Insulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links

Journal of Internal Medicine

Volumn 280, Issue 5, 2016, Pages 430-442

  Ribe, E M ^a   Lovestone, S ^a  

^a WARNEFORD HOSPITAL   (United Kingdom)

Author keywords

Alzheimer's disease; beta amyloid; diabetes; inflammation; insulin; tau

Indexed keywords

INSULIN; SOMATOMEDIN C;

AGING; ALZHEIMER DISEASE; BRAIN FUNCTION; DIABETES MELLITUS; DISORDERS OF MITOCHONDRIAL FUNCTIONS; EXPERIMENTAL MODEL; HUMAN; INFLAMMATION; INSULIN METABOLISM; METABOLIC DISORDER; NONHUMAN; OXIDATIVE STRESS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; SYSTEMATIC REVIEW (TOPIC); ANIMAL; BRAIN; COMPLICATION; METABOLISM; MITOCHONDRION; NERVE CELL; NON INSULIN DEPENDENT DIABETES MELLITUS;

AGING; ALZHEIMER DISEASE; ANIMALS; BRAIN; DIABETES MELLITUS, TYPE 2; HUMANS; INFLAMMATION; INSULIN; INSULIN-LIKE GROWTH FACTOR I; MITOCHONDRIA; NEURONS; OXIDATIVE STRESS; SIGNAL TRANSDUCTION;

EID: 84991491919     PISSN: 09546820     EISSN: 13652796     Source Type: Journal    
DOI: 10.1111/joim.12534     Document Type: Review

References (109)

1. de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008; 2: 1101–13.
2. 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.
3. Lu F-P, Lin K-P, Kuo H-K. Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. PLoS ONE 2009; 4: e4144.
4. Cooper C, Sommerlad A, Lyketsos CG, Livingston G. Modifiable predictors of dementia in mild cognitive impairment: a systematic review and meta-analysis. Am J Psychiatry 2015; 172: 323–34.
5. Kloppenborg RP, van den Berg E, Kappelle LJ, Biessels GJ. Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review Eur J Pharmacol 2008; 585: 97–108.
6. van de Vorst IE, Koek HL, de Vries R, Bots ML, Reitsma JB, Vaartjes I. Effect of vascular risk factors and diseases on mortality in individuals with dementia: a systematic review and meta-analysis. J Am Geriatr Soc 2016; 64: 37–46.
7. Chatterjee S, Peters SAE, Woodward M et al. Type 2 diabetes as a risk factor for dementia in women compared with men: a pooled analysis of 2.3 million people comprising more than 100,000 cases of dementia. Diabetes Care 2016; 39: 300–7.
8. Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: a meta-analysis of prospective observational studies. J Diabetes Investig 2013; 4: 640–50.
9. Cheng G, Huang C, Deng H, Wang H. Diabetes as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies. Intern Med J 2012; 42: 484–91.
10. Xu WL, von Strauss E, Qiu CX, Winblad B, Fratiglioni L. Uncontrolled diabetes increases the risk of Alzheimer's disease: a population-based cohort study. Diabetologia 2009; 52: 1031–9.
11. Wetterling T, Kanitz RD, Borgis KJ. Comparison of different diagnostic criteria for vascular dementia (ADDTC, DSM-IV, ICD-10, NINDS-AIREN). Stroke 1996; 27: 30–6.
12. Vagelatos NT, Eslick GD. Type 2 diabetes as a risk factor for Alzheimer's disease: the confounders, interactions, and neuropathology associated with this relationship. Epidemiol Rev 2013; 35: 152–60.
13. Verdile G, Fuller SJ, Martins RN. The role of type 2 diabetes in neurodegeneration. Neurobiol Dis 2015; 84: 22–38.
14. Li X, Song D, Leng SX. Link between type 2 diabetes and Alzheimer's disease: from epidemiology to mechanism and treatment. Clin Interv Aging 2015; 10: 549–60.
15. Bedse G, Di Domenico F, Serviddio G, Cassano T. Aberrant insulin signaling in Alzheimer's disease: current knowledge. Front Neurosci 2015; 9: 204.
16. Mushtaq G, Khan JA, Kamal MA. Biological mechanisms linking Alzheimer's disease and type-2 diabetes mellitus. CNS Neurol Disord Drug Targets 2014; 13: 1192–201.
17. Zemva J, Schubert M. The role of neuronal insulin/insulin-like growth factor-1 signaling for the pathogenesis of Alzheimer's disease: possible therapeutic implications. CNS Neurol Disord Drug Targets 2014; 13: 322–37.
18. El Khoury NB, Gratuze M, Papon M-A, Bretteville A, Planel E. Insulin dysfunction and Tau pathology. Front Cell Neurosci 2014; 8: 22.
19. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease. J Neurochem 2008; 104: 1433–9.
20. Solano DC, Sironi M, Bonfini C, Solerte SB, Govoni S, Racchi M. Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J 2000; 14: 1015–22.
21. Tokutake T, Kasuga K, Yajima R et al. Hyperphosphorylation of Tau induced by naturally secreted amyloid-beta at nanomolar concentrations is modulated by insulin-dependent Akt-GSK3beta signaling pathway. J Biol Chem 2012; 287: 35222–33.
22. Hong M, Lee VM. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem 1997; 272: 19547–53.
23. Stein TD, Johnson JA. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J Neurosci 2002; 22: 7380–8.
24. Schubert M, Brazil DP, Burks DJ et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. J Neurosci 2003; 23: 7084–92.
25. Killick R, Scales G, Leroy K et al. Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochem Biophys Res Commun 2009; 386: 257–62.
26. Buxbaum JN, Ye Z, Reixach N et al. Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity. Proc Natl Acad Sci USA 2008; 105: 2681–6.
27. Margolis RU, Altszuler N. Insulin in the cerebrospinal fluid. Nature 1967; 215: 1375–6.
28. Banks WA, Jaspan JB, Huang W, Kastin AJ. Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 1997; 18: 1423–9.
29. Hoyer S, Henneberg N, Knapp S, Lannert H, Martin E. Brain glucose metabolism is controlled by amplification and desensitization of the neuronal insulin receptor. Ann N Y Acad Sci 1996; 777: 374–9.
30. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol 2013; 47: 145–71.
31. Elmquist JK, Coppari R, Balthasar N, Ichinose M, Lowell BB. Identifying hypothalamic pathways controlling food intake, body weight, and glucose homeostasis. J Comp Neurol 2005; 493: 63–71.
32. Vogt MC, Bruning JC. CNS insulin signaling in the control of energy homeostasis and glucose metabolism – from embryo to old age. Trends Endocrinol Metab 2013; 24: 76–84.
33. Benoit SC, Air EL, Coolen LM et al. The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 2002; 22: 9048–52.
34. Konner AC, Janoschek R, Plum L et al. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab 2007; 5: 438–49.
35. Biessels GJ, Kamal A, Ramakers GM et al. Place learning and hippocampal synaptic plasticity in streptozotocin-induced diabetic rats. Diabetes 1996; 45: 1259–66.
36. Park CR, Seeley RJ, Craft S, Woods SC. Intracerebroventricular insulin enhances memory in a passive-avoidance task. Physiol Behav 2000; 68: 509–14.
37. Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH. Water maze learning and hippocampal synaptic plasticity in streptozotocin-diabetic rats: effects of insulin treatment. Brain Res 1998; 800: 125–35.
38. Hooper C, Markevich V, Plattner F et al. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur J Neurosci 2007; 25: 81–6.
39. Peineau S, Bradley C, Taghibiglou C et al. The role of GSK-3 in synaptic plasticity. Br J Pharmacol 2008; 153(Suppl): S428–37.
40. Peineau S, Taghibiglou C, Bradley C et al. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 2007; 53: 703–17.
41. Skeberdis VA, Lan J, Zheng X, Zukin RS, Bennett MV. Insulin promotes rapid delivery of N-methyl-D- aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci USA 2001; 98: 3561–6.
42. Kopf SR, Baratti CM. Effects of posttraining administration of insulin on retention of a habituation response in mice: participation of a central cholinergic mechanism. Neurobiol Learn Mem 1999; 71: 50–61.
43. Figlewicz DP, Szot P, Israel PA, Payne C, Dorsa DM. Insulin reduces norepinephrine transporter mRNA in vivo in rat locus coeruleus. Brain Res 1993; 602: 161–4.
44. Wang YT, Linden DJ. Expression of cerebellar long-term depression requires postsynaptic clathrin-mediated endocytosis. Neuron 2000; 25: 635–47.
45. Ge Y, Dong Z, Bagot RC et al. Hippocampal long-term depression is required for the consolidation of spatial memory. Proc Natl Acad Sci USA 2010; 107: 16697–702.
46. Zhao W, Chen H, Xu H et al. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 1999; 274: 34893–902.
47. Frolich L, Blum-Degen D, Bernstein HG et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm 1998; 105: 423–38.
48. Fernandes ML, Saad MJ, Velloso LA. Effects of age on elements of insulin-signaling pathway in central nervous system of rats. Endocrine 2001; 16: 227–34.
49. De Felice FG. Alzheimer's disease and insulin resistance: translating basic science into clinical applications. J Clin Invest 2013; 123: 531–9.
50. Zhao W-Q, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004; 490: 71–81.
51. Craft S, Peskind E, Schwartz MW, Schellenberg GD, Raskind M, Porte DJ. Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease: relationship to severity of dementia and apolipoprotein E genotype. Neurology 1998; 50: 164–8.
52. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J Alzheimers Dis 2005; 8: 247–68.
53. Hoyer S. The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review. J Neural Transm 2002; 109: 991–1002.
54. Schwartz MW, Figlewicz DF, Kahn SE, Baskin DG, Greenwood MR, Porte DJ. Insulin binding to brain capillaries is reduced in genetically obese, hyperinsulinemic Zucker rats. Peptides 1990; 11: 467–72.
55. Wallum BJ, Taborsky GJJ, Porte DJ et al. Cerebrospinal fluid insulin levels increase during intravenous insulin infusions in man. J Clin Endocrinol Metab 1987; 64: 190–4.
56. Talbot K, Wang H-Y, Kazi H et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2012; 122: 1316–38.
57. Steen E, Terry BM, Rivera EJ et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease–is this type 3 diabetes? J Alzheimers Dis 2005; 7: 63–80.
58. De Felice FG, Vieira MNN, Bomfim TR et al. Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 2009; 106: 1971–6.
59. Farris W, Mansourian S, Chang Y 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: 4162–7.
60. Cook DG, Leverenz JB, McMillan PJ et al. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol 2003; 162: 313–9.
61. Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM. Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 2005; 26: 645–54.
62. Gasparini L, Gouras GK, Wang R et al. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 2001; 21: 2561–70.
63. Bomfim TR, Forny-Germano L, Sathler LB et al. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Abeta oligomers. J Clin Invest 2012; 122: 1339–53.
64. De Felice FG, Ferreira ST. Beta-amyloid production, aggregation, and clearance as targets for therapy in Alzheimer's disease. Cell Mol Neurobiol 2002; 22: 545–63.
65. Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S. Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes. Arch Neurol 2011; 68: 51–7.
66. Czirr E, Wyss-Coray T. The immunology of neurodegeneration. J Clin Invest 2012; 122: 1156–63.
67. Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer's disease. Biol Psychiatry 2010; 68: 930–41.
68. Heneka MT, O'Banion MK. Inflammatory processes in Alzheimer's disease. J Neuroimmunol 2007; 184: 69–91.
69. Jones L, Holmans PA, Hamshere ML et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 2010; 5: e13950.
70. Lynch JR, Tang W, Wang H et al. APOE genotype and an ApoE-mimetic peptide modify the systemic and central nervous system inflammatory response. J Biol Chem 2003; 278: 48529–33.
71. Wyss-Coray T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat Med 2006; 12: 1005–15.
72. Pistell PJ, Morrison CD, Gupta S et al. Cognitive impairment following high fat diet consumption is associated with brain inflammation. J Neuroimmunol 2010; 219: 25–32.
73. Fishel MA, Watson GS, Montine TJ et al. Hyperinsulinemia provokes synchronous increases in central inflammation and beta-amyloid in normal adults. Arch Neurol 2005; 62: 1539–44.
74. Rui L, Aguirre V, Kim JK et al. Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 2001; 107: 181–9.
75. Gao Z, Hwang D, Bataille F et al. Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 2002; 277: 48115–21.
76. Yang J, Park Y, Zhang H et al. Feed-forward signaling of TNF-alpha and NF-kappaB via IKK-beta pathway contributes to insulin resistance and coronary arteriolar dysfunction in type 2 diabetic mice. Am J Physiol Heart Circ Physiol 2009; 296: H1850–8.
77. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.
78. Park KM, Bowers WJ. Tumor necrosis factor-alpha mediated signaling in neuronal homeostasis and dysfunction. Cell Signal 2010; 22: 977–83.
79. Grammas P, Ovase R. Inflammatory factors are elevated in brain microvessels in Alzheimer's disease. Neurobiol Aging 2001; 22: 837–42.
80. Ruan L, Kang Z, Pei G, Le Y. Amyloid deposition and inflammation in APPswe/PS1dE9 mouse model of Alzheimer's disease. Curr Alzheimer Res 2009; 6: 531–40.
81. Jin J-J, Kim H-D, Maxwell JA, Li L, Fukuchi K-I. Toll-like receptor 4-dependent upregulation of cytokines in a transgenic mouse model of Alzheimer's disease. J Neuroinflammation 2008; 5: 23.
82. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 1996; 271: 665–8.
83. Hirosumi J, Tuncman G, Chang L et al. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333–6.
84. Boden G, Duan X, Homko C et al. Increase in endoplasmic reticulum stress-related proteins and genes in adipose tissue of obese, insulin-resistant individuals. Diabetes 2008; 57: 2438–44.
85. Gourmaud S, Paquet C, Dumurgier J et al. Increased levels of cerebrospinal fluid JNK3 associated with amyloid pathology: links to cognitive decline. J Psychiatry Neurosci 2015; 40: 151–61.
86. Ma Q-L, Yang F, Rosario ER et al. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 2009; 29: 9078–89.
87. Yuan M, Konstantopoulos N, Lee J et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 2001; 293: 1673–7.
88. In t’ Veld BA, Ruitenberg A, Hofman A et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med 2001; 345: 1515–21.
89. Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JCS. Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology 2002; 59: 880–6.
90. Breitner JCS, Haneuse SJPA, Walker R et al. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology 2009; 72: 1899–905.
91. Scharf S, Mander A, Ugoni A, Vajda F, Christophidis N. A double-blind, placebo-controlled trial of diclofenac/misoprostol in Alzheimer's disease. Neurology 1999; 53: 197–201.
92. Aisen PS, Schmeidler J, Pasinetti GM. Randomized pilot study of nimesulide treatment in Alzheimer's disease. Neurology 2002; 58: 1050–4.
93. Pasqualetti P, Bonomini C, Dal Forno G et al. A randomized controlled study on effects of ibuprofen on cognitive progression of Alzheimer's disease. Aging Clin Exp Res 2009; 21: 102–10.
94. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed 2006; 8: 25.
95. Parker WDJ, Filley CM, Parks JK. Cytochrome oxidase deficiency in Alzheimer's disease. Neurology 1990; 40: 1302–3.
96. Kish SJ, Bergeron C, Rajput A et al. Brain cytochrome oxidase in Alzheimer's disease. J Neurochem 1992; 59: 776–9.
97. Orth M, Schapira AH. Mitochondria and degenerative disorders. Am J Med Genet 2001; 106: 27–36.
98. Calabrese V, Scapagnini G, Giuffrida Stella AM, Bates TE, Clark JB. Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity. Neurochem Res 2001; 26: 739–64.
99. Loh K, Deng H, Fukushima A et al. Reactive oxygen species enhance insulin sensitivity. Cell Metab 2009; 10: 260–72.
100. Serrano F, Klann E. Reactive oxygen species and synaptic plasticity in the aging hippocampus. Ageing Res Rev 2004; 3: 431–43.
101. Huang T-J, Price SA, Chilton L et al. Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons of type 1 diabetic rats in the presence of sustained hyperglycemia. Diabetes 2003; 52: 2129–36.
102. Moreira PI, Santos MS, Sena C, Seica R, Oliveira CR. Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 2005; 18: 628–37.
103. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 2003; 100: 7996–8001.
104. 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: 438–47.
105. Gerbitz KD, Gempel K, Brdiczka D. Mitochondria and diabetes. Genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 1996; 45: 113–26.
106. Moreira PI, Santos MS, Seica R, Oliveira CR. Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes. J Neurol Sci 2007; 257: 206–14.
107. Carvalho C, Cardoso S, Correia SC et al. Metabolic alterations induced by sucrose intake and Alzheimer's disease promote similar brain mitochondrial abnormalities. Diabetes 2012; 61: 1234–42.
108. Perluigi M, Di Domenico F, Buttterfield DA. Unraveling the complexity of neurodegeneration in brains of subjects with Down syndrome: insights from proteomics. Proteomics Clin Appl 2014; 8: 73–85.
109. Di Domenico F, Coccia R, Cocciolo A et al. Impairment of proteostasis network in Down syndrome prior to the development of Alzheimer's disease neuropathology: redox proteomics analysis of human brain. Biochim Biophys Acta 2013; 1832: 1249–59.