Targeting insulin signaling for the treatment of alzheimer's disease

Current Topics in Medicinal Chemistry

Volumn 16, Issue 5, 2016, Pages 485-492

  Chen, Yanxing ^a,b   Zhang, Jianfang ^a   Zhang, Baorong ^a   Gong, Cheng Xin ^b  

^a ZHEJIANG UNIVERSITY   (China)

^b NEW YORK STATE INSTITUTE FOR BASIC RESEARCH IN DEVELOPMENTAL DISABILITIES   (United States)

Author keywords

Alzheimer's disease; Anti diabetic drugs; Brain insulin signaling; Dipeptidyl peptidase IV inhibitors; Glucose metabolism; Incretins; Metformin; Thiazolidinediones

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EXENDIN 4; INCRETIN; INSULIN; LINAGLIPTIN; LIRAGLUTIDE; METFORMIN; PIOGLITAZONE; ROSIGLITAZONE; SAXAGLIPTIN; SITAGLIPTIN; TROGLITAZONE;

ALZHEIMER DISEASE; ARTICLE; DRUG EFFICACY; DRUG TARGETING; GLUCOSE METABOLISM; HUMAN; INSULIN RESISTANCE; INSULIN SENSITIVITY; MULTICENTER STUDY (TOPIC); NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); RANDOMIZED CONTROLLED TRIAL (TOPIC); SIGNAL TRANSDUCTION; ANIMAL; COGNITION DISORDERS; METABOLISM;

ALZHEIMER DISEASE; ANIMALS; COGNITION DISORDERS; HUMANS; INSULIN; SIGNAL TRANSDUCTION;

EID: 84973428782     PISSN: 15680266     EISSN: 18734294     Source Type: Journal    
DOI: 10.2174/1568026615666150813142423     Document Type: Article

References (109)

1. 2014 Alzheimer's disease facts and figures. Alzheimers Dement, 2014, 10, e47-92.
2. Todd, S.; Barr, S.; Roberts, M.; Passmore, A. P. Survival in dementia and predictors of mortality: A review. Int. J. Geriatr. Psychiatry, 2013, 28, 1109-1124.
3. Iqbal, K.; Grundke-Iqbal, I. Metabolic/signal transduction hypothesis of alzheimer's disease and other tauopathies. Acta Neuropathol., 2005, 109, 25-31.
4. de la Monte, S. M. Insulin resistance and alzheimer's disease. BMB Rep., 2009, 42, 475-481.
5. Chen, Y.; Deng, Y.; Zhang, B.; Gong, C. X. Deregulation of brain insulin signaling in alzheimer's disease. Neurosci. Bull., 2014, 30, 282-294.
6. El Khoury, N.B.; Gratuze, M.; Papon, M.A.; Bretteville, A.; Planel, E. Insulin dysfunction and tau pathology. Front Cell Neurosci., 2014, 8, 22.
7. Mosconi, L.; Pupi, A.; De Leon, M.J. Brain glucose hypometabolism and oxidative stress in preclinical alzheimer's disease. Ann. NY Acad. Sci., 2008, 1147, 180-195.
8. Derakhshan, F.; Toth, C. Insulin and the brain. Curr. Diabetes Rev., 2013, 9, 102-116.
9. Chen, Y.; Liang, Z.; Blanchard, J.; Dai, C.L.; Sun, S.; Lee, M.H.; Grundke-Iqbal, I.; Iqbal, K.; Liu, F., Gong, C.X. A non-transgenic mouse model (icv-stz mouse) of alzheimer's disease: Similarities to and differences from the transgenic model (3xtg-ad mouse). Mol. Neurobiol., 2013, 47, 711-725.
10. Chen, Y.; Liang, Z.; Tian, Z.; Blanchard, J.; Dai, C. L.; Chalbot, S.; Iqbal, K.; Liu, F., Gong, C.X. Intracerebroventricular streptozotocin exacerbates alzheimer-like changes of 3xtg-ad mice. Mol. Neurobiol., 2014, 49, 547-562.
11. Liu, Y.; Liu, F.; Grundke-Iqbal, I.; Iqbal, K.; Gong, C.X. Deficient brain insulin signalling pathway in alzheimer's disease and diabetes. J. Pathol., 2011, 225, 54-62.
12. Deng, Y.; Li, B.; Liu, Y.; Iqbal, K.; Grundke-Iqbal, I.; Gong, C.X. Dysregulation of insulin signaling, glucose transporters, oglcnacylation, and phosphorylation of tau and neurofilaments in the brain: Implication for alzheimer's disease. Am. J. Pathol., 2009, 175, 2089-2098.
13. Chen, Y.; Tian, Z.; Liang, Z.; Sun, S.; Dai, C. L.; Lee, M. H.; Laferla, F. M.; Grundke-Iqbal, I.; Iqbal, K.; Liu, F., Gong, C.X. Brain gene expression of a sporadic (icv-stz mouse) and a familial mouse model (3xtg-ad mouse) of alzheimer's disease. PLoS One, 2012, 7, e51432.
14. Chen, Y.; Zhao, Y.; Dai, C.L.; Liang, Z.; Run, X.; Iqbal, K.; Liu, F., Gong, C.X. Intranasal insulin restores insulin signaling, increases synaptic proteins, and reduces abeta level and microglia activation in the brains of 3xtg-ad mice. Exp. Neurol., 2014, 261C, 610-619.
15. Steen, E.; Terry, B.M.; Rivera, E.J.; Cannon, J.L.; Neely, T.R.; Tavares, R.; Xu, X.J.; Wands, J.R.; de la Monte, S.M. 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.
16. Hofman, A.; Ott, A.; Breteler, M.M.; Bots, M.L.; Slooter, A.J.; van Harskamp, F.; van Duijn, C.N.; Van Broeckhoven, C.; Grobbee, D.E. Atherosclerosis, apolipoprotein e, and prevalence of dementia and alzheimer's disease in the rotterdam study. Lancet, 1997, 349, 151-154.
17. Akomolafe, A.; Beiser, A.; Meigs, J.B.; Au, R.; Green, R.C.; Farrer, L.A.; Wolf, P.A.; Seshadri, S. Diabetes mellitus and risk of developing alzheimer disease: Results from the framingham study. Arch. Neurol., 2006, 63, 1551-1555.
18. Ott, A.; Stolk, R. P.; van Harskamp, F.; Pols, H. A.; Hofman, A.; Breteler, M.M. Diabetes mellitus and the risk of dementia: The rotterdam study. Neurology, 1999, 53, 1937-1942.
19. Liu, Y.; Liu, F.; Grundke-Iqbal, I.; Iqbal, K.; Gong, C. X. Brain glucose transporters, o-glcnacylation and phosphorylation of tau in diabetes and alzheimer's disease. J. Neurochem., 2009, 111, 242-249.
20. Yang, Y.; Zhang, J.; Ma, D.; Zhang, M.; Hu, S.; Shao, S.; Gong, C. X. Subcutaneous administration of liraglutide ameliorates alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. J. Alzheimers Dis., 2013, 37, 637-648.
21. Li, Z. G.; Zhang, W.; Sima, A.A. Alzheimer-like changes in rat models of spontaneous diabetes. Diabetes, 2007, 56, 1817-1824.
22. Kern, W.; Peters, A.; Fruehwald-Schultes, B.; Deininger, E.; Born, J.; Fehm, H.L. Improving influence of insulin on cognitive functions in humans. Neuroendocrinology, 2001, 74, 270-280.
23. Craft, S.; Asthana, S.; Cook, D.G.; Baker, L.D.; Cherrier, M.; Purganan, K.; Wait, C.; Petrova, A.; Latendresse, S.; Watson, G.S.; Newcomer, J.W.; Schellenberg, G.D.; Krohn, A.J. Insulin doseresponse effects on memory and plasma amyloid precursor protein in alzheimer's disease: Interactions with apolipoprotein e genotype. Psychoneuroendocrinology, 2003, 28, 809-822.
24. Born, J.; Lange, T.; Kern, W.; McGregor, G. P.; Bickel, U.; Fehm, H.L. Sniffing neuropeptides: A transnasal approach to the human brain. Nat. Neurosci., 2002, 5, 514-516.
25. Dhuria, S.V.; Hanson, L.R.; Frey, W.H. 2nd. Intranasal delivery to the central nervous system: Mechanisms and experimental considerations. J. Pharm. Sci., 2010, 99, 1654-1673.
26. Krug, R.; Benedict, C.; Born, J. Hallschmid, M. Comparable sensitivity of postmenopausal and young women to the effects of intranasal insulin on food intake and working memory. J. Clin. Endocrinol. Metab., 2010, 95, E468-472.
27. Benedict, C.; Kern, W.; Schultes, B.; Born, J.; Hallschmid, M. Differential sensitivity of men and women to anorexigenic and memory-improving effects of intranasal insulin. J. Clin. Endocrinol. Metab., 2008, 93, 1339-1344.
28. Benedict, C.; Hallschmid, M.; Hatke, A.; Schultes, B.; Fehm, H.L.; Born, J.; Kern, W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology, 2004, 29, 1326-1334.
29. Benedict, C.; Hallschmid, M.; Schmitz, K.; Schultes, B.; Ratter, F.; Fehm, H.L.; Born, J.; Kern, W. Intranasal insulin improves memory in humans: Superiority of insulin aspart. Neuropsychopharmacology, 2007, 32, 239-243.
30. Reger, M.A.; Watson, G.S.; Green, P.S.; Baker, L.D.; Cholerton, B.; Fishel, M.A.; Plymate, S.R.; Cherrier, M.M.; Schellenberg, G.D.; Frey, W.H. 2nd, Craft, S. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloidbeta in memory-impaired older adults. J. Alzheimers Dis., 2008, 13, 323-331.
31. Reger, M.A.; Watson, G.S.; Frey, W.H. 2nd; Baker, L. D.; Cholerton, B.; Keeling, M. L.; Belongia, D. A.; Fishel, M. A.; Plymate, S.R.; Schellenberg, G.D.; Cherrier, M.M.; Craft, S. Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by apoe genotype. Neurobiol. Aging, 2006, 27, 451-458.
32. Reger, M.A.; Watson, G.S.; Green, P.S.; Wilkinson, C.W.; Baker, L.D.; Cholerton, B.; Fishel, M.A.; Plymate, S.R.; Breitner, J.C.; DeGroodt, W.; Mehta, P.; Craft, S. Intranasal insulin improves cognition and modulates beta-amyloid in early ad. Neurology, 2008, 70, 440-448.
33. Craft, S.; Baker, L.D.; Montine, T.J.; Minoshima, S.; Watson, G.S.; Claxton, A.; Arbuckle, M.; Callaghan, M.; Tsai, E.; Plymate, S.R.; Green, P.S.; Leverenz, J.; Cross, D.; Gerton, B. Intranasal insulin therapy for alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch. Neurol., 2012, 69, 29-38.
34. Schilling, T.M.; Ferreira de Sa, D.S.; Westerhausen, R.; Strelzyk, F.; Larra, M.F.; Hallschmid, M.; Savaskan, E.; Oitzl, M.S.; Busch, H.P.; Naumann, E.; Schachinger, H. Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation. Hum. Brain Mapp., 2014, 35, 1944-1956.
35. Jauch-Chara, K.; Friedrich, A.; Rezmer, M.; Melchert, U.H.; Scholand-Engler G.H.; Hallschmid, M.; Oltmanns, K.M. Intranasal insulin suppresses food intake via enhancement of brain energy levels in humans. Diabetes, 2012, 61, 2261-2268.
36. Zhang, H.; Hao, Y.; Manor, B.; Novak, P.; Milberg, W.; Zhang, J.; Fang, J.; Novak, V. Intranasal insulin enhanced resting-state functional connectivity of hippocampal regions in type 2 diabetes. Diabetes, 2015, 64, 1025-1034.
37. Claxton, A.; Baker, L.D.; Hanson, A.; Trittschuh, E.H.; Cholerton, B.; Morgan, A.; Callaghan, M.; Arbuckle, M.; Behl, C., Craft, S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage alzheimer's disease dementia. J. Alzheimers Dis., 2015, 44, 897-906.
38. Yang, Y.; Ma, D.; Wang, Y.; Jiang, T.; Hu, S.; Zhang, M.; Yu, X.; Gong, C.X. Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. J. Alzheimers Dis., 2013, 33, 329-338.
39. Chen, Y.; Run, X.; Liang, Z.; Zhao, Y.; Dai, C. L.; Iqbal, K.; Liu, F.; Gong, C. X. Intranasal insulin prevents anesthesia-induced hyperphosphorylation of tau in 3xtg-ad mice. Front Aging Neurosci., 2014, 6, 100.
40. Campbell, J.E.; Drucker, D.J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab., 2013, 17, 819-837.
41. Drucker, D.J. The biology of incretin hormones. Cell Metab., 2006, 3, 153-165.
42. Verspohl, E.J. Novel therapeutics for type 2 diabetes: Incretin hormone mimetics (glucagon-like peptide-1 receptor agonists) and dipeptidyl peptidase-4 inhibitors. Pharmacol. Ther., 2009, 124, 113-138.
43. Orskov, C.; Wettergren, A., Holst, J.J. Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable. Diabetes, 1993, 42, 658-661.
44. Goke, R.; Fehmann, H.C.; Linn, T.; Schmidt, H.; Krause, M.; Eng, J.; Goke, B. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells. J. Biol. Chem., 1993, 268, 19650-19655.
45. Mentlein, R.; Gallwitz, B.; Schmidt, W.E. Dipeptidyl-peptidase iv hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem., 1993, 214, 829-835.
46. Papaetis, G.S. Incretin-based therapies in prediabetes: Current evidence and future perspectives. World J. Diabetes, 2014, 5, 817-834.
47. Agerso, H.; Jensen, L.B.; Elbrond, B.; Rolan, P.; Zdravkovic, M. The pharmacokinetics, pharmacodynamics, safety and tolerability of nn2211, a new long-acting glp-1 derivative, in healthy men. Diabetologia, 2002, 45, 195-202.
48. Kastin, A.J.; Akerstrom, V.; Pan, W. Interactions of glucagon-like peptide-1 (glp-1) with the blood-brain barrier. J. Mol. Neurosci., 2002, 18, 7-14.
49. Hunter, K.; Holscher, C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci., 2012, 13, 33.
50. Hamilton, A.; Holscher, C. Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. Neuroreport, 2009, 20, 1161-1166.
51. McClean, P.L.; 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.
52. McClean, P.L.; 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 Pt A, 57-67.
53. Hamilton, A.; Patterson, S.; Porter, D.; Gault, V.A.; Holscher, C. Novel glp-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J. Neurosci. Res., 2011, 89, 481-489.
54. Parthsarathy, V.; Holscher, C. Chronic treatment with the glp1 analogue liraglutide increases cell proliferation and differentiation into neurons in an ad mouse model. PLoS One, 2013, 8, e58784.
55. Han, W.N.; Holscher, C.; Yuan, L.; Yang, W.; Wang, X.H.; Wu, M.N.; Qi, J.S. Liraglutide protects against amyloid-beta proteininduced impairment of spatial learning and memory in rats. Neurobiol. Aging, 2013, 34, 576-588.
56. Long-Smith, C.M.; Manning, S.; McClean, P.L.; Coakley, M.F.; O'Halloran, D.J.; Holscher, C.; O'Neill, C. The diabetes drug liraglutide ameliorates aberrant insulin receptor localisation and signalling in parallel with decreasing both amyloid-beta plaque and glial pathology in a mouse model of alzheimer's disease. Neuromolecular Med., 2013, 15, 102-114.
57. Goke, R.; Larsen, P.J.; Mikkelsen, J.D.; Sheikh, S. P. 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.
58. Perry, T.; Lahiri, D.K.; Sambamurti, K.; Chen, D.; Mattson, M.P.; Egan, J.M.; Greig, N.H. Glucagon-like peptide-1 decreases endogenous amyloid-beta peptide (abeta) levels and protects hippocampal neurons from death induced by abeta and iron. J. Neurosci. Res., 2003, 72, 603-612.
59. Chen, S.; Liu, A.R.; An, F.M.; Yao, W.B.; Gao, X.D. Amelioration of neurodegenerative changes in cellular and rat models of diabetes-related alzheimer's disease by exendin-4. Age (Dordr), 2012, 34, 1211-1224.
60. Bomba, M.; Ciavardelli, D.; Silvestri, E.; Canzoniero, L.M.; Lattanzio, R.; Chiappini, P.; Piantelli, M.; Di Ilio, C.; Consoli, A.; Sensi, S.L. Exenatide promotes cognitive enhancement and positive brain metabolic changes in ps1-ki mice but has no effects in 3xtgad animals. Cell Death Dis., 2013, 4, e612.
61. Bomfim, T.R.; Forny-Germano, L.; Sathler, L.B.; Brito-Moreira, J.; Houzel, J.C.; Decker, H.; Silverman, M.A.; Kazi, H.; Melo, H.M.; McClean, P.L.; Holscher, C.; Arnold, S.E.; Talbot, K.; Klein, W.L.; Munoz, D.P.; Ferreira, S.T.; De Felice, F.G. 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, 1339-1353.
62. Perry, T.; Lahiri, D.K.; Chen, D.; Zhou, J.; Shaw, K.T.; Egan, J.M., Greig, N.H. A novel neurotrophic property of glucagon-like peptide 1: A promoter of nerve growth factor-mediated differentiation in pc12 cells. J. Pharmacol. Exp. Ther., 2002, 300, 958-966.
63. Duffy, A.M.; Holscher, C. The incretin analogue d-ala2gip reduces plaque load, astrogliosis and oxidative stress in an app/ps1 mouse model of alzheimer's disease. Neuroscience, 2013, 228, 294-300.
64. Gengler, S.; McClean, P.L.; McCurtin, R.; Gault, V.A.; Holscher, C. Val(8)glp-1 rescues synaptic plasticity and reduces dense core plaques in app/ps1 mice. Neurobiol. Aging, 2012, 33, 265-276.
65. During, M.J.; Cao, L.; Zuzga, D.S.; Francis, J.S.; Fitzsimons, H.L.; Jiao, X.; Bland, R.J.; Klugmann, M.; Banks, W.A.; Drucker, D.J.; Haile, C.N. Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat. Med., 2003, 9, 1173-1179.
66. Mikhail, N. Incretin mimetics and dipeptidyl peptidase 4 inhibitors in clinical trials for the treatment of type 2 diabetes. Expert Opin. Investig. Drugs, 2008, 17, 845-853.
67. Faivre, E.; Holscher, C. D-ala2gip facilitated synaptic plasticity and reduces plaque load in aged wild type mice and in an alzheimer's disease mouse model. J. Alzheimers Dis., 2013, 35, 267-283.
68. Faivre, E.; Holscher, C. Neuroprotective effects of d-ala(2)gip on alzheimer's disease biomarkers in an app/ps1 mouse model. Alzheimers Res. Ther., 2013, 5, 20.
69. Drucker, D.J.; Nauck, M.A. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 2006, 368, 1696-1705.
70. Goossen, K.; Graber, S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: Systematic review and meta-analysis. Diabetes Obes. Metab., 2012, 14, 1061-1072.
71. Dicker, D. Dpp-4 inhibitors: Impact on glycemic control and cardiovascular risk factors. Diabetes Care, 2011, 34 Suppl. 2, S276-278.
72. Kosaraju, J.; Murthy, V.; Khatwal, R.B.; Dubala, A.; Chinni, S.; Muthureddy Nataraj, S.K.; Basavan, D. Vildagliptin: An antidiabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced alzheimer's disease. J. Pharm. Pharmacol., 2013, 65(12), 1773-84.
73. Kosaraju, J.; Gali, C.C.; Khatwal, R.B.; Dubala, A.; Chinni, S.; Holsinger, R.M.; Madhunapantula, V.S.; Muthureddy Nataraj, S.K.; Basavan, D. Saxagliptin: A dipeptidyl peptidase-4 inhibitor ameliorates streptozotocin induced alzheimer's disease. Neuropharmacology, 2013, 72, 291-300.
74. Darsalia, V.; Ortsater, H.; Olverling, A.; Darlof, E.; Wolbert, P.; Nystrom, T.; Klein, T.; Sjoholm, A.; Patrone, C. The dpp-4 inhibitor linagliptin counteracts stroke in the normal and diabetic mouse brain: A comparison with glimepiride. Diabetes, 2013, 62, 1289-1296.
75. D'Amico, M.; Di Filippo, C.; Marfella, R.; Abbatecola, A.M.; Ferraraccio, F.; Rossi, F.; Paolisso, G. Long-term inhibition of dipeptidyl peptidase-4 in alzheimer's prone mice. Exp. Gerontol., 2010, 45, 202-207.
76. Kosaraju, J.; Murthy, V.; Khatwal, R.B.; Dubala, A.; Chinni, S.; Muthureddy Nataraj, S.K., Basavan, D. Vildagliptin: An antidiabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced alzheimer's disease. J. Pharm. Pharmacol., 2013, 65, 1773-1784.
77. Della-Morte, D.; Palmirotta, R.; Rehni, A.K.; Pastore, D.; Capuani, B.; Pacifici, F.; De Marchis, M.L.; Dave, K.R.; Bellia, A.; Fogliame, G.; Ferroni, P.; Donadel, G.; Cacciatore, F.; Abete, P.; Dong, C.; Pileggi, A.; Roselli, M.; Ricordi, C.; Sbraccia, P.; Guadagni, F.; Rundek, T.; Lauro, D. Pharmacogenomics and pharmacogenetics of thiazolidinediones: Role in diabetes and cardiovascular risk factors. Pharmacogenomics, 2014, 15, 2063-2082.
78. Combs, C.K.; Johnson, D.E.; Karlo, J.C.; Cannady, S.B.; Landreth, G.E. Inflammatory mechanisms in alzheimer's disease: Inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by ppargamma agonists. J. Neurosci., 2000, 20, 558-567.
79. Costello, D.A.; O'Leary, D.M.; Herron, C.E. Agonists of peroxisome proliferator-activated receptor-gamma attenuate the abeta-mediated impairment of ltp in the hippocampus in vitro. Neuropharmacology, 2005, 49, 359-366.
80. Kariharan, T.; Nanayakkara, G.; Parameshwaran, K.; Bagasrawala, I.; Ahuja, M.; Abdel-Rahman, E.; Amin, A. T.; Dhanasekaran, M.; Suppiramaniam, V., Amin, R.H. Central activation of ppar-gamma ameliorates diabetes induced cognitive dysfunction and improves bdnf expression. Neurobiol. Aging, 2014, 36(3):1451-61.
81. 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.
82. Nicolakakis, N.; Aboulkassim, T.; Ongali, B.; Lecrux, C.; Fernandes, P.; Rosa-Neto, P.; Tong, X.K.; Hamel, E. 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.
83. Prakash, A.; Kumar, A. Role of nuclear receptor on regulation of bdnf and neuroinflammation in hippocampus of beta-amyloid animal model of alzheimer's disease. Neurotox Res., 2014, 25, 335-347.
84. Yu, Y.; Li, X.; Blanchard, J.; Li, Y.; Iqbal, K.; Liu, F., Gong, C.X. Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xtg-ad mice. J. Neural. Transm., 2014, 122(4), 593-606
85. Watson, G.S.; Cholerton, B.A.; Reger, M.A.; Baker, L.D.; Plymate, S.R.; Asthana, S.; Fishel, M.A.; Kulstad, J.J.; Green, P.S.; Cook, D.G.; Kahn, S.E.; Keeling, M.L.; Craft, S. 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.
86. 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.
87. Gold, M.; Alderton, C.; Zvartau-Hind, M.; Egginton, S.; Saunders, A.M.; Irizarry, M.; Craft, S.; Landreth, G.; Linnamagi, U., Sawchak, S. 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.
88. Corbett, A.; Pickett, J.; Burns, A.; Corcoran, J.; Dunnett, S.B.; Edison, P.; Hagan, J.J.; Holmes, C.; Jones, E.; Katona, C.; Kearns, I.; Kehoe, P.; Mudher, A.; Passmore, A.; Shepherd, N.; Walsh, F.; Ballard, C. Drug repositioning for alzheimer's disease. Nat. Rev. Drug Discov., 2012, 11, 833-846.
89. Rena, G.; Pearson, E.R.; Sakamoto, K. Molecular mechanism of action of metformin: Old or new insights? Diabetologia, 2013, 56, 1898-1906.
90. Poels, J.; Spasic, M.R.; Callaerts, P.; Norga, K.K. Expanding roles for amp-activated protein kinase in neuronal survival and autophagy. Bioessays, 2009, 31, 944-952.
91. Labuzek, K.; Suchy, D.; Gabryel, B.; Bielecka, A.; Liber, S.; Okopien, B. Quantification of metformin by the hplc method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol. Rep., 2010, 62, 956-965.
92. Li, J.; Benashski, S.E.; Venna, V.R.; McCullough, L.D. Effects of metformin in experimental stroke. Stroke, 2010, 41, 2645-2652.
93. Abd-Elsameea, A.A.; Moustaf, A.A.; Mohamed, A.M. Modulation of the oxidative stress by metformin in the cerebrum of rats exposed to global cerebral ischemia and ischemia/reperfusion. Eur. Rev. Med. Pharmacol. Sci., 2014, 18, 2387-2392.
94. Liu, Y.; Tang, G.; Li, Y.; Wang, Y.; Chen, X.; Gu, X.; Zhang, Z.; Yang, G.Y. Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion. J. Neuroinflammation, 2014, 11, 177.
95. Jiang, T.; Yu, J.T.; Zhu, X.C.; Wang, H.F.; Tan, M.S.; Cao, L.; Zhang, Q.Q.; Gao, L.; Shi, J.Q.; Zhang, Y.D.; Tan, L. Acute metformin preconditioning confers neuroprotection against focal cerebral ischaemia by pre-activation of ampk-dependent autophagy. Br. J. Pharmacol., 2014, 171, 3146-3157.
96. Jin, Q.; Cheng, J.; Liu, Y.; Wu, J.; Wang, X.; Wei, S.; Zhou, X.; Qin, Z.; Jia, J., Zhen, X. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav. Immun., 2014, 40, 131-142.
97. Venna, V.R.; Li, J.; Hammond, M.D.; Mancini, N.S.; McCullough, L.D. Chronic metformin treatment improves post-stroke angiogenesis and recovery after experimental stroke. Eur. J. Neurosci., 2014, 39, 2129-2138.
98. Patil, S.P.; Jain, P.D.; Ghumatkar, P.J.; Tambe, R. Sathaye, S. Neuroprotective effect of metformin in mptp-induced parkinson's disease in mice. Neuroscience, 2014, 277, 747-754.
99. Alzoubi, K.H.; Khabour, O.F.; Al-Azzam, S.I.; Tashtoush, M.H.; Mhaidat, N. M. Metformin eased cognitive impairment induced by chronic l-methionine administration: Potential role of oxidative stress. Curr. Neuropharmacol., 2014, 12, 186-192.
100. Pintana, H.; Apaijai, N.; Pratchayasakul, W.; Chattipakorn, N., Chattipakorn, S.C. Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats. Life Sci., 2012, 91, 409-414.
101. Yoo, D.Y.; Kim, W.; Nam, S.M.; Yoo, K.Y.; Lee, C.H.; Choi, J.H.; Won, M.H.; Hwang, I.K.; Yoon, Y.S. Reduced cell proliferation and neuroblast differentiation in the dentate gyrus of high fat dietfed mice are ameliorated by metformin and glimepiride treatment. Neurochem. Res., 2011, 36, 2401-2408.
102. Gupta, A.; Bisht, B.; Dey, C.S. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and alzheimer'slike changes. Neuropharmacology, 2011, 60, 910-920.
103. Li, J.; Deng, J.; Sheng, W.; Zuo, Z. Metformin attenuates alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol. Biochem. Behav., 2012, 101, 564-574.
104. Kickstein, E.; Krauss, S.; Thornhill, P.; Rutschow, D.; Zeller, R.; Sharkey, J.; Williamson, R.; Fuchs, M.; Kohler, A.; Glossmann, H.; Schneider, R.; Sutherland, C.; Schweiger, S. Biguanide metformin acts on tau phosphorylation via mtor/protein phosphatase 2a (pp2a) signaling. Proc. Natl. Acad. Sci. USA, 2010, 107, 21830-21835.
105. Chen, Y.; Zhou, K.; Wang, R.; Liu, Y.; Kwak, Y.D.; Ma, T.; Thompson, R.C.; Zhao, Y.; Smith, L.; Gasparini, L.; Luo, Z.; Xu, H.; Liao, F.F. Antidiabetic drug metformin (glucophager) increases biogenesis of alzheimer's amyloid peptides via up-regulating bace1 transcription. Proc. Natl. Acad. Sci. USA, 2009, 106, 3907-3912.
106. Picone, P.; Nuzzo, D.; Caruana, L.; Messina, E.; Barera, A.; Vasto, S., Di Carlo, M. Metformin increases app expression and processing via oxidative stress, mitochondrial dysfunction and nfkappab activation: Use of insulin to attenuate metformin's effect. Biochim. Biophys. Acta, 2015, 1853(5), 1046-59.
107. Hettich, M.M.; Matthes, F.; Ryan, D.P.; Griesche, N.; Schroder, S.; Dorn, S.; Kraubeta, S.; Ehninger, D. The anti-diabetic drug metformin reduces bace1 protein level by interfering with the mid1 complex. PLoS One, 2014, 9, e102420.
108. Hsu, C.C.; Wahlqvist, M.L.; Lee, M.S.; Tsai, H.N. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. J. Alzheimers Dis., 2011, 24, 485-493.
109. Imfeld, P.; Bodmer, M.; Jick, S.S.; Meier, C.R. Metformin, other antidiabetic drugs, and risk of alzheimer's disease: A populationbased case-control study. J. Am. Geriatr. Soc., 2012, 60, 916-921.