receptor activity-modifying protein and is widely distributed within central nervous system. Both amylin and Aβ directly activate this G protein-coupled receptor and trigger multiple common intracellular signal transduction pathways that can culminate in apoptotic cell death. Moreover, amylin receptor antagonists can block both the biological and neurotoxic effects of human amylin and Aβ. Amylin receptors thus appear to be involved in the pathophysiology of Alzheimer's disease and diabetes, and could serve as a molecular link between the two conditions that are associated epidemiologically.
Available from: Eric B Dammer
- "Finally, insulin signaling has been linked to AD pathogenesis in multiple studies, where insulin-like growth factor 1 receptor (IGF1R) expression and signaling decreases in AD brain. IGF1R signaling has been shown to reverse amyloid beta toxicity, perhaps via regulation of amyloid precursor cleavage . IGF1R also significantly decreased 74% in the AD platelet membrane pools. "
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Peripheral biomarkers to diagnose Alzheimer's disease (AD) have not been established. Given parallels between neuron and platelet biology, we hypothesized platelet membrane-associated protein changes may differentiate patients clinically defined with probable AD from noncognitive impaired controls.
Purified platelets, confirmed by flow cytometry were obtained from individuals before fractionation by ultracentrifugation. Following a comparison of individual membrane fractions by SDS-PAGE for general proteome uniformity, equal protein weight from the membrane fractions for five representative samples from AD and five samples from controls were pooled. AD and control protein pools were further divided into molecular weight regions by one-dimensional SDS-PAGE, prior to digestion in gel. Tryptic peptides were analyzed by reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Ionized peptide intensities were averaged for each identified protein in the two pools, thereby measuring relative protein abundance between the two membrane protein pools. Log2-transformed ratio (AD/control) of protein abundances fit a normal distribution, thereby permitting determination of significantly changed protein abundances in the AD pool.
We report a comparative analysis of the membrane-enriched platelet proteome between patients with mild to moderate AD and cognitively normal, healthy subjects. A total of 144 proteins were determined significantly altered in the platelet membrane proteome from patients with probable AD. In particular, secretory (alpha) granule proteins were dramatically reduced in AD. Of these, we confirmed significant reduction of thrombospondin-1 (THBS1) in the AD platelet membrane proteome by immunoblotting. There was a high protein-protein connectivity of proteins in other pathways implicated by proteomic changes to the proteins that define secretory granules.
Depletion of secretory granule proteins is consistent with a preponderance of post-activated platelets in circulation in AD. Significantly changed pathways implicate additional AD-related defects in platelet glycoprotein synthesis, lipid homeostasis, amyloidogenic proteins, and regulators of protease activity, many of which may be useful plasma membrane-expressed markers for AD. This study highlights the utility of LC-MS/MS to quantify human platelet membrane proteins and suggests that platelets may serve as a source of blood-based biomarkers in neurodegenerative disease.
Available from: Jin-Tai Yu
- "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   . 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 . Compelling biological data reveals effects of IGF1 on molecular and cellular mechanisms underlying the pathology of AD. "
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ABSTRACT: A review of pathogenic findings in Alzheimer's brains and the functional consequences of altered insulin-like growth factor 1 (IGF1) input to the brain suggest the association between Alzheimer's disease (AD) and the disrupted IGF1 signaling. Recently, the identification of polymorphism rs972936 that was associated with both an increased risk of AD and high circulating levels of IGF1 was reported in Southern European population. In order to evaluate the involvement of the IGF1 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (794 LOAD cases and 796 controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P=0.006, allele P=0.047). The T allele of rs972936 demonstrated a 1.16-fold risk for developing LOAD when compared with the C allele, which diverges to the report in the Caucasian population. After stratification by apolipoprotein E (APOE) ɛ4-carrying status, rs972936 polymorphism was only significantly associated with LOAD in non-ApoE ɛ4 allele carriers (genotype P=0.002, allele P=0.039). Multivariate logistic regression analysis also conferred this positive association between the SNP rs972936 and LOAD in the recessive and additive model after adjustment for age, gender, and the ApoE ɛ4 carrier status. These results suggest that IGF1 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population.
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