The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: From model organisms to human disease
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.
- SourceAvailable from: Wen Fu
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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. "
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.Frontiers in Aging Neuroscience 08/2013; 5:42. DOI:10.3389/fnagi.2013.00042 · 2.84 Impact Factor
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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   . 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. "
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.Neuroscience Letters 10/2012; 531(1). DOI:10.1016/j.neulet.2012.10.015 · 2.06 Impact Factor
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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). "
ABSTRACT: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are complex human brain disorders that affect an increasing number of people worldwide. With the identification first of the proteins that aggregate in AD and FTLD brains and subsequently of pathogenic gene mutations that cause their formation in the familial cases, the foundation was laid for the generation of animal models. These recapitulate essential aspects of the human conditions; expression of mutant forms of the amyloid-β protein-encoding APP gene in mice reproduces amyloid-β (Aβ) plaque formation in AD, while that of mutant forms of the tau-encoding microtubule-associated protein tau (MAPT) gene reproduces tau-containing neurofibrillary tangle formation, a lesion that is also prevalent in FTLD-Tau. The mouse models have been complemented by those in lower species such as C. elegans or Drosophila, highlighting the crucial role for Aβ and tau in human neurodegenerative disease. In this review, we will introduce selected AD/FTLD models and discuss how they were instrumental, by identifying deregulated mRNAs, miRNAs and proteins, in dissecting pathogenic mechanisms in neurodegenerative disease. We will discuss some recent examples, which includes miRNA species that are specifically deregulated by Aβ, mitochondrial proteins that are targets of both Aβ and tau, and the nuclear splicing factor SFPQ that accumulates in the cytoplasm in a tau-dependent manner. These examples illustrate how a functional genomics approach followed by a careful validation in experimental models and human tissue leads to a deeper understanding of the pathogenesis of AD and FTLD and ultimately, may help in finding a cure.Frontiers in Physiology 08/2012; 3:320. DOI:10.3389/fphys.2012.00320 · 3.50 Impact Factor