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: Isabelle Virard[Show abstract] [Hide abstract]
ABSTRACT: Background The 5XFAD early onset mouse model of Alzheimer’s disease (AD) is gaining momentum. Behavioral, electrophysiological and anatomical studies have identified age-dependent alterations that can be reminiscent of human AD. However, transcriptional changes during disease progression have not yet been investigated. To this end, we carried out a transcriptomic analysis on RNAs from the neocortex and the hippocampus of 5XFAD female mice at the ages of one, four, six and nine months (M1, M4, M6, M9). Results Our results show a clear shift in gene expression patterns between M1 and M4. At M1, 5XFAD animals exhibit region-specific variations in gene expression patterns whereas M4 to M9 mice share a larger proportion of differentially expressed genes (DEGs) that are common to both regions. Analysis of DEGs from M4 to M9 underlines the predominance of inflammatory and immune processes in this AD mouse model. The rise in inflammation, sustained by the overexpression of genes from the complement and integrin families, is accompanied by an increased expression of transcripts involved in the NADPH oxidase complex, phagocytic processes and IFN-γ related pathways. Conclusions Overall, our data suggest that, from M4 to M9, sustained microglial activation becomes the predominant feature and point out that both detrimental and neuroprotective mechanisms appear to be at play in this model. Furthermore, our study identifies a number of genes already known to be altered in human AD, thus confirming the use of the 5XFAD strain as a valid model for understanding AD pathogenesis and for screening potential therapeutic molecules.Molecular Neurodegeneration 09/2014; 9(1):33. DOI:10.1186/1750-1326-9-33 · 5.29 Impact Factor
Article: Sirtuins[Show abstract] [Hide abstract]
ABSTRACT: Heart failure is the leading contributor of human morbidity and mortality in the developed world 1. Although a number of risk factors have been recognized for heart failure, the molecular mechanisms contributing to the initiation of heart failure are incompletely understood 2. Recent studies have demonstrated that heart failure can be prevented or reverted, at least in experimental models, by caloric restriction, a dietary regimen that limits calorie intake 3–5. The health benefits of calorie restriction are thought to be mediated by a family of NAD-dependent deacetylases called sirtuins. The mam-malian genome encodes seven ubiquitously expressed sirtuin isoforms (SIRT1–SIRT7), which are emerging as key regulators of a myriad of biological functions, ranging from cell growth to lifespan extension 6. Among the sirtuins, SIRT6, a chromatin-associated deacetylase, is considered to have a leading role in regulating genomic stability, cellular metabolism, stress response and aging 7–12. SIRT6 deacetylates H3K9 and acts as a transcriptional co-repressor of NF-κB and hypoxia inducible factor-1α (HIF-1α) target genes in a tissue-and context-dependent manner 8,10,13. SIRT6-deficient mice show severe hypoglycemia and a multisystemic accelerated aging phenotype and die at around 26 d after birth 12. The hypoglycemia of SIRT6-deficient mice seems to result from increased activity of HIF-1α target genes and increased glucose uptake by multiple organs 13,14. However, neither correction of hypoglycemia by feeding mice with glucose nor reduced NF-κB signaling could completely rescue the lethality of SIRT6-deficient mice, suggesting that additional mechanisms must contribute to the mutant phenotype of SIRT6-deficient mice 8,14. Mammalian aging and aging-associated diseases have been shown to be associated with dysregulation of IGF-Akt signaling 15. In the heart, although short-term activation of IGF-Akt signaling promotes physiologic growth, sustained hyperactivation leads to the development of pathologic hypertrophy and heart failure 16,17. Although much is known about the positive activators of this pathway, very little is known about the endogenous negative regulators, which might have potential to block the IGF-Akt pathway and protect the heart from developing heart failure. In this study, we show that SIRT6 directly controls IGF-Akt signal-ing at the level of chromatin through c-Jun, a stress-responsive transcription factor, and deacetylation of H3K9. Our findings also demonstrate that SIRT6 deficiency induces hyperactivation of IGF-Akt signaling, which culminates in the development of cardiac hypertrophy and heart failure in mice. RESULTS Loss of SIRT6 induces cardiac hypertrophy and failure To study the role of SIRT6 in the development of heart failure, we first analyzed SIRT6 expression in failing human hearts and in mouse hearts in which we had induced hypertrophy by either surgically creating transverse aortic constriction (TAC) or infusing the hypertrophic agonists
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ABSTRACT: Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer’s disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alarming increase in obesity and T2D in all age groups, understanding the relationship between MetS and AD is vital for the identification of potential therapeutic targets. Recently, several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in AD and dementia. In this review, we will discuss MetS as a risk factor for AD, focusing on IR and the recent progress and future directions of insulin-based therapies.03/2015; 47(3):e149. DOI:10.1038/emm.2015.3