Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome

Experimental and Molecular Medicine

Volumn 47, Issue 3, 2015, Pages

  Kim, Bhumsoo ^a   Feldman, Eva L ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMYLOID BETA PROTEIN; INSULIN; TAU PROTEIN;

ALZHEIMER DISEASE; ANIMAL; BRAIN; COGNITION DISORDERS; COMPLICATION; DRUG EFFECTS; HUMAN; INSULIN RESISTANCE; METABOLIC SYNDROME X; METABOLISM; MOLECULARLY TARGETED THERAPY; SIGNAL TRANSDUCTION;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BRAIN; COGNITION DISORDERS; HUMANS; INSULIN; INSULIN RESISTANCE; METABOLIC SYNDROME X; MOLECULAR TARGETED THERAPY; SIGNAL TRANSDUCTION; TAU PROTEINS;

EID: 84989332872     PISSN: 12263613     EISSN: 20926413     Source Type: Journal    
DOI: 10.1038/EMM.2015.3     Document Type: Review

References (153)

1. Duvnjak L, Duvnjak M. The metabolic syndrome—an ongoing story. J Physiol Pharmacol 2009; 60: 19–24.
2. Ervin RB. Prevalence of metabolic syndrome among adults 20 years of age and over, by sex, age, race and ethnicity, and body mass index: United States, 2003–2006. Natl Health Stat Report 2009; 5: 1–7.
3. Bruce KD, Hanson MA. The developmental origins, mechanisms, and implications of metabolic syndrome. JNutr2010; 140: 648–652.
4. Sesti G. Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab 2006; 20: 665–679.
5. Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer’s disease.Lancet 2011; 377: 1019–1031.
6. Selkoe D, Mandelkow E, Holtzman D. Deciphering Alzheimer disease. Cold Spring Harbor perspectives in medicine 2012; 2: a011460.
7. Schrijvers EM, Witteman JC, Sijbrands EJ, Hofman A, Koudstaal PJ, Breteler MM. Insulin metabolism and the risk of Alzheimer disease: the Rotterdam Study. Neurology 2010; 75: 1982–1987.
8. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y et al. Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology 2010; 75: 764–770.
9. 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: 51–57.
10. Frisardi V, Solfrizzi V, Capurso C, Imbimbo BP, Vendemiale G, Seripa D et al. Is insulin resistant brain state a central feature of the metaboliccognitive syndrome? JAlzheimersDis2010; 21: 57–63.
11. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. JAlzheimersDis2006; 9: 13–33.
12. Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab 2007; 5: 237–252.
13. Muntoni S, Muntoni S. Insulin resistance: pathophysiology and rationale for treatment. Ann Nutr Metab 2011; 58: 25–36.
14. Kim B, Feldman EL. Insulin resistance in the nervous system. Trends Endocrinol Metab 2012; 23: 133–141.
15. Boura-Halfon S, Zick Y. Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am J Physiol Endocrinol Metab 2009; 296: E581–E591.
16. Bouzakri K, Roques M, Gual P, Espinosa S, Guebre-Egziabher F, Riou JP et al. Reduced activation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 2003; 52: 1319–1325.
17. Langlais P, Yi Z, Finlayson J, Luo M, Mapes R, De Filippis E et al. Global IRS-1 phosphorylation analysis in insulin resistance. Diabetologia 2011; 54: 2878–2889.
18. Hay N. Akt isoforms and glucose homeostasis—the leptin connection. Trends Endocrinol Metab 2011; 22: 66–73.
19. Gonzalez E, McGraw TE. Insulin-modulated Akt subcellular localization determines Akt isoform-specific signaling.Proc Natl Acad Sci USA 2009; 106: 7004–7009.
20. Cusi K, Maezono K, Osman A, Pendergrass M, Patti ME, Pratipanawatr T et al. Insulin resistance differentially affects the PI 3-kinase-and MAP kinase-mediated signaling in human muscle. JClinInvest2000; 105: 311–320.
21. Baskin DG, Figlewicz DP, Woods SC, Porte D Jr., Dorsa DM. Insulin in the brain. Annu Rev Physiol 1987; 49: 335–347.
22. Unger JW, Livingston JN, Moss AM. Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 1991; 36: 343–362.
23. van der Heide LP, Ramakers GM, Smidt MP. Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 2006; 79: 205–221.
24. Benedict C, Frey WH 2nd, Schioth HB, Schultes B, Born J, Hallschmid M. Intranasal insulin as a therapeutic option in the treatment of cognitive impairments. Exp Gerontol 2011; 46: 112–115.
25. McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fatinduced insulin resistance. Neurobiol Learn Mem 2010; 93: 546–553.
26. Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ 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. JBiolChem1999; 274: 34893–34902.
27. de la Monte SM. Insulin resistance and Alzheimer's disease. BMB Rep 2009; 42: 475–481.
28. Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. Journal of aging research 2012; 2012: 384017.
29. Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging 2010; 31: 224–243.
30. Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. JPathol2011; 225: 54–62.
31. Bosco D, Fava A, Plastino M, Montalcini T, Pujia A. Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis. JCellMolMed2011; 15: 1807–1821.
32. Li L, Holscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain Res Rev 2007; 56: 384–402.
33. Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A et al. Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. JClinInvest2012; 122: 1316–1338.
34. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J Alzheimers Dis 2005; 7: 45–61.
35. Freude S, Schilbach K, Schubert M. The role of IGF-1 receptor and insulin receptor signaling for the pathogenesis of Alzheimer's disease: from model organisms to human disease. Curr Alzheimer Res 2009; 6: 213–223.
36. Gammeltoft S, Fehlmann M, Van Obberghen E. Insulin receptors in the mammalian central nervous system: binding characteristics and subunit structure. Biochimie 1985; 67: 1147–1153.
37. Tilvis RS, Kahonen-Vare MH, Jolkkonen J, Valvanne J, Pitkala KH, Strandberg TE. Predictors of cognitive decline and mortality of aged people over a 10-year period. J Gerontol A Biol Sci Med Sci 2004; 59: 268–274.
38. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999; 53: 1937–1942.
39. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 2002; 51: 1256–1262.
40. Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O'Brien PC et al. Risk of dementia among persons with diabetes mellitus: a populationbased cohort study. Am J Epidemiol 1997; 145: 301–308.
41. 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.
42. Cosway R, Strachan MW, Dougall A, Frier BM, Deary IJ. Cognitive function and information processing in type 2 diabetes. Diabet Med 2001; 18: 803–810.
43. 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.
44. Kim B, Backus C, Oh S, Hayes JM, Feldman EL. Increased tau phosphorylation and cleavage in mouse models of type 1 and type 2 diabetes. Endocrinology 2009; 150: 5294–5301.
45. Kim B, Backus C, Oh S, Feldman EL. Hyperglycemia-induced Tau cleavage in vitro and in vivo: a possible link between diabetes and Alzheimer's disease. JAlzheimersDis2013; 34: 727–739.
46. Kohjima M, Sun Y, Chan L. Increased food intake leads to obesity and insulin resistance in the tg2576 Alzheimer's disease mouse model. Endocrinology 2010; 151: 1532–1540.
47. Ke YD, Delerue F, Gladbach A, Gotz J, Ittner LM. Experimental diabetes mellitus exacerbates tau pathology in a transgenic mouse model of Alzheimer's disease. PLoS ONE 2009; 4: e7917.
48. Ma YQ, Wu DK, Liu JK. mTOR and tau phosphorylated proteins in the hippocampal tissue of rats with type 2 diabetes and Alzheimer's disease. Molecular medicine reports 2013; 7: 623–627.
49. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of obesity in the United States, 2009–2010. NCHS data brief 2012; 106: 1–8.
50. Pan L, Blanck HM, Sherry B, Dalenius K, Grummer-Strawn LM. Trends in the prevalence of extreme obesity among US preschool-aged children living in low-income families, 1998–2010. JAMA 2012; 308: 2563–2565.
51. Wolf G. Role of fatty acids in the development of insulin resistance and type 2 diabetes mellitus. Nutr Rev 2008; 66: 597–600.
52. Espinola-Klein C, Gori T, Blankenberg S, Munzel T. Inflammatory markers and cardiovascular risk in the metabolic syndrome. Front Biosci 2011; 16: 1663–1674.
53. Spielman LJ, Little JP, Klegeris A. Inflammation and insulin/IGF-1 resistance as the possible link between obesity and neurodegeneration. JNeuroimmunol2014; 273: 8–21.
54. Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V. Inflammatory process in Alzheimer's Disease. Frontiers in integrative neuroscience 2013; 7: 59.
55. Gamblin TC, King ME, Kuret J, Berry RW, Binder LI. Oxidative regulation of fatty acid-induced tau polymerization. Biochemistry 2000; 39: 14203–14210.
56. Patil S, Chan C. Palmitic and stearic fatty acids induce Alzheimer-like hyperphosphorylation of tau in primary rat cortical neurons. Neurosci Lett 2005; 384: 288–293.
57. Whitmer RA, Gunderson EP, Quesenberry CP Jr., Zhou J, Yaffe K. Body mass index in midlife and risk of Alzheimer disease and vascular dementia. Curr Alzheimer Res 2007; 4: 103–109.
58. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology 2008; 71: 1057–1064.
59. Fitzpatrick AL, Kuller LH, Lopez OL, Diehr P, O’Meara ES, Longstreth WT Jr. et al. Midlife and late-life obesity and the risk of dementia: cardiovascular health study. Arch Neurol 2009; 66: 336–342.
60. Luchsinger JA, Patel B, Tang MX, Schupf N, Mayeux R. Measures of adiposity and dementia risk in elderly persons. Arch Neurol 2007; 64: 392–398.
61. Winocur G, Greenwood CE. Studies of the effects of high fat diets on cognitive function in a rat model. Neurobiol Aging 2005; 26: 46–49.
62. Arnold SE, Lucki I, Brookshire BR, Carlson GC, Browne CA, Kazi H et al. High fat diet produces brain insulin resistance, synaptodendritic abnormalities and altered behavior in mice. Neurobiol Dis 2014; 67C: 79–87.
63. Thirumangalakudi L, Prakasam A, Zhang R, Bimonte-Nelson H, SambamurtiK,KindyMSet al. High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice. JNeurochem2008; 106: 475–485.
64. Bhat NR, Thirumangalakudi L. Increased Tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet. JAlzheimersDis2013; 36: 781–789.
65. Czech MP, Tencerova M, Pedersen DJ, Aouadi M. Insulin signalling mechanisms for triacylglycerol storage. Diabetologia 2013; 56: 949–964.
66. Di Scala C, Chahinian H, Yahi N, Garmy N, Fantini J. Interaction of Alzheimer's beta-amyloid peptides with cholesterol: mechanistic insights into amyloid pore formation. Biochemistry 2014; 53: 4489–4502.
67. Wood WG, Li L, Muller WE, Eckert GP. Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis. J Neurochem 2014; 129: 559–572.
68. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS et al. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis 2000; 7: 321–331.
69. Refolo LM, Pappolla MA, LaFrancois J, Malester B, Schmidt SD, Thomas Bryant T et al. A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease. Neurobiol Dis 2001; 8: 890–899.
70. Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha-secretase ADAM 10. Proc Natl Acad Sci USA 2001; 98: 5815–5820.
71. Anstey KJ, Lipnicki DM, Low LF. Cholesterol as a risk factor for dementia and cognitive decline: a systematic review of prospective studies with meta-analysis. Am J Geriatr Psychiatry 2008; 16: 343–354.
72. Notkola IL, Sulkava R, Pekkanen J, Erkinjuntti T, Ehnholm C, Kivinen P et al. Serum total cholesterol, apolipoprotein E epsilon 4 allele, and Alzheimer's disease. Neuroepidemiology 1998; 17: 14–20.
73. Kivipelto M, Helkala EL, Laakso MP, Hanninen T, Hallikainen M, Alhainen K et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. Bmj 2001; 322: 1447–1451.
74. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005; 64: 277–281.
75. Reitz C, Tang MX, Schupf N, Manly JJ, Mayeux R, Luchsinger JA. Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease. Arch Neurol 2010; 67: 1491–1497.
76. Mielke MM, Zandi PP, Sjogren M, Gustafson D, Ostling S, Steen B et al. High total cholesterol levels in late life associated with a reduced risk of dementia. Neurology 2005; 64: 1689–1695.
77. 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.
78. Iqbal K, Liu F, Gong CX, Alonso Adel C, Grundke-Iqbal I. Mechanisms of tau-induced neurodegeneration. Acta Neuropathol 2009; 118: 53–69.
79. Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D et al. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA 2004; 101: 3100–3105.
80. Bhat RV, Budd Haeberlein SL, Avila J. Glycogen synthase kinase 3: a drug target for CNS therapies. JNeurochem2004; 89: 1313–1317.
81. Kim B, Sullivan KA, Backus C, Feldman EL. Cortical neurons develop insulin resistance and blunted Akt signaling: a potential mechanism contributing to enhanced ischemic injury in diabetes. Antioxid Redox Signal 2011; 14: 1829–1839.
82. Takashima A. GSK-3 is essential in the pathogenesis of Alzheimer's disease. JAlzheimersDis2006; 9: 309–317.
83. Dias WB, Hart GW. O-GlcNAc modification in diabetes and Alzheimer's disease. Mol Biosyst 2007; 3: 766–772.
84. Myslicki JP, Belke DD, Shearer J. Role of O-GlcNAcylation in nutritional sensing, insulin resistance and in mediating the benefits of exercise. Appl Physiol Nutr Metab 2014; 39: 1205–1213.
85. Whelan SA, Hart GW. Proteomic approaches to analyze the dynamic relationships between nucleocytoplasmic protein glycosylation and phosphorylation. Circ Res 2003; 93: 1047–1058.
86. Deng Y, Li B, Liu Y, Iqbal K, Grundke-Iqbal I, Gong CX. Dysregulation of insulin signaling, glucose transporters, O-GlcNAcylation, and phosphorylation of tau and neurofilaments in the brain: Implication for Alzheimer's disease. Am J Pathol 2009; 175: 2089–2098.
87. Yuzwa SA, Cheung AH, Okon M, McIntosh LP, Vocadlo DJ. O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers. J Mol Biol 2014; 426: 1736–1752.
88. Yarchoan M, Toledo JB, Lee EB, Arvanitakis Z, Kazi H, Han LY et al. Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer’s disease and tauopathies. Acta Neuropathol 2014; 128: 679–689.
89. Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ et al. Betaamyloid 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: 9078–9089.
90. Calvo-Ochoa E, Hernandez-Ortega K, Ferrera P, Morimoto S, Arias C. Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus. J Cereb Blood Flow Metab 2014; 34: 1001–1008.
91. Ramos-Rodriguez JJ, Ortiz-Barajas O, Gamero-Carrasco C, de la Rosa PR, Infante-Garcia C, Zopeque-Garcia N et al. Prediabetes-induced vascular alterations exacerbate central pathology in APPswe/PS1dE9 mice. Psychoneuroendocrinology 2014; 48: 123–135.
92. Leboucher A, Laurent C, Fernandez-Gomez FJ, Burnouf S, Troquier L, Eddarkaoui S et al. Detrimental Effects of Diet-Induced Obesity on tau Pathology Are Independent of Insulin Resistance in tau Transgenic Mice. Diabetes 2013; 62: 1681–1688.
93. Planel E, Tatebayashi Y, Miyasaka T, Liu L, Wang L, Herman M et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. JNeurosci2007; 27: 13635–13648.
94. Schubert M, Brazil DP, Burks DJ, Kushner JA, Ye J, Flint CL et al. Insulin receptor substrate-2 deficiency impairs brain growth and promotes tau phosphorylation. JNeurosci2003; 23: 7084–7092.
95. Pandini G, Pace V, Copani A, Squatrito S, Milardi D, Vigneri R. Insulin has multiple antiamyloidogenic effects on human neuronal cells. Endocrinology 2013; 154: 375–387.
96. Muyllaert D, Kremer A, Jaworski T, Borghgraef P, Devijver H, Croes S et al. Glycogen synthase kinase-3beta, or a link between amyloid and tau pathology? Genes Brain Behav 2008; 7: 57–66.
97. Shineman DW, Dain AS, Kim ML, Lee VM. Constitutively active Akt inhibits trafficking of amyloid precursor protein and amyloid precursor protein metabolites through feedback inhibition of phosphoinositide 3kinase. Biochemistry 2009; 48: 3787–3794.
98. Chun YS, Park Y, Oh HG, Kim TW, Yang HO, Park MK et al. O GlcNAcylation Promotes Non-Amyloidogenic Processing of Amyloid-beta Protein Precursor via Inhibition of Endocytosis from the Plasma Membrane. JAlzheimersDis2014; 44: 261–275.
99. Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. JBiol Chem 2007; 282: 33305–33312.
100. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP 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: 1971–1976.
101. Liu X, Teng Z, Cui C, Wang R, Liu M, Zhang Y. Amyloid beta-derived diffusible ligands (ADDLs) induce abnormal expression of insulin receptors in rat hippocampal neurons. J Mol Neurosci 2014; 52: 124–130.
102. Lee HK, Kumar P, Fu Q, Rosen KM, Querfurth HW. The insulin/Akt signaling pathway is targeted by intracellular beta-amyloid. Mol Biol Cell 2009; 20: 1533–1544.
103. Willette AA, Johnson SC, Birdsill AC, Sager MA, Christian B, Baker LD et al. Insulin resistance predicts brain amyloid deposition in late middleaged adults. Alzheimer’s Dement (e-pub ahead of print 17 July 2014; doi:10.1016/j.jalz.2014.03.011).
104. Luo D, Hou X, Hou L, Wang M, Xu S, Dong C et al. Effect of pioglitazone on altered expression of Abeta metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance. Eur J Pharmacol 2011; 664: 14–19.
105. Zhao WQ, Lacor PN, Chen H, Lambert MP, Quon MJ, Krafft GA et al. Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. JBiolChem2009; 284: 18742–18753.
106. Yamamoto N, Matsubara T, Sobue K, Tanida M, Kasahara R, Naruse K et al. Brain insulin resistance accelerates Abeta fibrillogenesis by inducing GM1 ganglioside clustering in the presynaptic membranes. J Neurochem 2012; 121: 619–628.
107. Haj-ali V, Mohaddes G, Babri SH. Intracerebroventricular insulin improves spatial learning and memory in male Wistar rats. Behavioral neuroscience 2009; 123: 1309–1314.
108. Shingo AS, Kanabayashi T, Kito S, Murase T. Intracerebroventricular administration of an insulin analogue recovers STZ-induced cognitive decline in rats. Behav Brain Res 2013; 241: 105–111.
109. Yang Y, Ma D, Wang Y, Jiang T, Hu S, Zhang M et al. Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. JAlzheimersDis2013; 33: 329–338.
110. Kern W, Peters A, Fruehwald-Schultes B, Deininger E, Born J, Fehm HL. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology 2001; 74: 270–280.
111. MacLeod KM, Hepburn DA, Frier BM. Frequency and morbidity of severe hypoglycaemia in insulin-treated diabetic patients. Diabet Med 1993; 10: 238–245.
112. Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 2007; 32: 239–243.
113. Reger MA, Watson GS, Frey WH 2nd, Baker LD, Cholerton B, Keeling ML et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 2006; 27: 451–458.
114. Reger MA, Watson GS, Green PS, Wilkinson CW, Baker LD, Cholerton B et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008; 70: 440–448.
115. Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol 2012; 69: 29–38.
116. Reger MA, Watson GS, Green PS, Baker LD, Cholerton B, Fishel MA et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. JAlzheimersDis2008; 13: 323–331.
117. Verges B. Clinical interest of PPARs ligands. Diabetes Metab 2004; 30: 7–12.
118. de la Monte SM, Tong M, Lester-Coll N, Plater M Jr., Wands JR. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease. JAlzheimersDis2006; 10: 89–109.
119. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR. Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 2006; 199: 265–273.
120. Yu Y, Li X, Blanchard J, Li Y, Iqbal K, Liu F et al. Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice. J Neural Transm (e-pub ahead of print 13 August 2014).
121. Escribano L, Simon AM, Gimeno E, Cuadrado-Tejedor M, Lopez de Maturana R, Garcia-Osta A et al. Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology 2010; 35: 1593–1604.
122. Masciopinto F, Di Pietro N, Corona C, Bomba M, Pipino C, Curcio M et al. Effects of long-term treatment with pioglitazone on cognition and glucose metabolism of PS1-KI, 3xTg-AD, and wild-type mice. Cell death & disease 2012; 3: e448.
123. Papadopoulos P, Rosa-Neto P, Rochford J, Hamel E. Pioglitazone improves reversal learning and exerts mixed cerebrovascular effects in a mouse model of Alzheimer's disease with combined amyloid-beta and cerebrovascular pathology. PLoS ONE 2013; 8: e68612.
124. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S et al. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 2005; 13: 950–958.
125. Abbatecola AM, Lattanzio F, Molinari AM, Cioffi M, Mansi L, Rambaldi P et al. Rosiglitazone and cognitive stability in older individuals with type 2 diabetes and mild cognitive impairment. Diabetes Care 2010; 33: 1706–1711.
126. Risner ME, Saunders AM, Altman JF, Ormandy GC, Craft S, Foley IM et al. Efficacy of rosiglitazone in a genetically defined population with mild-tomoderate Alzheimer's disease. The pharmacogenomics journal 2006; 6: 246–254.
127. Tzimopoulou S, Cunningham VJ, Nichols TE, Searle G, Bird NP, Mistry P et al. A multi-center randomized proof-of-concept clinical trial applying [(1)(8)F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease. JAlzheimersDis2010; 22: 1241–1256.
128. Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, Irizarry M et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 2010; 30: 131–146.
129. Harrington C, Sawchak S, Chiang C, Davies J, Donovan C, Saunders AM et al. Rosiglitazone does not improve cognition or global function when used as adjunctive therapy to AChE inhibitors in mild-to-moderate Alzheimer's disease: two phase 3 studies. Curr Alzheimer Res 2011; 8: 592–606.
130. 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. JAmGeriatrSoc2009; 57: 177–179.
131. Sato T, Hanyu H, Hirao K, Kanetaka H, Sakurai H, Iwamoto T. Efficacy of PPAR-gamma agonist pioglitazone in mild Alzheimer disease. Neurobiol Aging 2011; 32: 1626–1633.
132. Geldmacher DS, Fritsch T, McClendon MJ, Landreth G. A randomized pilot clinical trial of the safety of pioglitazone in treatment of patients with Alzheimer disease. Arch Neurol 2011; 68: 45–50.
133. McIntyre RS, Powell AM, Kaidanovich-Beilin O, Soczynska JK, Alsuwaidan M, Woldeyohannes HO et al. The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders. Behav Brain Res 2013; 237: 164–171.
134. Goke R, Larsen PJ, Mikkelsen JD, Sheikh SP. Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites. Eur J Neurosci 1995; 7: 2294–2300.
135. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003; 26: 2929–2940.
136. McClean PL, Gault VA, Harriott P, Holscher C. Glucagon-like peptide-1 analogues enhance synaptic plasticity in the brain: a link between diabetes and Alzheimer's disease. Eur J Pharmacol 2010; 630: 158–162.
137. Talbot K. Brain insulin resistance in Alzheimer's disease and its potential treatment with GLP-1 analogs. Neurodegener Dis Manag 2014; 4:31–40.
138. Holscher C. Insulin, incretins and other growth factors as potential novel treatments for Alzheimer's and Parkinson's diseases. Biochem Soc Trans 2014; 42: 593–599.
139. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X et al. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 2003; 9: 1173–1179.
140. Abbas T, Faivre E, Holscher C. Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: Interaction between type 2 diabetes and Alzheimer's disease. Behav Brain Res 2009; 205: 265–271.
141. Li Y, Duffy KB, Ottinger MA, Ray B, Bailey JA, Holloway HW et al. GLP-1 receptor stimulation reduces amyloid-beta peptide accumulation and cytotoxicity in cellular and animal models of Alzheimer's disease. JAlzheimersDis2010; 19: 1205–1219.
142. Chen S, An FM, Yin L, Liu AR, Yin DK, Yao WB et al. Glucagon-like peptide-1 protects hippocampal neurons against advanced glycation end product-induced tau hyperphosphorylation. Neuroscience 2014; 256: 137–146.
143. Xiong H, Zheng C, Wang J, Song J, Zhao G, Shen H et al. The neuroprotection of liraglutide on Alzheimer-like learning and memory impairment by modulating the hyperphosphorylation of tau and neurofilament proteins and insulin signaling pathways in mice. JAlzheimersDis 2013; 37: 623–635.
144. McClean PL, Holscher C. Liraglutide can reverse memory impairment, synaptic loss and reduce plaque load in aged APP/PS1 mice, a model of Alzheimer's disease. Neuropharmacology 2014; 76: 57–67.
145. McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease. J Neurosci 2011; 31: 6587–6594.
146. Yang Y, Zhang J, Ma D, Zhang M, Hu S, Shao S et al. Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. J Alzheimers Dis2013; 37: 637–648.
147. Holscher C. The incretin hormones glucagonlike peptide 1 and glucosedependent insulinotropic polypeptide are neuroprotective in mouse models of Alzheimer's disease. Alzheimer's Dement 2014; 10: S47–S54.
148. Ma T, Du X, Pick JE, Sui G, Brownlee M, Klann E. Glucagon-like peptide 1 cleavage product GLP-1(9-36) amide rescues synaptic plasticity and memory deficits in Alzheimer's disease model mice. JNeurosci2012; 32: 13701–13708.
149. Iwai T, Sawabe T, Tanimitsu K, Suzuki M, Sasaki-Hamada S, Oka J. Glucagon-like peptide-1 protects synaptic and learning functions from neuroinflammation in rodents. JNeurosciRes2014; 92: 446–454.
150. Egefjord L, Gejl M, Moller A, Braendgaard H, Gottrup H, Antropova O et al. Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer s disease—protocol for a controlled, randomized doubleblinded trial. Danish Med J 2012; 59: A4519.
151. Aviles-Olmos I, Dickson J, Kefalopoulou Z, Djamshidian A, Ell P, Soderlund T et al. Exenatide and the treatment of patients with Parkinson's disease. JClinInvest2013; 123: 2730–2736.
152. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006; 5: 228–234.
153. Ewers M, Buerger K, Teipel SJ, Scheltens P, Schroder J, Zinkowski RP et al. Multicenter assessment of CSF-phosphorylated tau for the prediction of conversion of MCI. Neurology 2007; 69: 2205–2212.