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Insulin resistance: an emerging link in Alzheimer’s disease

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Abstract

Relentless progression of Alzheimer’s disease (AD) poses a grave situation for the biomedical community to tackle. Agents starting as hot favorites in clinical trials have failed in later stages and it is time we reconsidered our approaches to intervene the disease. Quite some interesting work in the last decade has introduced a new school of thought which factors in neuronal glycemic imbalance as a major component for the development of AD. Insulin resistance in the brain has brought forward subsequent sequelae which might work towards amyloid accretion and/or tau hyperphosphorylation. It is also pointed out that insulin works by distributing iron to neuronal tissue and an insulin resistant state throws it off gear leading to iron overloading of neurons which is ultimately detrimental. A relatively recent investigation finds the role of c-Jun-N-terminal kinase (JNK3) in AD which also seems to bear a link with insulin resistance.

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References

  1. Brookmeyer R, Jhonson E, Zieglr-Graham K, Arrighi HM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement 3:186–191

    Article  PubMed  Google Scholar 

  2. Cllaway E (2012) Alzheimer’s drug take a new track. Nature 489:13–14

    Article  Google Scholar 

  3. Burns JM, Donnelly JE, Anderson HS, Mayo MS, Spencer-Gardner L, Thomas G (2007) Peripheral insulin and brain structure in early Alzheimer’s disease. Neurology 69:1094–1104

    Article  PubMed  CAS  Google Scholar 

  4. Erol A (2008) An integrated and unifying hypothesis for the metabolic basis of sporadic Alzheimer’s disease. J Alzheimers Dis 13:241–253

    PubMed  CAS  Google Scholar 

  5. Hopkins DFC, Williams G (1997) Insulin receptors are widely distributed in human brain and bind human and porcine insulin with equal affinity. Diabet Med 14:1044–1050

    Article  PubMed  CAS  Google Scholar 

  6. Adamo M, LeRoith D, Simon J, Roth J (1989) Effect of altered nutritional states on insulin receptors. Annu Rev Nutr 8:149–166

    Article  Google Scholar 

  7. Russo VC, Gluckman PD, Feldman EL, Werther GA (2005) The insulin-like growth factor system and its pleiotropic functions in brain. Endocrinol Rev 26:916–943

    Article  CAS  Google Scholar 

  8. Chiu SL, Cline HT (2010) Insulin receptor signalling in the development of neuronal structure and function. Neural Dev 5:1–18

    Article  Google Scholar 

  9. Zhao W, Wu X, Xie H, Ke Y, Yung WH (2010) Permissive role of insulin in the expression of long-term potentiation in the hippocampus of immature rats. Neurosignals 18:236–245

    Article  PubMed  CAS  Google Scholar 

  10. Wang X, Zheng W, Xie JW, Wang T, Wang SL, Teng WP, Wang ZY (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioural deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 2:46

    Article  CAS  Google Scholar 

  11. Kahn CR, Suzuki R (2010) Diabetes, insulin and Alzheimer’s disease. In: Craft S, Christen Y (eds) Research and perspective in Alzheimer’s disease. Springer, Heidelberg, pp 1–21

    Google Scholar 

  12. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX (2011) Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol 225:54–62

    Article  PubMed  CAS  Google Scholar 

  13. Gasparini L, Netzer WJ, Greengard P, Xu H (2002) Does insulin dysfunction play a role in Alzheimer’s disease? Trends Pharmacol Sci 23:288–293

    Article  PubMed  CAS  Google Scholar 

  14. Johnston AM, Pirola L, Van Obberghen E (2003) Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signalling. FEBS Lett 546:32–36

    Article  PubMed  CAS  Google Scholar 

  15. Van der Heide LP, Ramakers GMJ, Smidt MP (2006) Insulin signalling in the central nervous system: learning to survive. Prog Neurobiol 79:205–221

    Article  PubMed  Google Scholar 

  16. Johnston AM, Pirola L, Van Obberghen E (2003) Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signalling. FEBS Lett 546:32–36

    Article  PubMed  CAS  Google Scholar 

  17. McEwen BS, Reagan LP (2004) Glucose transporter expression in the central nervous system: relationship to synaptic function. Eur J Pharmacol 19:13–24

    Article  Google Scholar 

  18. Cross DAE, Culbert AA, Chalmers KA, Facci L, Skaper SD, Reith AD (2001) Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death. J Neurochem 77:94–102

    Article  PubMed  CAS  Google Scholar 

  19. Phiel Christopher J, Wilson Christina A, Lee Virginia M-Y, Klein Peter S (2011) GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides. Nature 423:435–439

    Article  Google Scholar 

  20. Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H (2001) Stimulation of beta amyloid precursor protein by insulin reduces intra neuronal beta amyloid and requires mitogen activated protein kinase signalling. J Neurosci 21:2561–2570

    PubMed  CAS  Google Scholar 

  21. Dou JT, Chen M, Dufour F, Alkon DL, Zhao WQ (2005) Insulin receptor signalling in long-term memory consolidation following spatial learning. Learn Mem 12:646–655

    Article  PubMed  Google Scholar 

  22. Sheng M, Kim MJ (2002) Postsynaptic signalling and plasticity mechanisms. Science 25:776–780

    Article  Google Scholar 

  23. Park CR (2001) Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 25:311–323

    Article  PubMed  CAS  Google Scholar 

  24. Zhao WQ, Chen H, Quon MJ, Alkon DL (2004) Insulin and insulin receptors in experimental models of learning and memory. Eur J Pharmacol 490:71–81

    Article  PubMed  CAS  Google Scholar 

  25. Katakam PV, Tulbert CD, Snipes JA, Erdos B, Miller AW, Busija DW (2005) Impaired insulin induced vasodilatation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species. Am J Physiol Heart Circ Physiol 288:H854–H860

    Article  PubMed  CAS  Google Scholar 

  26. Craft S (2009) The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol 66:300–305

    Article  PubMed  Google Scholar 

  27. Zao WQ, Dl Alkon (2001) Role of insulin and insulin receptor in learning and memory. Mol Cell Endocrinol 177:125–134

    Article  Google Scholar 

  28. Dou JJ, Chen M, Dufour F, Alkon DL, Zao WQ (2005) Insulin receptor signalling in long term memory consolidation following spatial learning. Learn Mem 12:646–655

    Article  PubMed  Google Scholar 

  29. Scautam D, Surjo D, Ueki K, Baudler S, Schubert D et al (2004) Role for neuronal insulin resistance in neurodegenerative diseases. Proc Nat Acad Sci 101:3100–3105

    Article  Google Scholar 

  30. Chen L, Magliano DJ, Zimmet PZ (2011) The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol 8:228–236

    Article  PubMed  Google Scholar 

  31. McCrimmon RJ, Ryan CM, Frier BM (2012) Diabetes and cognitive dysfunction. Lancet 379:2291–2299

    Article  PubMed  Google Scholar 

  32. Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Berne C, Lannfelt L, Kilander L (2008) Impaired insulin secretion increases the risk of Alzheimer disease. Neurology 71:1065–1071

    Article  PubMed  Google Scholar 

  33. Hassing LB, Hofer SM, Nilsson SE, Berg S, Pedersen NL, McClearn G, Johansson B (2004) Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study. Age Ageing 33:355–361

    Article  PubMed  Google Scholar 

  34. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV (2009) Hypoglycaemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 301:1565–1572

    Article  PubMed  CAS  Google Scholar 

  35. Weiss R, Dufour S, Taksali SE, Tambortlane WV, Petersen KF, Bonadonna RC, Boselli L, Barbetta G, Alle K, Rife F, Savoye M, Dziura J, Sherwin R, Shulman R, Caprio S (2003) Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Lancet 362:951–957

    Article  PubMed  CAS  Google Scholar 

  36. Small GW, Ercoli LM, Silverman DH et al (2000) Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease. Proc Natl Acad Sci 97(11):6037–6042

    Article  PubMed  CAS  Google Scholar 

  37. Rasgon NL, Kenna HA, Wroolie TE et al (2011) Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging 32:1942–1948

    Article  PubMed  CAS  Google Scholar 

  38. Forlich L, Blum- Degen D, Bernstein HG, Engelsberger S, Humrich J, Lauffer S, Muschner D et al (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Transm 105:423–438

    Article  Google Scholar 

  39. Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl 72:217–233

    Article  PubMed  CAS  Google Scholar 

  40. Unoki H, Yamagishi S (2008) Advanced glycation end products and insulin resistance. Curr Pharm Des 14:987–989

    Article  PubMed  CAS  Google Scholar 

  41. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774

    Article  PubMed  CAS  Google Scholar 

  42. Pahnke J, Walker LC, Scheffler K, Krohn M (2009) Alzheimer’s disease and blood-brain barrier function—why have anti-β-amyloid therapies failed to prevent dementia progression? Neurosci Biobehav Rev 2009(33):1099–1108

    Article  Google Scholar 

  43. Vogelgesang S et al (2002) Deposition of Alzheimer’s beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 12:535–541

    Article  PubMed  CAS  Google Scholar 

  44. Cirrito JR, Deane R, Fagan AM, Spinner ML, Parsadanian M, Finn MB et al (2005) P-glycoprotein deficiency at the blood–brain barrier increases amyloid-β deposition in an Alzheimer disease mouse model. J Clin Invest 115:3285–3290

    Article  PubMed  CAS  Google Scholar 

  45. Ling S, Zou J, Rudd JA, Hu Z, Fang M (2011) The recent approaches of therapeutic approaches against Aβ for the treatment of Alzheimer’s disease. Anat Rec 294:1307–1318

    Article  CAS  Google Scholar 

  46. Carter TL, Pedrini S, Ghiso J, Ehrlich ME, Gandy S (2006) Brain neprilysin activity and susceptibility to transgene-induced Alzheimer amyloidosis. Neurosci Lett 392:235–239

    Article  PubMed  CAS  Google Scholar 

  47. Hellstrom-Lindahl E, Ravid R, Nordberg A (2006) Age-dependent decline of neprilysin in Alzheimer’s disease and normal brain: inverse correlation with Aβ levels. Neurobiol Aging 29(2):210–221

    Article  PubMed  Google Scholar 

  48. Devi L, Alldred Melissa J, Ginsberg SD, Ohno M (2012) Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer’s disease. PLoS ONE 7:e32792

    Article  PubMed  CAS  Google Scholar 

  49. Gong CX, Liu F, Grundke-iqbal I, Iqbal K (2006) Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. J Alzheimer’s Dis 9(1):1–12

    CAS  Google Scholar 

  50. Goto I, Taniwaki T, Hosokawa S, Otsuka M, Ichiya Y, Ichimiya A (1993) Positron emission tomographic (PET) studies in dementia. J Neurol Sci 114:1–6

    Article  PubMed  CAS  Google Scholar 

  51. Loring JF, Wen X, Lee JM, Seilhamer J, Somogyi R (2001) A gene expression profile of Alzheimer’s disease. DNA Cell Biol 20:683–695

    Article  PubMed  CAS  Google Scholar 

  52. Gerozissis K (2003) Brain insulin: regulation, mechanisms of action, and functions. Cell Mol Neurobiol 23(4–5):873–874

    Article  Google Scholar 

  53. Ishiguro K, Shiratsuchi A, Sato S et al (1993) Glycogen synthase kinase 3β is identical to tau protein kinase I generating several epitopes of paired helical filaments. FEBS Lett 325:167–172

    Article  PubMed  CAS  Google Scholar 

  54. Hong M, Lee VMY (1997) Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 272:19547–19553

    Article  PubMed  CAS  Google Scholar 

  55. Wells L, Whelan SA, Hart GW (2003) O-GlcNAc: a regulatory post-translational modification. Biochem Biophys Res Commun 302:435–441

    Article  PubMed  CAS  Google Scholar 

  56. Gong CX, Liu F, Iqbal IG, Iqbal K (2006) Impaired brain glucose metabolism leads to Alzheimer’s neurofibrillary neurodegeneration through a decrease in Tau-O-GlcNacylation. J Alzheimers Dis 9:1–12

    PubMed  CAS  Google Scholar 

  57. Jahanshad N, Kohannim O, Hibar DP, Stein JL, McMahon KL, de Zubicaray GI, Medland SE, Montgomery GW, Whitfield JB, Martin NG, Wright MJ, Toga AW, Thompson PM (2012) Brain structure in healthy adults is related to serum transferrin and the H63D polymorphism in the HFE gene. Proc Natl Acad Sci USA 3(109):E851–E859

    Article  Google Scholar 

  58. Connor JR, Menzies SL, St Martin SM, Mufson EJ (1992) A histochemical study of iron, transferrin, and ferritin in Alzheimer’s diseased brains. J Neurosci Res 31:75–83

    Article  PubMed  CAS  Google Scholar 

  59. O’Donnell MJ, Watson J, Martin P, Chapman C, Barnett AH (1991) Transferrinuria in type 2 diabetes: the effect of glycaemic control. Ann Clin Biochem 28:174–178

    PubMed  Google Scholar 

  60. Swaminathan S, Alam MG, Fonseca VA, Shah SV (2007) The role of iron in diabetes and its complications. Diabetes Care 30:1926–1933

    Article  PubMed  CAS  Google Scholar 

  61. Fernández-Real JM (2008) Insulin resistance and atherosclerosis. The impact of oxidative stress on endothelial function. Rev Esp Cardiol 8(Suppl C):42–49

    Google Scholar 

  62. Tanner LI, Lienhard GE (1987) Insulin elicits a redistribution of transferrin receptors in 3T3-L1 adipocytes through an increase in the rate constant for receptor externalization. J Biol Chem 262:8975–8980

    PubMed  CAS  Google Scholar 

  63. Jehn ML, Guallar E, Clark JM, Couper D, Duncan BB, Ballantyne CM et al (2007) A prospective study of plasma ferritin level and incident diabetes. Am J Epidemiol 165:1047–1054

    Article  PubMed  Google Scholar 

  64. Choi KM, Lee KW, Kim HW et al (2005) Association among serum ferritin, alanine aminotransferase levels, and metabolic syndrome in Korean postmenopausal women. Metabolism 54:1510–1514

    Article  PubMed  CAS  Google Scholar 

  65. Abdelli S, Abderrahmani A, Hering BJ, Beckmann JS, Bonny C (2007) The c-Jun N-terminal kinase JNK participates in cytokine- and isolation stress-induced rat pancreatic islet apoptosis. Diabetologia 50:1660–1669

    Article  PubMed  CAS  Google Scholar 

  66. Gupta S, Barrett T, Whitmarsh AJ, Cavanagh J, Sluss HK et al (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15:2760–2770

    PubMed  CAS  Google Scholar 

  67. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  PubMed  CAS  Google Scholar 

  68. Fowler AE, da Silva NF, Burman C, Harte AL, McTernan PG, Kumar S (2004) Increased C-jun N terminal kinase (JNK) activity may link insulin resistance and inflammation in human central obesity. Endocr Abstr 7:49

    Google Scholar 

  69. Yoon SO, Park DJ, Ryu JC, Ozer HC, Tep C, Shin YJ et al (2012) JNK3 perpetuates metabolic stress induced by Aβ peptides. Neuron 75:824–837

    Article  PubMed  CAS  Google Scholar 

  70. Duarte AI, Moreira PI, Oliveira CR. (2012) Insulin in CNS: more than just a peripheral hormone. J Aging Res 1–21

  71. Salkovic Petrisic M, Laekovic Z (2003) Intracerebroventricular administration of betacytotoxics alters expression of brain monoamine transporter genes. J Neural Transm 110:15–29

    PubMed  CAS  Google Scholar 

  72. Talbot K, Wang HY, Kazi M, Han LY, Bakshi KP, Stucky A, Rl Fuino (2012) Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF 1 resistance, IRS 1 dysfunction, cognitive decline. J Clin Investig 122:1316–1338

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Research Block B, 4th Floor, Room No. 4043, Chandigarh, 160012, India

    Bikash Medhi & Mrinmoy Chakrabarty

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Medhi, B., Chakrabarty, M. Insulin resistance: an emerging link in Alzheimer’s disease. Neurol Sci 34, 1719–1725 (2013). https://doi.org/10.1007/s10072-013-1454-1

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