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Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress

Abstract

Oxidative stress is an important determinant not only in the pathogenesis of Alzheimer's disease (AD), but also in insulin resistance (InsRes) and diabetic complications. Forkhead box class O (FoxO) transcription factors are involved in both insulin action and the cellular response to oxidative stress, thereby providing a potential integrative link between AD and InsRes. For example, the expression of intra- and extracellular antioxidant enzymes, such as manganese-superoxide dismutase and selenoprotein P, is regulated by FoxO proteins, as is the expression of important hepatic enzymes of gluconeogenesis. Here, we review the molecular mechanisms involved in the pathogenesis of AD and InsRes and discuss the function of FoxO proteins in these processes. Both InsRes and oxidative stress may promote the transcriptional activity of FoxO proteins, resulting in hyperglycaemia and a further increased production of reactive oxygen species (ROS). The consecutive activation of c-Jun N-terminal kinases and inhibition of Wingless (Wnt) signalling may result in the formation of β-amyloid plaques and τ protein phosphorylation. Wnt inhibition may also result in a sustained activation of FoxO proteins with induction of apoptosis and neuronal loss, thereby completing a vicious circle from oxidative stress, InsRes and hyperglycaemia back to the formation of ROS and consecutive neurodegeneration. In view of their central function in this model, FoxO proteins may provide a potential molecular target for the treatment of both InsRes and AD.

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References

  1. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P . Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 2006; 5: 64–74.

    Article  PubMed  Google Scholar 

  2. Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC . Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004; 53: 474–481.

    Article  CAS  PubMed  Google Scholar 

  3. Sabayan B, Foroughinia F, Mowla A, Borhanihaghighi A . Role of insulin metabolism disturbances in the development of Alzheimer disease: mini review. Am J Alzheimers Dis Other Demen 2008; 23: 192–199.

    Article  PubMed  Google Scholar 

  4. Brownlee M . The pathobiology of diabetic complications: a unifying mechanism. Diabetes 2005; 54: 1615–1625.

    Article  CAS  PubMed  Google Scholar 

  5. Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A . Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 2009; 89: 27–71.

    Article  CAS  PubMed  Google Scholar 

  6. Barthel A, Schmoll D, Unterman TG . FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab 2005; 16: 183–189.

    Article  CAS  PubMed  Google Scholar 

  7. Glenner GG, Wong CW . Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885–890.

    Article  CAS  PubMed  Google Scholar 

  8. Wong CW, Quaranta V, Glenner GG . Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. Proc Natl Acad Sci USA 1985; 82: 8729–8732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pastorino L, Lu KP . Pathogenic mechanisms in Alzheimer's disease. Eur J Pharmacol 2006; 545: 29–38.

    Article  CAS  PubMed  Google Scholar 

  10. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI . Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83: 4913–4917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Daly NL, Hoffmann R, Otvos Jr L, Craik DJ . Role of phosphorylation in the conformation of tau peptides implicated in Alzheimer's disease. Biochemistry 2000; 39: 9039–9046.

    Article  CAS  PubMed  Google Scholar 

  12. Mandelkow EM, Stamer K, Vogel R, Thies E, Mandelkow E . Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses. Neurobiol Aging 2003; 24: 1079–1085.

    Article  CAS  PubMed  Google Scholar 

  13. Chun W, Johnson GVW . The role of tau phosphorylation and cleavage in neuronal cell death. Front Biosci 2007; 12: 733–756.

    Article  CAS  PubMed  Google Scholar 

  14. Muyllaert D, Terwel D, Kremer A, Sennvik K, Borghgraef P, Devijver H et al. Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice—a model for hippocampal sclerosis and neocortical degeneration. Am J Pathol 2008; 172: 470–485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Camins A, Verdaguer E, Folch J, Canudas AM, Pallas M . The role of CDK5/P25 formation/inhibition in neurodegeneration. Drug News Perspect 2006; 19: 453–460.

    Article  CAS  PubMed  Google Scholar 

  16. Markesbery WR, Carney JM . Oxidative alterations in Alzheimer's disease. Brain Pathol 1999; 9: 133–146.

    Article  CAS  PubMed  Google Scholar 

  17. Beal MF . Oxidatively modified proteins in aging and disease. Free Radic Biol Med 2002; 32: 797–803.

    Article  CAS  PubMed  Google Scholar 

  18. Dias-Santagata D, Fulga TA, Duttaroy A, Feany MB . Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J Clin Invest 2007; 117: 236–245.

    Article  CAS  PubMed  Google Scholar 

  19. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457–461.

    Article  PubMed  CAS  Google Scholar 

  20. Shen C, Chen Y, Liu H, Zhang K, Zhang T, Lin A et al. Hydrogen peroxide promotes Abeta production through JNK-dependent activation of gamma-secretase. J Biol Chem 2008; 283: 17721–17730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tabner BJ, El-Agnaf OM, Turnbull S, German MJ, Paleologou KE, Hayashi Y et al. Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia. J Biol Chem 2005; 280: 35789–35792.

    Article  CAS  PubMed  Google Scholar 

  22. de la Monte SM, Wands JR . Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. J Alzheimers Dis 2006; 9: 167–181.

    Article  PubMed  Google Scholar 

  23. Montine TJ, Neely MD, Quinn JF, Beal MF, Markesbery WR, Roberts LJ et al. Lipid peroxidation in aging brain and Alzheimer's disease. Free Radic Biol Med 2002; 33: 620–626.

    Article  CAS  PubMed  Google Scholar 

  24. Kruman I, Bruce-Keller AJ, Bredesen D, Waeg G, Mattson MP . Evidence that 4-hydroxynonenal mediates oxidative stress-induced neuronal apoptosis. J Neurosci 1997; 17: 5089–5100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Siegel SJ, Bieschke J, Powers ET, Kelly JW . The oxidative stress metabolite 4-hydroxynonenal promotes Alzheimer protofibril formation. Biochemistry 2007; 46: 1503–1510.

    Article  CAS  PubMed  Google Scholar 

  26. Choi J, Sullards MC, Olzmann JA, Rees HD, Weintraub ST, Bostwick DE et al. Oxidative damage of DJ-1 is linked to sporadic Parkinson and Alzheimer diseases. J Biol Chem 2006; 281: 10816–10824.

    Article  CAS  PubMed  Google Scholar 

  27. Kaestner KH, Knochel W, Martinez DE . Unified nomenclature for the winged helix/forkhead transcription factors. Genes Dev 2000; 14: 142–146.

    CAS  PubMed  Google Scholar 

  28. Kaufmann E, Knochel W . Five years on the wings of fork head. Mech Dev 1996; 57: 3–20.

    Article  CAS  PubMed  Google Scholar 

  29. Hatta M, Cirillo LA . Chromatin opening and stable perturbation of core histone: DNA contacts by FoxO1. J Biol Chem 2007; 282: 35583–35593.

    Article  CAS  PubMed  Google Scholar 

  30. van der Heide LP, Hoekman MFM, Smidt MP . The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J 2004; 380: 297–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nakae J, Oki M, Cao Y . The FoxO transcription factors and metabolic regulation. FEBS Lett 2008; 582: 54–67.

    Article  CAS  PubMed  Google Scholar 

  32. Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP . FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 2003; 278: 35959–35967.

    Article  CAS  PubMed  Google Scholar 

  33. Hoekman MF, Jacobs FM, Smidt MP, Burbach JP . Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain. Gene Expr Patterns 2006; 6: 134–140.

    Article  CAS  PubMed  Google Scholar 

  34. Nakae J, Park BC, Accili D . Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem 1999; 274: 15982–15985.

    Article  CAS  PubMed  Google Scholar 

  35. Rena G, Prescott AR, Guo S, Cohen P, Unterman TG . Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14–3–3 binding, transactivation and nuclear targetting. Biochem J 2001; 354: 605–612.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rena G, Woods YL, Prescott AR, Peggie M, Unterman TG, Williams MR et al. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J 2002; 21: 2263–2271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci USA 2005; 102: 1649–1654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A . Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA 2003; 100: 11285–11290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Manolagas SC, Almeida M . Gone with the Wnts: beta-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol Endocrinol 2007; 21: 2605–2614.

    Article  CAS  PubMed  Google Scholar 

  40. Greer EL, Brunet A . FOXO transcription factors in ageing and cancer. Acta Physiol (Oxf) 2008; 192: 19–28.

    Article  CAS  Google Scholar 

  41. Schinner S, Scherbaum WA, Bornstein SR, Barthel A . Molecular mechanisms of insulin resistance. Diabet Med 2005; 22: 674–682.

    Article  CAS  PubMed  Google Scholar 

  42. Barthel A, Schmoll D . Novel concepts in insulin regulation of hepatic gluconeogenesis. Am J Physiol Endocrinol Metab 2003; 285: E685–E692.

    Article  CAS  PubMed  Google Scholar 

  43. Lenaz G, Baracca A, Fato R, Genova ML, Solaini G . New insights into structure and function of mitochondria and their role in aging and disease. Antioxid Redox Signal 2006; 8: 417–437.

    Article  CAS  PubMed  Google Scholar 

  44. Decoursey TE, Ligeti E . Regulation and termination of NADPH oxidase activity. Cell Mol Life Sci 2005; 62: 2173–2193.

    Article  CAS  PubMed  Google Scholar 

  45. Barthel A, Klotz LO . Phosphoinositide 3-kinase signaling in the cellular response to oxidative stress. Biol Chem 2005; 386: 207–216.

    Article  CAS  PubMed  Google Scholar 

  46. Linnane AW, Kios M, Vitetta L . Healthy aging: regulation of the metabolome by cellular redox modulation and prooxidant signaling systems: the essential roles of superoxide anion and hydrogen peroxide. Biogerontology 2007; 8: 445–467.

    Article  CAS  PubMed  Google Scholar 

  47. Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 2002; 419: 316–321.

    Article  CAS  PubMed  Google Scholar 

  48. Nemoto S, Finkel T . Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 2002; 295: 2450–2452.

    Article  CAS  PubMed  Google Scholar 

  49. Walter PL, Steinbrenner H, Barthel A, Klotz LO . Stimulation of selenoprotein P promoter activity in hepatoma cells by FoxO1a transcription factor. Biochem Biophys Res Commun 2008; 365: 316–321.

    Article  CAS  PubMed  Google Scholar 

  50. Speckmann B, Walter PL, Alili L, Reinehr R, Sies H, Klotz LO et al. Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors. Hepatology 2008; 48: 1998–2006.

    Article  CAS  PubMed  Google Scholar 

  51. Bejsovec A . Wnt pathway activation: new relations and locations. Cell 2005; 120: 11–14.

    CAS  PubMed  Google Scholar 

  52. Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL . Increased lipid oxidation causes oxidative stress, increased peroxisome proliferator-activated receptor-gamma expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem 2009; 284: 27438–27448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC . Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 2005; 308: 1181–1184.

    Article  CAS  PubMed  Google Scholar 

  54. Hoogeboom D, Essers MAG, Polderman PE, Voets E, Smits LMM, Burgering BMT . Interaction of FOXO with {beta}-catenin inhibits {beta}-catenin/T cell factor activity. J Biol Chem 2008; 283: 9224–9230.

    Article  CAS  PubMed  Google Scholar 

  55. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999; 96: 857–868.

    Article  CAS  PubMed  Google Scholar 

  56. Reif K, Burgering BM, Cantrell DA . Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase. J Biol Chem 1997; 272: 14426–14433.

    Article  CAS  PubMed  Google Scholar 

  57. Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM et al. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 2002; 168: 5024–5031.

    Article  CAS  PubMed  Google Scholar 

  58. Schmidt M, de Mattos SF, van der Horst A, Klompmaker R, Kops G, Lam EWF et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol Cell Biol 2002; 22: 7842–7852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. de Mattos SF, Essafi A, Soeiro I, Pietersen AM, Birkenkamp KU, Edwards CS et al. FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism. Mol Cell Biol 2004; 24: 10058–10071.

    Article  CAS  Google Scholar 

  60. Buteau J, Accili D . Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. Diabetes Obes Metab 2007; 9: 140–146.

    Article  CAS  PubMed  Google Scholar 

  61. Martinez SC, Tanabe K, Cras-Meneur C, Abumrad NA, Bernal-Mizrachi E, Permutt MA . Inhibition of Foxo1 protects pancreatic islet beta-cells against fatty acid and endoplasmic reticulum stress-induced apoptosis. Diabetes 2008; 57: 846–859.

    Article  CAS  PubMed  Google Scholar 

  62. Bellinger FP, He QP, Bellinger MT, Lin Y, Raman AV, White LR et al. Association of selenoprotein p with Alzheimer's pathology in human cortex. J Alzheimers Dis 2008; 15: 465–472.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sompol P, Ittarat W, Tangpong J, Chen Y, Doubinskaia I, Batinic-Haberle I et al. A neuronal model of Alzheimer's disease: an insight into the mechanisms of oxidative stress-mediated mitochondrial injury. Neuroscience 2008; 153: 120–130.

    Article  CAS  PubMed  Google Scholar 

  64. Jope RS, Johnson GV . The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 2004; 29: 95–102.

    Article  CAS  PubMed  Google Scholar 

  65. Liang MH, Chuang DM . Regulation and function of glycogen synthase kinase-3 isoforms in neuronal survival. J Biol Chem 2007; 282: 3904–3917.

    Article  CAS  PubMed  Google Scholar 

  66. Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere CA, Imahori K . Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK)I glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol 1996; 92: 232–241.

    Article  CAS  PubMed  Google Scholar 

  67. Ishizawa T, Sahara N, Ishiguro K, Kersh J, McGowan E, Lewis J et al. Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice. Am J Pathol 2003; 163: 1057–1067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Hooper C, Killick R, Lovestone S . The GSK3 hypothesis of Alzheimer's disease. J Neurochem 2008; 104: 1433–1439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Phiel CJ, Wilson CA, Lee VM, Klein PS . GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides. Nature 2003; 423: 435–439.

    Article  CAS  PubMed  Google Scholar 

  70. Brewster JL, Linseman DA, Bouchard RJ, Loucks FA, Precht TA, Esch EA et al. Endoplasmic reticulum stress and trophic factor withdrawal activate distinct signaling cascades that induce glycogen synthase kinase-3 beta and a caspase-9-dependent apoptosis in cerebellar granule neurons. Mol Cell Neurosci 2006; 32: 242–253.

    Article  CAS  PubMed  Google Scholar 

  71. Smith WW, Norton DD, Gorospe M, Jiang H, Nemoto S, Holbrook NJ et al. Phosphorylation of p66Shc and forkhead proteins mediates Abeta toxicity. J Cell Biol 2005; 169: 331–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yuan Z, Lehtinen M, Merlo P, Villén J, Gygi S, Bonni A . Regulation of neuronal cell death by MST1-FOXO1 signaling. J Biol Chem 2009; 284: 11285–11292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Troy CM, Rabacchi SA, Xu Z, Maroney AC, Connors TJ, Shelanski ML et al. Beta-amyloid-induced neuronal apoptosis requires c-Jun N-terminal kinase activation. J Neurochem 2001; 77: 157–164.

    Article  CAS  PubMed  Google Scholar 

  74. Reynolds CH, Utton MA, Gibb GM, Yates A, Anderton BH . Stress-activated protein kinase/c-jun N-terminal kinase phosphorylates tau protein. J Neurochem 1997; 68: 1736–1744.

    Article  CAS  PubMed  Google Scholar 

  75. Morishima Y, Gotoh Y, Zieg J, Barrett T, Takano H, Flavell R et al. Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand. J Neurosci 2001; 21: 7551–7560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lim JH, Lee HJ, Ho Jung M, Song J . Coupling mitochondrial dysfunction to endoplasmic reticulum stress response: a molecular mechanism leading to hepatic insulin resistance. Cell Signal 2009; 21: 169–177.

    Article  CAS  PubMed  Google Scholar 

  77. Valenti L, Rametta R, Dongiovanni P, Maggioni M, Fracanzani AL, Zappa M et al. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes 2008; 57: 1355–1362.

    Article  CAS  PubMed  Google Scholar 

  78. Cao D, Lu H, Lewis TL, Li L . Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J Biol Chem 2007; 282: 36275–36282.

    Article  CAS  PubMed  Google Scholar 

  79. Neumann KF, Rojo L, Navarrete LP, Farias G, Reyes P, Maccioni RB . Insulin resistance and Alzheimer's disease: molecular links & clinical implications. Curr Alzheimer Res 2008; 5: 438–447.

    Article  CAS  PubMed  Google Scholar 

  80. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003; 100: 4162–4167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Martin B, Mattson MP, Maudsley S . Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev 2006; 5: 332–353.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Granic I, Dolga AM, Nijholt IM, van Dijk G, Eisel UL . Inflammation and NF-kappaB in Alzheimer's disease and diabetes. J Alzheimers Dis 2009; 16: 809–821.

    Article  PubMed  CAS  Google Scholar 

  83. Nicolakakis N, Aboulkassim T, Ongali B, Lecrux C, Fernandes P, Rosa-Neto P et al. Complete rescue of cerebrovascular function in aged Alzheimer's disease transgenic mice by antioxidants and pioglitazone, a peroxisome proliferator-activated receptor gamma agonist. J Neurosci 2008; 28: 9287–9296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Hanyu H, Sato T, Kiuchi A, Sakurai H, Iwamoto T . Pioglitazone improved cognition in a pilot study on patients with Alzheimer's disease and mild cognitive impairment with diabetes mellitus. J Am Geriatr Soc 2009; 57: 177–179.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from the BMBF to the DZD e.V. (FKZ01GI0924); DFG SFB 655 ‘from cells to tissues’ and by the Centre for Regenerative Therapy Dresden (CRTD) to SRB, SFB 728/B3 to LOK and Deutsche Diabetes Gesellschaft to AB.

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Manolopoulos, K., Klotz, LO., Korsten, P. et al. Linking Alzheimer's disease to insulin resistance: the FoxO response to oxidative stress. Mol Psychiatry 15, 1046–1052 (2010). https://doi.org/10.1038/mp.2010.17

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