Insulin is a two-edged knife on the brain

Journal of Alzheimer's Disease

Volumn 18, Issue 3, 2009, Pages 483-507

  Cardoso, Susana ^a,b   Correia, Sónia ^a,b   Santos, Renato X ^a,b   Carvalho, Cristina ^a,b   Santos, Maria S ^a,b   Oliveira, Catarina R ^a,c   Perry, George ^d,e   Smith, Mark A ^e   Zhu, Xiongwei ^e   Moreira, Paula I ^a,c  

^a UNIVERSITY OF COIMBRA   (Portugal)

^b UNIVERSITY OF COIMBRA   (Portugal)

^c UNIVERSITY OF COIMBRA   (Portugal)

^d University of San Antonio   (United States)

^e CASE WESTERN RESERVE UNIVERSITY   (United States)

Author keywords

Brain; Insulin; Insulin sensitizers; Insulin signaling; Neurodegenerative disorders

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; CIGLITAZONE; HUMAN INSULIN; IBUPROFEN; INSULIN; INSULIN ASPART; INSULIN SENSITIZING AGENT; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIOGLITAZONE; ROSIGLITAZONE; TROGLITAZONE;

ALZHEIMER DISEASE; AMNESIA; AMYOTROPHIC LATERAL SCLEROSIS; BRAIN; BRAIN FUNCTION; CLINICAL TRIAL; DEGENERATIVE DISEASE; DIABETES MELLITUS; DISEASE ASSOCIATION; HUMAN; HUNTINGTON CHOREA; NERVE DEGENERATION; NONHUMAN; PARKINSON DISEASE; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; THERAPY EFFECT;

EID: 75249106915     PISSN: 13872877     EISSN: None     Source Type: Journal    
DOI: 10.3233/JAD-2009-1155     Document Type: Review

References (289)

1. Barbaccia M, Chuang D, Costa E (1982) Is insulin a neuromodulator? Adv Biochem Neuropharmacol 33, 511-518.
2. Boyd Jr FT, Clarke DW, Raizada MK (1986) Insulin inhibits specific norepinephrine uptake in neuronal cultures from rat brain. Brain Res 398, 1-5.
3. Duarte AI, Santos MS, Seica R, de OliveiraCR(2003) Insulin affects synaptosomal GABA and glutamate transport under oxidative stress conditions. Brain Res 977, 23-30.
4. 2+ pool and of neuropeptide secretion. Nature 385, 343-346.
5. Recio-Pinto E, Lang FF, Ishii DN (1984) Insulin and insulinlike growth factor II permit nerve growth factor binding and the neurit formation response in cultured human neuroblastoma cells. Proc Natl Acad Sci U S A 81, 2562-2566.
6. Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT (1997) Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 388, 686-690.
7. Gerozissis K (2003) Brain insulin: regulation, mechanisms of action and functions. Cell Mol Neurobiol 23, 1-25.
8. Bingham EM, Hopkins D, Smith D, Pernet A, Hallett W, Reed L, Marsden PK, Amiel SA (2002) The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes 51, 3384-3390.
9. Schulingkamp RJ, Pagano TC, Hung D, Raffa RB (2000) Insulin receptors and insulin action in the brain: review and clinical implications. Neurosci Biobehav Rev 24, 855-872.
10. El Messari S, Ait-Ikhlef A, Ambroise DH, Penicaud L, ArluisonM( 2002) Expression of insulin-responsive glucose transporter GLUT4 mRNA in the rat brain and spinal cord: an in situ hybridization study. J Chem Neuroanat 24, 225-242.
11. Sankar R, Thamotharan S, Shin D, Moley KH, Devaskar SU (2002) Insulin-responsive glucose transporters-GLUT8 and GLUT4 are expressed in the developing mammalian brain. Mol Brain Res 107, 157-165.
12. Wozniak M, Rydzewski B, Baker SP, Raizada MK (1993) The cellular and physiological actions of insulin in the central nervous system. Neurochem Int 22, 1-10.
13. Havrankova J, Roth J, BrownsteinM(1978) Insulin receptors are widely distributed in the central nervous system of the rat. Nature 272, 827-829.
14. Van Houten M, Posner BI, Kopriwa BM, Brawer JR (1979) Insulin-binding sites in the rat brain: in vivo localization to the circumventricular organs by quantitative radioautography. Endocrinology 105, 666-673.
15. Baura GD, Foster DM, Porte D Jr, Kahn SE, Bergman RN, Cobelli C, Schwartz MW (1993) Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J Clin Invest 92, 1824-1830.
16. Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS (1994) Insulin gene expression and insulin synthesis in mammalian neuronal cells. J Biol Chem 269, 8445-8454.
17. Schechter R, AbboudM(2001) Neuronal synthesized insulin roles on neural differentiation within fetal rat neuron cell cultures. Dev Brain Res 127, 41-49.
18. Woods SC, Seeley RJ, Baskin DG, Schwartz MW (2003) Insulin and the blood-brain barrier. Curr Pharm Des 9, 795-800.
19. ZhaoW, Chen H, Xu H, Moore E, Meiri N, Quon MJ, Alkon D (1999) Brain insulin receptors and spatial memory. Interrelated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 274 34893-34902.
20. Schechter R, Beju D, Gaffney T, Schaefer F, Whetsell L (1996) Preproinsulin I and II mRNAs and insulin electron microscopic immunoreaction are present within the rat fetal nervous system. Brain Res 736, 16-27.
21. Geroldi C, Frisoni GB, Paolisso G, Bandinelli S, Lamponi M, Abbatecola AM, Zanetti O, Guralnik JM, Ferrucci L (2005) Insulin resistance in cognitive impairment: the InCHIANTI study. Arch Neurol 62, 1067-1072.
22. Stolk RP, Breteler MM, Ott A, Pols HA, Lamberts SW, Grobbee DE, Hofman A (1997) Insulin and cognitive function in an elderly population. The Rotterdam Study. Diabetes Care 20, 792-795.
23. Watson GS, Craft S (2004) Modulation of memory by insulin and glucose: neuropsychological observations in Alzheimer's disease. Eur J Pharmacol 490, 97-113.
24. Hoyer S (2004) Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 490, 115-125.
25. Frölich L, Blum-Degen D, Bernstein HG, Engelsberger S, Humrich J, Laufer S, Muschner D, Thalheimer A, Turk A, Hoyer S, Zochling R, Boissl KW, Jellinger K, Riederer P (1998) Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J Neural Transm 105, 423-438.
26. Frölich L, Blum-Degen D, Riederer P, Hoyer S (1999) A disturbance in the neuronal insulin receptor signal transduction in sporadic Alzheimer's disease. Ann N Y Acad Sci 893, 290-293.
27. Brands AM, Kessels RP, de Haan EH, Kappelle LJ, Biessels GJ (2004) Cerebral dysfunction in type 1 diabetes: effects of insulin, vascular risk factors and blood-glucose levels. Eur J Pharmacol 490, 159-168.
28. Brands AMA, Biessels GJ, De Haan EHF, Kappelle LJ, Kessels RPC (2005) The effects of type 1 diabetes on cognitive performance: a meta-analysis. Diabetes Care 28, 726-735.
29. Ryan CM, Geckle MO (2000) Why is learning and memory dysfunction in type 2 diabetes limited to older adults? Diabetes Metab Res Rev 16, 308-315.
30. Messier C, Teutenberg K (2005) The role of insulin, insulin growth factor, and insulin-degrading enzyme in brain aging and Alzheimer's disease. Neural Plast 12, 311-328.
31. Craft S, Watson GS (2004) Insulin and neurodegenerative disease: shared and specific mechanisms. Lancet Neurol 3, 169-178.
32. Sandyk R (1993) The relationship between diabetes mellitus and Parkinson's disease. Int J Neurosci 69, 125-130.
33. Hoyer S, Muller D, Plaschke K (1994) Desensitization of brain insulin receptor. Effect on glucose/energy and related metabolism. J Neural Transm 44, 259-268.
34. Podolsky S, Leopold NA (1977) Abnormal glucose tolerance and arginine tolerance tests in Huntington's disease. Gerontology 23, 55-63.
35. Farrer LA (1985) Diabetes mellitus in Huntington disease. Clin Genet 27, 62-67.
36. Kopf SR, Baratti CM (1994) Memory-improving actions of glucose: involvement of a central cholinergic muscarinic mechanism. Behav Neur Biol 62, 237-243.
37. Parkes M, White KG (2000) Glucose attenuation of memory impairments. Behav Neurosci 114, 307-319.
38. Park CR, Seely RJ, Craft S, Woods SC (2000) Intracerebroventricular Insulin enhances memory in a passiveavoidance task. Physiol Behav 68, 509-514.
39. Winocur G, Gagnon S (1998) Glucose treatment attenuates spatial learning and memory deficts of aged rats on tests of hippocampal function. Neurobiol Aging 19, 233-241.
40. Messier C, Gagnon M, Knott V (1997) Effect of glucose and peripheral glucose regulation on memory in the elderly. Neurobiol Aging 18, 297-304.
41. Manning CA, Stone WS, Korol DL, Gold PE (1998) Glucose enhancement of 24-h memory retrieval in healthy elderly humans. Behav Brain Res 93, 71-76.
42. Messier C, Gagnon M (1996) Glucose regulation and cognitive functions: relation to Alzheimer's disease and diabetes. Behav Brain Res 75, 1-11.
43. Manning CA, Ragozzino ME, Gold PE (1993) Glucose enhancement of memory in patients with probable senile dementia of the Alzheimer's type. Neurobiol Aging 14, 523-528.
44. Craft S, Asthana S, Newcomer JW, Wilkinson CW, Matos IT, Baker LD, Cherrier M, Lofgreen C, Latendresse S (1999) Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. Arch Gen Psychiatry 56, 1135-1140.
45. Greenwood CE, Winocur G (2001) Glucose treatment reduces memory deficits in young adult rats fed high-fed diets. Neurobiol Learn Mem 75, 179-189.
46. Havrankova J, Roth J, Brownstein MJ (1979) Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels. Studies of obese and streptozotocintreated rodents. J Clin Invest 64, 636-642. (Pubitemid 9235011)
47. Hoyer S, Henneberg N, Knapp S, Lannert H, Martin E (1996) Brain glucose metabolism is controlled by amplification and desensitization of the neuronal insulin receptor. AnnNY Acad Sci 777, 374-379.
48. Zhao WQ, Chen H, Quon MJ, Alkon DL (2004) Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 490, 71-81.
49. Margolis RU, Altszuler N (1967) Insulin in the cerebrospinal fluid. Nature 215, 1375-1376.
50. Banks WA, Jaspan JB, Huang W, Kastin AJ (1997) Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin. Peptides 18, 1423-1429.
51. Park CR (2001) Cognitive effects of insulin in the central nervous system. Neurosci Biobehav Rev 25, 311-323.
52. Clarke DW, Mudd L, Boyd FT Jr, Fields M, Raizada MK (1986) Insulin is released from rat brain neuronal cells in culture. J Neurochem 47, 831-836.
53. Schechter R, Sadiq HF, Devaskar SU (1990) Insulin and insulin mRNA are detected in neuronal cell cultures maintained in an insulin-free/serum-free medium. J Histochem Cytochem 38, 829-836.
54. Schechter R, Whitmire J, Wheet GS, Beju D, Jackson KW, Harlow R, Gavin JR 3rd (1994) Immunohistochemical and in situ hybridization study of an insulin-like substance in fetal neuron cell cultures. Brain Res 636, 9-27.
55. Zhao WQ, Dou JT, Liu QWM, AlkonDC(2002) Evidence for locally produced insulin in the adult rat brain as a neuroactive peptide. Soc Neurosci Abstr, Program No. 375.12.
56. Gerozissis K (2008) Brain insulin, energy and glucose homeostasis; genes, environment and metabolic pathologies. Eur J Pharmacol 585, 38-49.
57. Ullrich A, Bell JR, Chen EY, Herrera R, Petruzzelli IM, Dull TJ, Gray A, Coussens L, Liao Y-C, Tsubokawa M, Mason A, Seeburg PH, Grunfeld C, Rosen OM,Ramachandran J (1985) Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes. Nature 313, 756-761.
58. Ebina Y, Ellis L, Jarnagin K, Edery M, Grat L, Clauser E, Ou J-H, Masiarz F, Kan YW, Goldfine ID, Roth RA, Rutter WJ (1985) The human insulin receptor cDNA: the structural basis for hormone-activated transmembrane signaling. Cell 40, 747-758.
59. Seino S, Seino M, Nishi S, Bell GI (1989) Structure of human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci U S A 86, 114-118.
60. Paz K, Voliovitch H, Hadari YR, Roberts CT, LeRoith D, Zick Y (1996) Interaction between the insulin receptor and its downstream effectors. J Biol Chem 271, 6998-7003.
61. Kahn CR, White MF (1988) The insulin receptor and the molecular mechanism of insulin action. J Clin Invest 82, 1151-1156.
62. Draznin B (2006) Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85alpha: the two sides of a coin. Diabetes 55, 2392-2397.
63. Saltiel AR, Pessin JE (2002) Insulin signaling pathways in time and space. Trends Cell Biol 12, 65-71.
64. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655-1657.
65. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70, 535-602.
66. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13, 2905-2927.
67. Bruss MD, Arias EB, Lienhard GE, Cartee GD (2005) Increased phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle in response to insulin or contractile activity. Diabetes 54, 41-50.
68. van der Heide LP, Ramakers GM, Smidt MP (2006) Insulin signaling in the central nervous system: learning to survive. Prog Neurobiol 79, 205-221.
69. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231-241.
70. Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasley LE, Reusch JE (2000) Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 275, 10761-10766.
71. Jefferson LS, Fabian JR, Kimball SR (1999) Glycogen synthase kinase-3 is the predominant insulin-regulated eukaryotic initiation factor 2B kinase in skeletal muscle. Int J Biochem Cell Biol 31, 191-200.
72. Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S (2002)Aprotein kinase B-dependent and rapamycinsensitive pathway controls skeletal muscle growth but not fiber type specification. Proc Natl Acad Sci U S A 99, 9213-9218.
73. van der Horst A, Burgering BMT (2007) Stressing the role of FoxO proteins in lifespan and disease. Cell Nat Rev Mol Biol 8, 440-450.
74. Lucas JJ, Hernandez F, Gomez-Ramos P, Moran MA, Hen R, Avila J (2001) Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20, 27-39.
75. Kaytor MD, OrrHT(2002) The GSK3 beta signaling cascade and neurodegenerative disease. Curr OpinNeurobiol 12, 275-278.
76. Grimes CA, Jope RS (2001) The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 65, 391-426.
77. Bijur GN, Jope RS (2001) Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 beta. J Biol Chem 276, 37436-37442.
78. Hansen TO, Rehfeld JF, Nielsen FC (2004) GSK-3beta reduces cAMP-induced cholecystokinin gene expression by inhibiting CREB binding. Neuroreport 15, 841-845.
79. Duarte AI, Santos MS, Oliveira CR, Rego AC (2005) Insulin neuroprotection against oxidative stress in cortical neurons- involvement of uric acid and glutathione antioxidant defenses. Free Radic Biol Med 39, 876-889.
80. Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC (2008) Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta 1783, 994-1002.
81. Brunet A, Datta SR, Greenberg ME (2001) Transcriptiondependent and independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr Opin Neurobiol 11, 297-305.
82. Zheng WH, Kar S, Quirion R (2002) Insulin-like growth factor-1-induced phosphorylation of transcription factor FKHRL1 is mediated by phosphatidylinositol 3-kinase/Akt kinase and role of this pathway in insulin-like growth factor- 1-induced survival of cultured hippocampal neurons. Mol Pharmacol 62, 225-233.
83. Gilley J, Coffer PJ, Ham J (2003) FOXO transcription factors directly activate bim gene expression and promote apoptosis in sympathetic neurons. J Cell Biol 162, 613-622.
84. KawanoT, Morioka M,Yano S, Hamada J, UshioY,Miyamoto E, Fukunaga K (2002) Decreased Akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus. J Cereb Blood Flow Metab 22, 926-934.
85. Yamaguchi A, Tamatani M, Matsuzaki H, Namikawa K, Kiyama H, Vitek MP, Mitsuda N, Tohyama M (2001) Akt activation protects hippocampal neurons from apoptosis by inhibiting transcriptional activity of p53. J Biol Chem 276, 5256-5264.
86. Quevedo C, Salinas M, Alćazar A (2002) Regulation of capdependent translation by insulin-like growth factor-1 in neuronal cells. Biochem Biophys Res Commun 291, 560-566.
87. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18, 1926-1945.
88. Bryant NJ, Govers R, James DE (2002) Regulated transport of the glucose transporter GLUT4. Nat Rev Mol Cell Biol 3, 267-277.
89. Keller SR (2003) The insulin-regulated aminopeptidase: a companion and regulator of GLUT4. Front Biosci 8, 410-420.
90. Fernando RN, Albiston AL, Chai SY (2008) The insulinregulated aminopeptidase IRAP is colocalised with GLUT4 in the mouse hippocampus-potential role in modulation of glucose uptake in neurones? Eur J Neurosci 28, 588-598.
91. Bhattacharya SK, Saraswati M (1991) Effect of intracerebroventricularly administered insulin on brain monoamines and acetylcholine in euglycaemic and alloxan-induced hyperglycaemic rats. Indian J Exp Biol 29, 1095-1100.
92. Figlewicz DP, Szot P (1991) Insulin stimulates membrane phospholipid metabolism by enhancing endogenous α1- adrenergic activity in the rat hippocampus. Brain Res 550, 101-107.
93. Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M, Malenka RC (2000) Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat Neurosci 3, 1291-1300.
94. Lin JW, Ju W, Foster K, Lee SH, Ahmadian G, Wyszynski M, Wang YT, Shen M (2000) Distinct molecular mecha nisms and divergent endocytotic pathways of AMPAreceptor internalization. Nat Neurosci 3, 1282-1290.
95. SkeberdisVA, Lan J, Zheng X, Zukin RS,BennettMV(2001) Insulin promotes rapid delivery of N-methyl-d-aspartate receptors to the cell surface by exocytosis. Proc Natl Acad Sci U S A 98, 3561-3566.
96. van der Heide LP, Hoekman MF, Biessels GJ, Gispen WH (2003) Insulin inhibits extracellular regulated kinase 1/2 phosphorylation in a phosphatidylinositol 3-kinase (PI3) kinase-dependent manner in Neuro2a cells. J Neurochem 86, 86-91.
97. Zhou Q, Xiao MY, Nicoll RA (2001) Contribution of cytoskeleton to the internalization of AMPA receptors. Proc Natl Acad Sci USA98, 1261-1266.
98. Zhao WQ, Alkon DC (2001) Role of insulin and insulin receptors in learning and memory. Mol Cell Endocrinol 177, 125-134.
99. Satin LS, Kinard TA. (1998) Neurotransmitters and their receptors in the islets of Langerhans of the pancreas: what messages do acetylcholine, glutamate, and GABA transmit? Endocrine 8, 213-223.
100. Nelson TJ, Sun MK, Hongpaisan J, Alkon DL (2008) Insulin, PKC signaling pathways and synaptic remodeling during memory storage and neuronal repair. Eur J Pharmacol 585, 76-87.
101. Bonini JS, Da Silva WC, Bevilaqua LR, Medina JH, Izquierdo I, CammarotaM(2007) On the participation of hippocampal PKC in acquisition, consolidation and reconsolidation of spatial memory. Neuroscience 147, 37-45. (Pubitemid 46876700)
102. Zhang GR, Liu M, Cao H, Kong L,Wang X, O'Brien JA,Wu SC, Cook RG, Geller AI (2009) Improved spatial learning in aged rats by genetic activation of protein kinase C in small groups of hippocampal neurons. Hippocampus 19, 413-423.
103. Lin Y, Jover-Mengual T, Wong J, Bennett MV, Zukin RS (2006) PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating. Proc Natl Acad Sci U S A 103, 19902-19907.
104. Ma XH, Zhong P, Gu Z, Feng J, Yan Z (2003) Muscarinic potentiation of GABA(A) receptor currents is gated by insulin signaling in the prefrontal cortex. J Neurosci 23, 1159-1168.
105. Lee CC, Huang CC, Wu MY, Hsu KS (2005) Insulin stimulates post-synaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. J Biol Chem 280, 18543-18550.
106. El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS (2000) PSD-95 involvement in maturation of excitatory synapses. Science 290, 1364-1368.
107. Huang CC, Lee CC, Hsu KS (2004) An investigation into signal transduction mechanisms involved in insulin-induced long-term depression in the CA1 region of the hippocampus. J Neurochem 89, 217-231.
108. Man HY, Lin JW, Ju WH, Ahmadian G, Liu L, Becker LE, Sheng M, Wang YT (2000) Regulation of AMPA receptormediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 25, 649-662.
109. 2+ but requires phosphorylation by Akt at Ser (1179). J Biol Chem 276, 30392-30398.
110. Doreulee N, Sergeeva OA, Yanovsky Y, Chepkova AN, Selbach O, Godecke A, Schrader J, Haas HL (2003) Corticostriatal synaptic plasticity in endothelial nitric oxide synthase deficient mice. Brain Res 964, 159-163.
111. Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14, 311-317.
112. Haddad JJ (2005) N-Methyl-D-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention? Prog Neurobiol 11, 252-282.
113. Subramaniam S, Shahani N, Strelau J, Laliberte C, Brandt R, Kaplan D, Unsicker K (2005) Insulin-like growth factor 1 inhibits extracellular signal-regulated kinase to promote neuronal survival via the phosphatidylinositol3-kinase/protein kinase A/c-Raf pathway. J Neurosci 25, 2838-2852.
114. Sweat JD (2001) The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76, 1-10.
115. Thiels E, Klann E (2001) Extracellular signal-regulated kinase, synaptic plasticity, and memory. Rev Neurosci 12, 327-345.
116. Cammarota M, Bevilagua LR, Ardenghi P, Paratcha G, Levi de Stein M, Izquierdo I, Medina JH (2000), Learningassociated activation of nuclear MAPK, CREB and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance. Mol Brain Res 76, 36-46.
117. Hoyer S (2002) The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD).Amini-review. J Neural Transm 109, 991-1002.
118. Cole GM, Frautschy SA (2007) The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer's Disease. Exp Gerontol 42, 10-21.
119. Witte AV, Fobker M, Gellner R, Knecht S, Flöel A (2009) Caloric restriction improves memory in elderly humans. Proc Natl Acad Sci U S A 106, 1255-1260.
120. Chong ZZ, Li F, Maiese K (2005) Oxidative stress in the brain: Novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75, 207-246.
121. Kimura T, Takamatsu J, Ikeda K, Kondo A, Miyakawa T, Horiuchi S (1996) Accumulation of advanced glycation end products of the Maillard reaction with age in human hippocampal neurons. Neurosci Lett 208, 53-56. (Pubitemid 26128106)
122. D́avila D, Torres-Aleman I (2008) Neuronal death by oxidative stress involves activation of FOXO3 through a two-arm pathway that activates stress kinases and attenuates insulinlike growth factor i signaling. Mol Biol Cell 19, 2014-2025.
123. Taylor JM, Ali U, Iannello RC, Hertzog P, Crack, PJ (2005) Diminished Akt phosphorylation in neurons lacking glutathione peroxidase-1 (Gpx1) leads to increased susceptibility to oxidative stress-induced cell death. J Neurochem 92, 283-293.
124. Sas K, Robotka H, Toldi J, V́ecsei L (2007) Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci 257, 221-239.
125. Moreira PI, Santos MS, Seiça R, Oliveira CR (2007) Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes. J Neurol Sci 257, 206-214.
126. Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8, 1376-1382.
127. Brands AMA, Kessels RPC, de Haan EHF, Kappelle LJ, Biessels GJ (2004) Cerebral dysfunction in type 1 diabetes: effects of insulin, vascular risk factors and blood-glucose levels. Eur J Pharmacol 490, 159-168.
128. Wessels AM, Scheltens P, Barkhof F, Heine RJ (2008) Hyperglycaemia as a determinant of cognitive decline in patients with type 1 diabetes. Eur J Pharmacol 585, 88-96.
129. Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23, 542-549.
130. Perantie DC,Wu J, Koller JM, Lim A,Warren SL, Black KJ, Sadler M, White NH, Hershey T (2007) Regional brain volume differences associated with hyperglycemia and severe hypoglycemia in youth with type 1 diabetes. Diabetes Care 30, 2331-2337.
131. Malone JI, Hanna S, Saporta S, Mervis RF, Park CR, Chong L, Diamond DM (2008). Hyperglycemia not hypoglycemia alters neuronal dendrites and impairs spatial memory. Pediatr Diabetes 9, 531-5399.
132. Hino K, Nishikawa M, Sato E, Inoue M (2005) L-carnitine inhibits hypoglycemia-induced brain damage in the rat. Brain Res 1053, 77-87.
133. Biessels GJ, Kamal A, Urban IJ, Spruijt BM, Erkelens DW, Gispen WH (1998) Water maze learning and hippocampal synaptic plasticity in streptozotocin- diabetic rats: effects of insulin treatment. Brain Res 800, 125-135.
134. Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA, Masliah E (2008) Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer 's disease and correction by insulin. J Neurosci Res 86, 3265-3274.
135. Ott A, Stolk RP, Hofman A, van Harskamp F, Grobbee DE, Breteler MM(1996) Association of diabetes mellitus and dementia: the Rotterdam Study. Diabetologia 39, 1392-1397.
136. Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM (1999) Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 53, 1937-1942.
137. Leibson CL, Rocca WA, Hanson VA, Cha R, Kokmen E, O'Brien PC, Palumbo PJ (1997) Risk of dementia among persons with diabetes mellitus: a population-based cohort study. Am J Epidemiol 145, 301-308. (Pubitemid 27082028)
138. Peila R, Rodriguez BL, Launer LJ; Honolulu-Asia Aging Study (2002) Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes 51, 1256-1262.
139. Irie F, Fitzpatrick AL, Lopez OL, Kuller LH, Peila R, Newman AB, Launer LJ (2008) Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol 65, 89-93.
140. Kuusisto J, Koivisto K, Mykkanen L, Helkala EL, Vanhanen M, Hanninen T, Kervinen K, Kesaniemi YA, Riekkinen PJ, LaaksoM(1997) Association between features of the insulin resistance syndrome and Alzheimer's disease independently of apolipoprotein E4 phenotype: cross sectional population based study. BMJ 315, 1045-1049.
141. Luchsinger JA, Tang MX, Shea S, Mayeux R (2004) Hyperinsulinemia and risk of Alzheimer disease. Neurology 63, 1187-1192.
142. Miklossy J, Qing H, Radenovic A, Kis A, Vileno B, L̀aszĺo F, Miller L, Martins RN, Waeber G, Mooser V, Bosman F, Khalili K, Darbinian-Sarlissian N, McGeer PL (2008) Beta amyloid and hyperphosphorylated tau deposits in the pancreas in type 2 diabetes. Neurobiol Aging, in press.
143. Ho L, Qin W, Pompl PN, Xiang Z, Wang J, Zhao Z, Peng Y, Cambareri G, Rocher A, Mobbs CV, Hof PR, Pasinetti GM (2004) Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEBJ 18, 902-904.
144. Hoyer S (2000) Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update. Exp Gerontol 35, 1363-1372.
145. Shi Q, Xu H, Kleinman WA, Gibson GE (2008) Novel functions of the alpha-ketoglutarate dehydrogenase complex may mediate diverse oxidant-induced changes in mitochondrial enzymes associated with Alzheimer's disease. Biochim Biophys Acta 1782, 229-238.
146. Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57, 695-703.
147. Sims NR, Bowen DM, Allen SJ, Smith CC, Neary D, Thomas DJ, Davison AN (1983) Presynaptic cholinergic dysfunction in patients with dementia. J Neurochem 40, 503-509.
148. Baskin DS, Browning JL, Pirozzolo FJ, Korporaal S, Baskin JA, Appel SH (1999) Brain choline acetyltransferase and mental function in Alzheimer disease. Arch Neurol 56, 1121-1123.
149. Wang B, Yang L, Wang Z, Zheng H (2007) Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter. Proc Natl Acad Sci USA104, 14140-14145.
150. Fukuyama H, Ogawa M, Yamauchi H, Yamaguchi S, Kimura J, Yonekura Y, Konishi J (1994) Altered cerebral energy metabolism in Alzheimer's disease: a PET study. J Nucl Med 35, 1-6.
151. Haxby JV, Rapoport SI (1986) Abnormalities of regional brain metabolism in Alzheimer's disease and their relation to functional impairment. Prog Neuropsychopharmacol Biol Psychiatry 10, 427-438.
152. Herholz K (1995) FDG PET and differential diagnosis of dementia. Alzheimer Dis Assoc Disord 9, 6-16.
153. Hoyer S (1998) Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J Neural Transm 105, 415-422.
154. Doyle P, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B (1995) Four-day hyperinsulinemia in euglycemic conditions alters local cerebral glucose utilization in specific brain nuclei of freely moving rats. Brain Res 684, 47-55.
155. Lucignani G, Namba H, Nehlig A, Porrino LJ, Kennedy C, Sokoloff L (1987) Effects of insulin on local cerebral glucose utilization in the rat. J Cereb Blood Flow Metab 7, 309-314. (Pubitemid 17112032)
156. Bondy CA, Cheng CM (2004) Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol 490, 25-31.
157. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S (2003) 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 U S A 100, 4162-4167.
158. Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ (1998) Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 273, 32730-32738.
159. Bernstein HG, Ansorge S, Riederer P, Reiser M, Frölich L, Bogerts B (1999) Insulin-degrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques. Neurosci Lett 263, 161-164.
160. Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA, Schellenberg GD, Jin LW, Kovacina KS, Craft S (2003) Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipo protein E-epsilon4 allele. Am J Pathol 162, 313-319.
161. Morelli L, Llovera RE, Mathov I, Lue LF, Frangione B, Ghiso J, Castaño EM (2004) Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy. J Biol Chem 279, 56004-56013.
162. LeissringMA,FarrisW, ChangAY,WalshDM,Wu X, Sun X, Frosch MP, Selkoe DJ (2003) Enhanced proteolysis of betaamyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40, 1087-1093.
163. Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P, Xu H (2001) Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 21, 2561-2570.
164. Ṕerez A, Morelli L, Cresto JC, Castaño EM (2000) Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brains. Neurochem Res 25, 247-255.
165. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, SmallGW, Roses AD, Haines JL, Pericak-Vance MA (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921-923.
166. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP,Viola KL, Zhao WQ,Ferreira ST, Klein WL (2009) Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A 106, 1971-1976.
167. Lee KY, Koh SH, Noh MY, Kim SH, Lee YJ (2008) Phosphatidylinositol-3- kinase activation blocks amyloid beta-induced neurotoxicity. Toxicology 243, 43-50.
168. Takashima A, Noguchi K, Michel G, Mercken M, Hoshi M, Ishiguro K, Imahori K (1996) Exposure of rat hippocampal neurons to amyloid beta peptide (25-35) induces the inactivation of phosphatidyl inositol-3 kinase and the activation of tau protein kinase I/glycogen synthase kinase-3 beta. Neurosci Lett 203, 33-36.
169. Koh SH, Noh MY, Kim SH (2008) Amyloid-beta-induced neurotoxicity is reduced by inhibition of glycogen synthase kinase-3. Brain Res 1188, 254-262.
170. Busciglio J, Lorenzo A, Yeh J, Yankner BA (1995) betaamyloid fibrils
171. Noble W, Planel E, Zehr C, Olm V, Meyerson J, Suleman F, Gaynor K, Wang L, LaFrancois J, Feinstein B, Burns M, Krishnamurthy P, Wen Y, Bhat R, Lewis J, Dickson D, Duff K (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci U S A 102, 6990-6995.
172. David DC, Hauptmann S, Scherping I, Schuessel K, Keil U, Rizzu P, Ravid R, Drose S, Brandt U, Muller WE, Eckert A, Gotz J (2005) Proteomic and functional analyses reveal a mitochondrial dysfunction in P301L tau transgenic mice. J Biol Chem 280, 23802-23814.
173. Lesort M, Johnson GV (2000) Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons. Neuroscience 99, 305-316.
174. Cheng CM, Tseng V,Wang J,Wang D, Matyakhina L, Bondy CA (2005) Tau is hyperphosphorylated in the insulin-like growth factor-I null brain. Endocrinology 146, 5086-5091.
175. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444, 860-867.
176. Facchini FS, Hua NW, Reaven GM, Stoohs RA (2000) Hyperinsulinemia: the missing link among oxidative stress and age-related diseases? Free Radic Biol Med 29, 1302-1306.
177. Fontaine V, Mohand-Said S, Hanoteau N, Fuchs C, Pfizenmaier K, Eisel U (2002) Neurodegenerative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF receptor 2. J Neurosci 22, 216-222.
178. Duarte AI, Proença T, Oliveira CR, Santos MS, Rego AC (2006) Insulin restores metabolic function in cultured cortical neurons subjected to oxidative stress. Diabetes 55, 2863-2870.
179. Ferńandez-Vizarra P, Ferńandez AP, Castro-Blanco S, Serrano J, Bentura ML, Mart́inez-Murillo R, Mart́inez A, Rodrigo J (2004) Intra- and extracellular Abeta and PHF in clinically evaluated cases of Alzheimer's disease. Histol Histopathol 19, 823-844. (Pubitemid 38855065)
180. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS,Wu H (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304, 448-452
181. Moreira PI, Siedlak SL, Wang X, Santos MS, Oliveira CR, Tabaton M Nunomura A, Szweda LI, Aliev G, Smith MA, Zhu X, Perry G (2007) Autophagocytosis of mitochondria is prominent in Alzheimer disease. J Neuropathol Exp Neurol 66, 525-532. (Pubitemid 46869694)
182. Hirai K, Aliev G, Nunomura A, Fujioka H, Russell R L, Atwood C S, Johnson A B, Kress Y, Vinters H V, Tabaton M, Shimohama S, Cash A D, Siedlak S L, Harris P L R, Jones P K, Petersen R B, Perry G, and Smith M A (2001) Mitochondrial Abnormalities in Alzheimer's Disease. J Neurosci 21, 3017-3023.
183. Moreira PI, Santos MS, Moreno A, Oliveira C (2001) Amyloid beta-peptide promotes permeability transition pore in brain mitochondria. Biosci Rep 21, 789-800.
184. Moreira PI, Santos MS, Moreno A, Rego AC, Oliveira C (2002) Effect of amyloid beta-peptide on permeability transition pore: a comparative study. J Neurosci Res 69, 257-267.
185. Moreira PI, Santos MS, Moreno AM, Seiça R, Oliveira CR (2003) Increased vulnerability of brain mitochondria in diabetic (Goto-Kakizaki) rats with aging and amyloid-beta exposure. Diabetes 52, 1449-1456.
186. Moreira PI, Santos MS, Sena C, Seiça R, Oliveira CR (2005) Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 18, 628-637. (Pubitemid 40332720)
187. Pearson HA, Peers C (2006) Physiological roles for amyloid beta peptides. J Physiol 575, 5-10.
188. Gabuzda D, Busciglio J, Chen L, Matsudaira P, Yankner BA (1994) Inhibition of energy metabolism alters the processing of amyloid precursor protein and induces a potentially amyloidogenic derivative. J Biol Chem 269, 13623-13628.
189. Moreira PI, Santos MS, Sena C, Seiça R, Oliveira CR (2005) Insulin protects against amyloid beta-peptide toxicity in brain mitochondria of diabetic rats. Neurobiol Dis 18, 628-637. (Pubitemid 40332720)
190. Duarte AI, Santos MS, Seiça R, Oliveira CR (2004) Oxidative stress affects synaptosomal gamma-aminobutyric acid and glutamate transport in diabetic rats: the role of insulin. Diabetes 53, 2110-2116.
191. Grünblatt E, Salkovic-Petrisic M, Osmanovic J, Riederer P, Hoyer S (2007) Brain insulin system dysfunction in strep tozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein. J Neurochem 101, 757-770.
192. Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm 72, 217-1133
193. Devi L, Raghavendran V, Prabhu BM, Avadhani NG, Anandatheerthavarada HK (2008) Mitochondrial import and accumulation of ?-synuclein impair complex I in human dopaminergic neuronal cultures and Parkinson disease brain. J Biol Chem 283, 9089-9100.
194. Cleeter MW, Cooper JM, Schapira AH (1992) Irreversible inhibition of mitochondrial complex I by 1-methyl-4- phenylpyridinium: evidence for free radical involvement. J Neurochem 58, 786-789.
195. Salinas M, Martin D, Alvarez A, Cuadrado A (2001) Akt1/ PKBalpha protects PC12 cells against the parkinsonisminducing neurotoxin 1- methyl-4- phenylpyridinium and reduces the levels of oxygen-free radicals. Mol Cell Neurosci 17, 67-77.
196. Quesada A, Lee BY, Micevych PE (2008) PI3 kinase/Akt activation mediates estrogen and IGF-1 nigral DA neuronal neuroprotection against a unilateral rat model of Parkinson's disease. Dev Neurobiol 68, 632-644.
197. Offen D, Shtaif B, Hadad D, Weizman A, Melamed E, Gil- Ad I (2001) Protective effect of insulin-like-growth-factor-1 against dopamine-induced neurotoxicity in human and rodent neuronal cultures: possible implications for Parkinson's disease. Neurosci Lett 316, 129-132.
198. Ebert AD, Beres AJ, Barber AE, Svendsen CN (2008) Human neural progenitor cells over-expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's disease. Exp Neurol 209, 213-223.
199. Chalmanov V, Vurbanova M (1987) Diabetes mellitus in parkinsonism patients. Vutr Boles 26, 68-73.
200. Arvanitakis Z, Wilson RS, Bienias JL, Bennett DA (2007) Diabetes and parkinsonian signs in older persons. Alzheimer Dis Assoc Disord 21, 144-149.
201. Hu G, Jousilahti P, Bidel S, Antikainen R, Tuomilehto J (2007) Type 2 diabetes and the risk of Parkinson's disease. Diabetes Care 30, 842-847.
202. Blum-Degen D, Frölich L, Hoyer S, Riederer P (1995) Altered regulation of brain glucose metabolism as a cause of neurodegenerative disorders? J Neural Transm Suppl 46, 139-147.
203. Takahashi M, Yamada T, Tooyama I, Moroo I, Kimura H, Yamamoto T, Okada H (1996) Insulin receptor mRNA in the substantia nigra in Parkinson's disease. Neurosci Lett 204, 201-204.
204. Moroo I, Yamada T, Makino H, Tooyama I, McGeer PL, McGeer EG, Hirayama K (1994) Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson's disease. Acta Neuropathol (Berl.) 87, 343-348.
205. Figlewicz DP, Szot P, ChavezM,Woods SC,Veith RC (1994) Intraventricular insulin increases dopamine transporter mRNA in rat VTA/substantia nigra. Brain Res 644, 331-334.
206. Liu Z,Wang Y, Zhao W, Ding J, Mei Z, Guo L, Cui D, Fei J (2001) Peptide derived from insulin with regulatory activity of dopamine transporter. Neuropharmacology 41, 464-471.
207. Figlewicz DP, Brot MD, McCall AL, Szot P (1996) Diabetes causes differential changes in CNS noradrenergic and dopaminergic neurons in the rat: a molecular study. Brain Res 736, 54-60.
208. Lozovsky D, Saller CF, Kopin IJ (1981) Dopamine receptor binding is increased in diabetic rats. Science 214, 1031-1033.
209. Browne SE, Bowling AC, MacGarvey U, Baik MJ, Berger SC, Muqit MM, Bird ED, Beal MF (1997) Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann Neurol 41, 646-653.
210. Lim D, Fedrizzi L,Tartari M, ZuccatoC,CattaneoE, Brini M, Carafoli E (2008) Calcium homeostasis and mitochondrial dysfunction in striatal neurons of Huntington disease. J Biol Chem 283, 5780-5789.
211. Milakovic T, Quintanilla RA, Johnson GV (2006) Mutant huntingtin expression induces mitochondrial calcium handling defects in clonal striatal cells: functional consequences. J Biol Chem 281, 34785-34795.
212. Podolsky S, LeopoldNA, Sax DS (1972) Increased frequency of diabetes mellitus in patients with Huntington's chorea. Lancet 1, 1356-1358.
213. Lalíc NM, Maríc J, Svetel M, Jotíc A, Stefanova E, Lalíc K, Dragasevíc N, Milicid́c T, Lukíc L, Kostíc VS (2008) Glucose homeostasis in Huntington disease: abnormalities in insulin sensitivity and early-phase insulin secretion. Arch Neurol 65, 476-480.
214. Gamberino WC, Brennan WA Jr (1994) Glucose transporter isoform expression in Huntington's disease brain. J Neurochem 63, 1392-1397.
215. Kuhl DE, Metter EJ, Riege WH, Markham CH (1984) Patterns of cerebral glucose utilization in Parkinson's disease and Huntington's disease. Ann Neurol 15 Suppl, 119-125.
216. Hurlbert MS, Zhou W, Wasmeier C, Kaddis FG, Hutton JC, Freed CR (1999) Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes. Diabetes 48, 649-651.
217. Andreassen OA, Dedeoglu A, Stanojevic V, Hughes DB, Browne SE, Leech CA, Ferrante RJ, Habener JF, Beal MF, Thomas MK (2002) Huntington's disease of the endocrine pancreas: insulin deficiency and diabetes mellitus due to impaired insulin gene expression. Neurobiol Dis 11, 410-424.
218. Björkqvist M, FexM, Renström E,Wierup N, Peterśen A, Gil J, Bacos K, Popovic N, Li J-Y, Sundler F, Brundin P, Mulder H (2005) The R6/2 transgenic mouse model of Huntington's disease develops diabetes due to deficient b-cell mass and exocytosis. Hum Mol Genet 14, 565-574.
219. Josefsen K, Nielsen MD, Jørgensen KH, Bock T, Nø rremølle A, Sørensen SA, Naver B, Hasholt L (2008) Impaired glucose tolerance in the R6/1 transgenic mouse model of Huntington's disease. J Neuroendocrinol 20, 165-172.
220. Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F (2002) The IGF- 1/Akt pathway is neuroprotective in Huntington's disease and involves huntingtin phosphorylation by Akt. Dev Cell 2, 831-837.
221. Yamamoto A, Cremona ML, Rothman JE (2006) Autophagymediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 172, 719-731.
222. Colin E, Ŕegulier E, Perrin V, Dürr A, Brice A, Aebischer P, D́eglon N, Humbert S, Saudou F (2005) Akt is altered in an animal model of Huntington's disease and in patients. Eur J Neurosci 21, 1478-1488.
223. Menzies FM, Cookson MR, Taylor RW, Turnbull DM, Chrzanowska-Lightowlers ZM, Dong L, Figlewicz DA, Shaw PJ (2002) Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis. Brain 125, 1522-1533.
224. Dupuis L, Gonzalez de Aguilar JL, Oudart H, de Tapia M, Barbeito L, Loeffler JP (2004) Mitochondria in amyotrophic lateral sclerosis: a trigger and a target. Neurodegener Dis 1, 245-254. (Pubitemid 40960427)
225. Liu D, Wen J, Liu J, Li L (1999) The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids. FASEB J 13, 2318-2328.
226. Babu GN, Kumar A, Chandra R, Puri SK, Singh RL, Kalita J, Misra UK (2008) Oxidant-antioxidant imbalance in the erythrocytes of sporadic amyotrophic lateral sclerosis patients correlates with the progression of disease. Neurochem Int 52, 1284-1289.
227. Guo Z, Kindy MS, Kruman I, Mattson MP (2000) ALSlinked Cu/Zn-SOD mutation impairs cerebral synaptic glucose and glutamate transport and exacerbates ischemic brain injury. J Cereb Blood Flow Metab 20, 463-468.
228. Pradat PF, Bruneteau G, Gordon PH, Dupuis L, Bonnefont- Rousselot D, Simon D, Salachas F, Corcia P, Frochot V, Lacorte JM, Jardel C, Coussieu C, Forestier NL, Lacomblez L, Loeffler JP, Meininger V (2009) Impaired glucose tolerance in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 20, 1-6.
229. Shaw PJ, Eggett CJ (2000) Molecular factors underlying selective vulnerability of motor neurons to neurodegeneration in amyotrophic lateral sclerosis. J Neurol 247, 17-27.
230. Spreux-Varoquaux O, Bensimon G, Lacomblez L, Salachas F, Pradat PF, Le Forestier N, Marouan A, Dib M, MeiningerV (2002) Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients. J Neurol Sci 193, 73-78.
231. Carriedo SG, Yin HZ, Weiss JH (1996) Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J Neurosci 16, 4069-4079.
232. Schubert D, Piasecki D (2001) Oxidative glutamate toxicity can be a component of the excitotoxicity cascade. J Neurosci 21, 7455-7462.
233. Vincent AM, Mobley BC, Hiller A, Feldman EL (2004) IGFI prevents glutamate-induced motor neuron programmed cell death. Neurobiol Dis 16, 407-416.
234. Kaspar BK, Llad́o J, Sherkat N, Rothstein JD, Gage FH (2003) Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301, 839-842.
235. Franz CK, Federici T, Yang J, Backus C, Oh SS, Teng Q, Carlton E, Bishop KM, Gasmi M, Bartus RT, Feldman EL, Boulis NM (2009) Intraspinal cord delivery of IGF-I mediated by adeno-associated virus 2 is neuroprotective in a rat model of familial ALS. Neurobiol Dis 33, 473-481.
236. Wickelgren I (1998) Tracking insulin to the mind. Science 280, 517-519.
237. Unger JW, Livingston JN, MossAM(1991) Insulin receptors in the central nervous system: localization, signalling mechanisms and functional aspects. Prog Neurobiol 36, 343-362.
238. Eichenbaum H (1999) The hippocampus and mechanisms of declarative memory. Behav Brain Res 103, 123-133.
239. Eichenbaum H (2004) Hippocampus: cognitive processes and neural representations that underlie declarative memory. Neuron 44, 109-120.
240. Squire LR (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev 99, 195-231.
241. Moosavi M, Naghdi N, Maghsoudi N, Zahedi Asl S (2006) The effect of intrahippocampal insulin microinjection on spatial learning and memory. Horm Behav 50, 748-752.
242. Babri S, Badie HG, Khamenei S, Seyedlar MO (2007) Intrahippocampal insulin improves memory in a passiveavoidance task in male wistar rats. Brain Cogn 64, 86-91.
243. Craft S, Asthana S, Cook DG, Baker LD, Cherrier M, Purganan K,Wait C, Petrova A, Latendresse S,Watson GS, Newcomer JW, Schellenberg GD, Krohn AJ (2003) Insulin dose- response effects on memory and plasma amyloid precursor protein in Alzheimer's disease: interactions with apolipoprotein E genotype. Psychoneuroendocrinology 28, 809-822.
244. Craft S, Asthana S, Schellenberg G, Cherrier M, Baker LD, Newcomer J, Plymate S, Latendresse S, Petrova A, Raskind M, Peskind E, Lofgreen C, Grimwood K (1999) Insulin metabolism in Alzheimer's disease differs according to apolipoprotein E genotype and gender. Neuroendocrinology 70, 146-152.
245. Craft S, Newcomer J, Kanne S, Dagogo-Jack S, Cryer P, Sheline Y, Luby J, Dagogo-Jack A, Alderson A (1996) Memory improvement following induced hyperinsulinemia in Alzheimer's disease. Neurobiol Aging 17, 123-130.
246. Watson GS, Peskind ER, Asthana S, Purganan K, Wait C, Chapman D, Schwartz MW, Plymate S, Craft S (2003) Insulin increases CSF Abeta42 levels in normal older adults. Neurology 60, 1899-1903.
247. Kern W, Peters A, Fruehwald-Schultes B, Deininger E, Born J, Fehm HL (2001) Improving influence of insulin on cognitive functions in humans. Neuroendocrinology 74, 270-280.
248. Izumi Y, Yamada KA, Matsukawa M, Zorumski CF (2003) Effects of insulin on long-term potentiation in hippocampal slices from diabetic rats. Diabetologia 46, 1007-1012.
249. Reger MA, Watson GS, Frey WH, Baker LD, Cholerton B, Keeling ML, Belongia DA, Fishel MA, Plymate SR, Schellenberg GD, Cherrier MM, Craft S (2006) Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging 27, 451-458.
250. Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W (2004) Intranasal insulin improves memory in humans. Psychoneuroendocrinology 29, 1326-1334.
251. Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL, Born J,KernW(2007) Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology 32, 239-243.
252. Desvergne B, Wahli W (1999) Peroxisome proliferatoractivated receptors: nuclear control of metabolism. Endocr Rev 20, 649-688.
253. Reddy JK, Hashimoto T (2001) Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 21, 193-230.
254. Heneka MT, Landreth GE (2007) PPARs in the brain. Biochim Biophys Acta 1771, 1031-1045.
255. Bordet R, Ouk T, Petrault O, Geĺe P, Gautier S, Laprais M, Deplanque D, Duriez P, Staels B, Fruchart JC, Bastide M (2006) PPAR: a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases. Biochem Soc Trans 34, 1341-1346.
256. Heneka MT, Landreth GE, Feinstein DL (2001) Role for peroxisome proliferator-activated receptor-gamma in Alzheimer's disease. Ann Neurol 49, 276.
257. Sundararajan S, Jiang Q, Heneka M, Landreth G. (2006) PPARgamma as a therapeutic target in central nervous system diseases. Neurochem Int 49, 136-144.
258. Kiaei M, Kipiani K, Chen J, Calingasan NY, Beal MF (2005) Peroxisome proliferator-activated receptor-gamma agonist extends survival in transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurol 191, 331-336. (Pubitemid 40092877)
259. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Fiebich BL, Finch CE, Frautschy S, Griffin WS, Hampel H, Hull M, Landreth G, Lue L, Mrak R, Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Shen Y, StreitW, Strohmeyer R, Tooyoma I, Van Muiswinkel FL, Veerhuis R, Walker D, Webster S, Wegrzyniak B,Wenk G,Wyss-Coray T (2000) Inflammation and Alzheimer's disease. Neurobiol Aging 21, 383-421.
260. Luna-Medina R, Cortes-Canteli M, Alonso M, Santos A, Mart́inez A, Perez-Castillo A (2005) Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator- activated receptor γ activation. J Biol Chem 280, 21453-21462.
261. Wang N, Verna L, Chen NG, Chen J, Li H, Forman BM, Stemerman MB (2002) Constitutive activation of peroxisome proliferator-activated receptor-gamma suppresses proinflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem 277, 34176-34181.
262. Klotz L, Sastre M, Kreutz A, Gavrilyuk V, Klockgether T, Feinstein DL, Heneka MT (2003) Noradrenaline induces expression of peroxisome proliferator activated receptor gamma (PPARgamma) in murine primary astrocytes and neurons. J Neurochem 86, 907-916.
263. Camacho IE, Serneels L, Spittaels K, Merchiers P, Dominguez D, De Strooper B (2004) Peroxisomeproliferator- activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide. J Neurosci 24, 10908-10917.
264. Wada K, Nakajima A, Katayama K, Kudo C, Shibuya A, Kubota N, Terauchi Y, Tachibana M, Miyoshi H, Kamisaki Y, Mayumi T, Kadowaki T, Blumberg RS (2006) Peroxisome proliferator-activated receptor gamma-mediated regulation of neural stem cell proliferation and differentiation. J Biol Chem 281, 12673-12681.
265. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE (2000) Inflammatory mechanisms in Alzheimer's disease: inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J Neurosci 20, 558-567.
266. Kim EJ, Kwon KJ, Park J-Y, Lee SH, Moon C-H, Baik EJ (2002) Effects of peroxisome proliferator-activated receptor agonists on LPS-induced neuronal death in mixed cortical neurons: associated with iNOS and COX-2. Brain Res 941, 1-10.
267. Yan Q, Zhang J, Liu H, Babu-Khan S, Vassar R, Biere AL, Citron M, Landreth G (2003) Anti-inflammatory drug therapy alters β-amyloid processing and deposition in an animal model of Alzheimer's disease. J Neurosci 23, 7504-7509.
268. Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, Van Leuven F (2005) Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2, 22.
269. Sastre M, Dewachter I, Landreth GE, Willson TM, KlockgetherT, van Leuven F, HenekaMT(2003) Nonsteroidal antiinflammatory drugs and peroxisome proliferator-activated receptor-γ agonists modulate immunostimulated processing of amyloid precursor protein through regulation of β- secretase. J Neurosci 23, 9796-9804.
270. Sastre M, Klockgether T, Heneka MT (2006) Contribution ofinflammatory processes to Alzheimer's disease: molecular mechanisms. Int J Dev Neurosci 24, 167-176.
271. Ghosh S, Patel N, Rahn D, McAllister J, Sadeghi S, Horwitz G, Berry D, Wang KX, Swerdlow RH (2007) The thiazolidinedione pioglitazone alters mitochondrial function in human neuron-like cells. Mol Pharmacol 71, 1695-1702.
272. Pedersen WA, McMillan PJ, Kulstad JJ, Leverenz JB, Craft S, Haynatzki GR (2006) Rosiglitazone attenuates learning and memory deficits in Tg2576 Alzheimer mice. Exp Neurol 199, 265-273.
273. Fuenzalida K, Quintanilla R, Ramos P, Piderit D, Fuentealba RA, Martinez G, Inestrosa NC, Bronfman M (2007) Peroxisome proliferator-activated receptor gamma up-regulates the Bcl-2 anti-apoptotic protein in neurons and induces mitochondrial stabilization and protection against oxidative stress and apoptosis. J Biol Chem 282, 37006-37015.
274. Risner ME, Saunders AM, Altman JFB, Ormandy GC, Craft S, Foley IM, Zvartau-Hind ME, Hosford DA, Roses AD; Rosiglitazone in Alzheimer's Disease Study Group (2006) Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 6, 246-254.
275. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE, Keeling ML, Craft S (2005) Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. Am J Geriatr Psychiatry 13, 950-958.
276. Brodbeck J, Balestra ME, Saunders AM, Roses AD, Mahley RW, Huang Y (2008) Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons. Proc Natl Acad Sci U S A 105, 1343-1346.
277. Breidert T, Callebert J, Heneka MT, Landreth G, Launay JM, Hirsch EC (2002) Protective action of the peroxisome proliferator-activated receptor-gamma agonist pioglitazone in a mouse model of Parkinson's disease. J Neurochem 82, 615-624.
278. Dehmer T, Heneka MT, Sastre M, Dichgans J, Schulz JB (2004) Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation. J Neurochem 88, 494-501.
279. Quinn LP, Crook B, Hows ME, Vidgeon-Hart M, Chapman H, Upton N, Medhurst AD, Virley DJ (2008) The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B. Br J Pharmacol 154, 226-233.
280. Hunter RL, Choi DY, Ross SA, Bing G (2008) Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague-Dawley rats. Neurosci Lett 432, 198-201.
281. Hunter RL, Dragicevic N, Seifert K, Choi DY, Liu M, Kim HC, Cass WA, Sullivan PG, Bing G (2007) Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system. J Neurochem 100, 1375-1386.
282. Xing B, Liu M, Bing G (2007) Neuroprotection with pioglitazone against LPS insult on dopaminergic neurons may be associated with its inhibition of NF-kappaB and JNK activation and suppression of COX-2 activity. J Neuroimmunol 192, 89-98.
283. Xing B, Xin T, Hunter RL, Bing G (2008) Pioglitazone inhibition of lipopolysaccharide-induced nitric oxide synthase is associated with altered activity of p38 MAP kinase and PI3K/Akt. J Neuroinflammation 5, 4-15.
284. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127, 59-69.
285. Schütz B, Reimann J, Dumitrescu-Ozimek L, Kappes-Horn K, Landreth GE, Schürmann B, Zimmer A, Heneka MT (2005) The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice. J Neurosci 25, 7805-7812.
286. Strum JC, Shehee R, Virley D, Richardson J, Mattie M, Selley P, Ghosh S, Nock C, Saunders A, Roses A (2007) Rosiglitazone induces mitochondrial biogenesis in mouse brain. J Alzheimers Dis 11, 45-51.
287. Quintanilla RA, Jin YN, Fuenzalida K, Bronfman M, Johnson GV (2008) Rosiglitazone treatment prevents mitochondrial dysfunction in mutant huntingtin-expressing cells: possible role of peroxisome proliferator-activated receptor-gamma (PPARgamma) in the pathogenesis of Huntington disease. J Biol Chem 283, 25628-25637.
288. Drachman DB, Frank K, Dykes-Hoberg M, Teismann P, Almer G, Przedborski S, Rothstein JD (2002) Cyclooxygenase 2 inhibition protects motor neurons and prolongs survival in a transgenic mouse model of ALS. Ann Neurol 52, 771-778.
289. Almer G, Vukosavic S, Romero N, Przedborski S (1999) Inducible nitric oxide synthase up-regulation in a transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem 72, 2415-2425.