TGF-β1 pathway as a new target for neuroprotection in alzheimer's disease

CNS Neuroscience and Therapeutics

Volumn 17, Issue 4, 2011, Pages 237-249

  Caraci, Filippo ^a   Battaglia, Giuseppe ^b   Bruno, Valeria ^b   Bosco, Paolo ^c   Carbonaro, Viviana ^a   Giuffrida, Maria Laura ^a   Drago, Filippo ^a   Sortino, Maria Angela ^a   Nicoletti, Ferdinando ^b,d   Copani, Agata ^a,e  

^a UNIVERSITY OF CATANIA   (Italy)

^b IRCCS NEUROMED   (Italy)

^c OASI RESEARCH INSTITUTE IRCCS   (Italy)

^d SAPIENZA UNIVERSITY OF ROME   (Italy)

^e CNR   (Italy)

Author keywords

amyloid; Alzheimer's disease; Apoptosis; Cell cycle; Lithium; Neurofibrillary tangles; Neuroprotection; Transforming growth factor 1

Indexed keywords

CANCER GROWTH FACTOR; CYCLIN DEPENDENT KINASE 5; DICKKOPF 1 PROTEIN; GLYCOGEN SYNTHASE KINASE 3BETA; INTERLEUKIN 6; LATENCY ASSOCIATED PEPTIDE; N METHYL DEXTRO ASPARTIC ACID; SMAD ANCHOR FOR RECEPTOR ACTIVATION; SMAD2 PROTEIN; SMAD3 PROTEIN; SMAD5 PROTEIN; SMAD8 PROTEIN;

ALZHEIMER DISEASE; CENTRAL NERVOUS SYSTEM; CEREBROSPINAL FLUID; COLON POLYPOSIS; IN VITRO STUDY; IN VIVO STUDY; MILD COGNITIVE IMPAIRMENT; NERVE DEGENERATION; NEUROPROTECTION; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION;

ALZHEIMER DISEASE; HUMANS; NEUROPROTECTIVE AGENTS; SIGNAL TRANSDUCTION; TRANSFORMING GROWTH FACTOR BETA1;

EID: 79960357742     PISSN: 17555930     EISSN: 17555949     Source Type: Journal    
DOI: 10.1111/j.1755-5949.2009.00115.x     Document Type: Review

References (134)

1. Ballard C, Day S, Sharp S, Wing G, Sorensen S. Neuropsychiatric symptoms in dementia: Importance and treatment considerations. Int Rev Psychiatry 2008;20:396-404.
2. Mount C, Downton C. Alzheimer's disease: Progress or profit? Nature Med 2006;12:780-784.
3. Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain 2006;129:2840-2855.
4. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science 2002;297:353-356.
5. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 2005;280:17294-17300.
6. Butterfield DA, Reed T, Newman SF, Sultana R. Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radic Bio Med 2007;43:658-677.
7. Mattson MP, Cheng B, Davis D, Bryant K, Lieberburg I, Rydel RE. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992;12:376-389.
8. Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer's disease. Neurochem Int 2004;45:583-595.
9. Giovanni A, Wirtz-Brugger F, Keramaris E, Slack R, Park DS. Involvement of cell cycle elements, cyclin-dependent kinases, pRb, and E2F-DP, in β-amyloid-induced neuronal death. J Biol Chem 1999;274:19011-19016.
10. Copani A, Condorelli F, Caruso A, et al. Mitotic signaling by beta-amyloid causes neuronal death. FASEB J 1999;13:2225-2234.
11. Copani A, Sortino MA, Caricasole A, et al. Erratic expression of DNA polymerases by beta-amyloid causes neuronal death. FASEB J 2002;16:2006-2008.
12. Herrup K, Neve R, Ackerman SL, Copani A. Divide and die: Cell cycle events as triggers of nerve cell death. J Neurosci 2004;24:9232-9239.
13. Copani A, Hoozemans JJ, Caraci F, et al. DNA polymerase-ß is early expressed in neurons of Alzheimer's Disease brain and is loaded into DNA replication forks in neurons challenged with ß-amyloid. J Neurosci 2006;26:10949-10957.
14. Otth C, Concha II, Arendt T, et al. AbetaPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576. J Alzheimers Dis 2002;4:417-430.
15. Takashima A, Honda T, Yasutake K, et al. Activation of tau protein kinase I/glycogen synthase kinase-3beta by amyloid beta peptide (25-35) enhances phosphorylation of tau in hippocampal neurons. Neurosci Res 1998;31:317-323.
16. Lucas JJ, Hernández F, Gómez-Ramos P, Morán MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 2001;20:27-39.
17. Hock BJ Jr, Lamb BT. Transgenic mouse models of Alzheimer's disease. Trends Genet 2001;17:S7-S12.
18. Malin DH, Crothers MK, Lake JR, et al. Hippocampal injections of amyloid beta-peptide 1-40 impair subsequent one-trial/day reward learning. Neurobiol Learn Mem 2001;76:125-137.
19. Miguel-Hidalgo JJ, Cacabelos R. Beta-amyloid(1-40)-induced neurodegeneration in the rat hippocampal neurons of the CA1 subfield. Acta Neuropathol (Berl) 1998;95:455-465.
20. Morimoto K, Yoshimi K, Tonohiro T, Yamada N, Oda T, Kaneko I. Co-injection of beta-amyloid with ibotenic acid induces synergistic loss of rat hippocampal neurons. Neuroscience 1998;84:479-487.
21. Connor B, Dragunow M. The role of neuronal growth factors in neurodegenerative disorders of the human brain. Brain Res Brain Res Rev 1998;27:1-39.
22. Castren E, Tanila H. Neurotrophins and dementia-keeping in touch. Neuron 2006;51:1-3.
23. Wyss-Coray T. Tgf-Beta pathway as a potential target in neurodegeneration and Alzheimer's. Curr Alzh Res 2006;3:191-195.
24. Brionne TC, Tesseur I, Masliah E, Wyss Coray T. Loss of TGF-β1 leads to increased neuronal cell death and microgliosis in mouse brain. Neuron 2003;40:1133-1145.
25. Ten Dijke P, Hill CS. New insights into TGF-beta-Smad signalling. Trends Biochem Sci 2004;29:265-273.
26. Taipale J, Saharinen J, Keski-Oja J. Extracellular matrixassociated transforming growth factor-beta: Role in cancer cell growth and invasion. Adv Cancer Res 1998;75:87-134.
27. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-β regulation of immune responses. Annu Rev Immunol 2006;24:99-146.
28. Dubois CM, Laprise MH, Blanchette F, Gentry LE, Leduc R. Processing of transforming growth factor beta 1 precursor by human furin convertase. J Biol Chem 1995;270:10618-10624.
29. Lawrence DA, Pircher R, Kryceve-Martinerie C, Jullien P. Normal embryo fibroblasts release transforming growth factors in a latent form. J Cell Physiol 1984;121:184-188.
30. Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFbeta activation. J Cell Sci 2003;116:217-224.
31. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 2003;113:685-700.
32. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577-584.
33. Caraci F, Gili E, Calafiore M, et al. TGF-beta1 targets the GSK-3beta/beta-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts. Pharmacol Res 2008;57:274-282.
34. König HG, Kögel D, Rami A, Prehn JH. TGF-{beta}1 activates two distinct type I receptors in neurons: Implications for neuronal NF-{kappa}B signaling. J Cell Biol 2005;168:1077-1086.
35. Caraci F, Battaglia G, Busceti C, et al. TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway. Neurobiol Dis 2008;30:234-242.
36. Vivien D, Ali C. Transforming growth factor-β signalling in brain disorder. Cytokine Growth Factor Rev 2006;17:121-128.
37. Finch CE, Laping NJ, Morgan TE, Nichols NR, Pasinetti GM. TGF-β1 is an organizer of response to neurodegeneration. J Cell Biochem 1993;53:314-322.
38. Salvioli S, Capri M, Bucci L, et al. Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunol Immunother 2009;58:1909-1917.
39. Franceschi C, Bonafe M, Valensin S, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann NY Acad Sci 2000;908:244-254.
40. Frippiat C, Chen QM, Zdanov S, Magalhaes JP, Remacle J, Toussaint O. Subcytotoxic H2O2 stress triggers a release of transforming growth factor-beta 1, which induces biomarkers of cellular senescence of human diploid fibroblasts. J Biol Chem 2001;276:2531-2537.
41. Carrieri G, Marzi E, Olivieri F, et al. The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: A study in Italian centenarians. Aging Cell 2004;3:443-448.
42. Forsey RJ, Thompson JM, Ernerudh J, et al. Plasma cytokine profiles in elderly humans. Mech Ageing Dev 2003;124:487-493.
43. Tarkowski E, Issa R, Sjögren M, et al. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer's disease and vascular dementia. Neurobiol Aging 2002;23:237-243.
44. Chao CC, Ala TA, Hu S, et al. Serum cytokine levels in patients with Alzheimer's disease. Clin Diagn Lab Immunol 1994;1:433-436.
45. Mocali A, Cedrola S, Della Malva N, et al. Increased plasma levels of soluble CD40, together with the decrease of TGF beta 1, as possible differential markers of Alzheimer disease. Exp Gerontol 2004;39:1555-1561.
46. Arosio B, Bergamaschini L, Galimberti L, et al. +10 T/C polymorphisms in the gene of transforming growth factor-beta1 are associated with neurodegeneration and its clinical evolution. Mech Ageing Dev 2007;128:553-557.
47. Lee HG, Ueda M, Zhu X, Perry G, Smith MA. Ectopic expression of phospho-Smad2 in Alzheimer's disease: Uncoupling of the transforming growth factor-beta pathway? J Neurosci Res 2006;84:1856-1861.
48. Tesseur I, Zou K, Esposito L, et al. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J Clin Invest 2006;116:3060-3069.
49. Ueberham U, Ueberham E, Gruschka H, Arendt T. Altered subcellular location of phosphorylated Smads in Alzheimer's disease. Eur J Neurosci 2006;24:2327-2334.
50. Chalmers KA, Love S. Neurofibrillary tangles may interfere with Smad 2/3 signaling in neurons. J Neuropathol Exp Neurol 2007;66:158-167.
51. Burton T, Liang B, Dibrov A, Amara F. Transforming growth factor-beta-induced transcription of the Alzheimer beta-amyloid precursor protein gene involves interaction between the CTCFcomplex and Smads. Biochem Biophys Res Commun 2002;295:713-723.
52. Lesne S, Docagne F, Gabriel C, et al. Transforming growth factor-beta 1 potentiates amyloid-beta generation in astrocytes and in transgenic mice. J Biol Chem 2003;278:18408-18418.
53. Wyss-Coray T, Masliah E, Mallory M, et al. Amyloidogenic role of cytokine TGF-β1 in transgenic mice and Alzheimer's disease. Nature 1997;389:603-606.
54. Gaertner RF, Wyss-Coray T, Von Euw D, Lesne S, Vivien D, Lacombe P. Reduced brain tissue perfusion in TGF-beta 1 transgenic mice showing Alzheimer's disease-like cerebrovascular abnormalities. Neurobiol Dis 2005;19:38-46.
55. Harris-White ME, Chu T, Balverde Z, Sigel JJ, Flanders KC, Frautschy SA. Effects of transforming growth factor-beta (isoforms 1-3) on amyloid-beta deposition, inflammation, and cell targeting in organotypic hippocampal slice cultures. J Neurosci 1998;18:10366-10374.
56. Grammas P, Ovase R. Cerebrovascular transforming growth factor-beta contributes to inflammation in the Alzheimer's disease brain. Am J Pathol 2002;160:1583-1587.
57. Town T, Laouar Y, Pittenger C, et al. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 2008;14:681-687.
58. Wyss-Coray T, Lin C, Yan F, et al. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med 2001;7:612-618.
59. Luterman JD, Haroutunian V, Yemul S, et al. Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol 2000;57:1153-1160.
60. Lee EO, Kang JL, Chong YH. The amyloid-beta peptide suppresses transforming growth factor-beta1-induced matrix metalloproteinase-2 production via Smad7 expression in human monocytic THP-1 cells. J Biol Chem 2005;280:7845-7853.
61. Arendt T, Brückner MK. Linking cell-cycle dysfunction in Alzheimer's disease to a failure of synaptic plasticity. Biochim Biophys Acta 2007;1772:413-421.
62. Vincent I, Rosado M, Davies P. Mitotic mechanisms in Alzheimer's disease? J Cell Biol 1996;132:413-425.
63. Herrup K, Neve R, Ackerman SL, Copani A. Divide and die: Cell cycle events as triggers of nerve cell death. J Neurosci 2004;24:9232-9239.
64. Copani A, Caraci F, Hoozemans JJ, Calafiore M, Sortino MA, Nicoletti F. The nature of the cell cycle in neurons: Focus on a "non-canonical" pathway of DNA replication causally related to death. Biochim Biophys Acta 2007;1772:409-412.
65. Flanders KC, Ren RF, Lippa CF. Transforming growth factor-βs in neurodegenerative disease. Prog Neurobiol 1998;54:71-85.
66. Dhandapani KM, Hadman M, De Sevilla L, Wade MF, Mahesh VB, Brann DW. Astrocyte protection of neurons: Role of transforming growth factor-beta signaling via a c-Jun-AP-1 protective pathway. J Biol Chem 2003;278:43329-43339.
67. Sortino MA, Chisari M, Merlo S, et al. Glia mediates the neuroprotective action of estradiol on beta-amyloid-induced neuronal death. Endocrinology 2004;145:5080-5086.
68. Prehn JH, Bindokas VP, Jordan J, et al. Protective effect of transforming growth factor-beta 1 on beta-amyloid neurotoxicity in rat hippocampal neurons. Mol Pharmacol 1996;49:319-328.
69. Ren RF, Flanders KC. Transforming growth factors-beta protect primary rat hippocampal neuronal cultures from degeneration induced by beta-amyloid peptide. Brain Res 1996;732:16-24.
70. Ren RF, Hawver DB, Kim RS, Flanders KC. Transforming growth factor-beta protects human hNT cells from degeneration induced by beta-amyloid peptide: Involvement of the TGF-beta type II receptor. Brain Res Mol Brain Res 1997;48:315-322.
71. Kim ES, Kim RS, Ren RF, Hawver DB, Flanders KC. Transforming growth factor-beta inhibits apoptosis induced by beta-amyloid peptide fragment 25-35 in cultured neuronal cells. Brain Res Mol Brain Res 1998;62:122-130.
72. Inman GJ, Nicolas FJ, Callahan JF, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol 2002;62:65-74.
73. Boche D, Cunningham C, Docagne F, Scott H, Perry VH. TGFbeta1 regulates the inflammatory response during chronic neurodegeneration. Neurobiol Dis 2006;22:638-650.
74. Okello A, Edison P, Archer HA, et al. Microglial activation and amyloid deposition in mild cognitive impairment: A PET study. Neurology 2009;72:56-62.
75. Maccioni RB, Rojo LE, Fernández JA, Kuljis RO. The role of neuroimmunomodulation in Alzheimer's disease. Ann N Y Acad Sci 2009;1153:240-246.
76. Frautschy SA, Cole GM, Baird A. Phagocytosis and deposition of vascular β-amyloid in rat brains injected with Alzheimer β-amyloid. Am J Pathol 1992;140:1389-1399.
77. Magnus T, Chan A, Linker RA, Toyka KV, Gold R. Astrocytes are less efficient in the removal of apoptotic lymphocytes than microglia cells: Implications for the role of glial cells in the inflamed central nervous system. J Neuropathol Exp Neurol 2002;61:760-766.
78. Unsicker K, Krieglstein K. Co-activation of TGF-β and cytokine signaling pathways are required for neurotropic functions. Cytokine Growth Factor Rev 2000;11:97-102.
79. Unsicker K, Krieglstein K. TGF-betas and their roles in the regulation of neuron survival. Adv Exp Med Biol 2002;513:353-374.
80. Schober A, Peterziel H, von Bartheld CS, Simon H, Krieglstein K, Unsicker K. GDNF applied to the MPTP-lesioned nigrostriatal system requires TGF-beta for its neuroprotective action. Neurobiol Dis 2007;25:378-391.
81. Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer's disease and Parkinson's disease. Prog Neurobiol 2001;63:71-124.
82. Cotman CW. The role of neurotrophins in brain aging: A perspective in honor of Regino Perez-Polo. Neurochem Res 2005;30:877-881.
83. Sometani A, Kataoka H, Nitta A, Fukumitsu H, Nomoto H, Furukawa S. Transforming growth factor-beta1 enhances expression of brain-derived neurotrophic factor and its receptor, TrkB, in neurons cultured from rat cerebral cortex. J Neurosci Res 2001;66:369-376.
84. Zhu Y, Ahlemeyer B, Bauerbach E, Krieglstein J. TGF-beta1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures. Neurochem Int 2001;38:227-235.
85. Zhu Y, Yang G-Y, Ahlemeyer B, et al. Transforming growth factor-b1 increases bad phosphorylation and protects neurons against damage. J Neurosci 2002;22:3898-3909.
86. Zhu Y, Culmsee C, Klumpp S, Krieglstein J. Neuroprotection by transforming growth factor-beta1 involves activation of nuclear factor-kappaB through phosphatidylinositol-3-OH kinase/Akt and mitogen-activated protein kinase-extracellular-signal regulated kinase1, 2 signaling pathways. Neuroscience 2004;123:897-906.
87. Hübscher U, Nasheuer HP, Syväoja JE. Eukaryotic DNA polymerases, a growing family. Trends Biochem Sci 2004;25:143-147.
88. Yang Y, Geldmacher DS, Herrup K. DNA replication precedes neuronal cell death in Alzheimer's disease. J Neurosci 2001;21:2661-2668.
89. Slee EA, O'Connor DJ, Lu X. To die or not to die: How does p53 decide? Oncogene 2004;23:2809-2818.
90. Paradis E, Douillard H, Koutroumanis M, Goodyer C, LeBlanc A. Amyloid beta peptide of Alzheimer's disease downregulates Bcl-2 and upregulates bax expression in human neurons. J Neurosci 1996;16:7533-7539.
91. Caricasole A, Copani A, Caraci F, et al. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci 2004;24:6021-6027.
92. Willert K, Nusse R. 1998. Beta-catenin: A key mediator of Wnt signaling. Curr Opin Genet Dev 1998;8:95-102.
93. Fuentealba RA, Farias G, Scheu J, Bronfman M, Marzolo MP, Inestrosa NC. Signal transduction during amyloid-beta-peptide neurotoxicity: Role in Alzheimer disease. Brain Res Brain Res Rev 2004;47:275-289.
94. Murase S, Mosser E, Schuman EM. Depolarization drives beta-catenin into neuronal spines promoting changes in synaptic structure and function. Neuron 2002;35:91-105.
95. Yu X, Malenka RC. Beta-catenin is critical for dendritic morphogenesis. Nat Neurosci 2003;6:1169-1177.
96. Liolitsa D, Powell J, Lovestone S. Genetic variability in the insulin signalling pathway may contribute to the risk of late onset Alzheimer's disease. J Neurol Neurosurg Psychiatry 2002;73:261-266.
97. Castri P, Iacovelli L, De Blasi A, et al. Reduced insulin-induced phosphatidylinositol-3-kinase activation in peripheral blood mononuclear leucocytes from patients with Alzheimer's disease. Eur J Neurosci 2007;26:2469-2472.
98. Tuszynski MH, Thal L, Pay M, et al. A phase I clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 2005;11:551-555.
99. Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med 2009;15:331-337.
100. Pollack SJ, Harper SJ. Small molecule Trk receptor agonists and other neurotrophic factor mimetics. Curr Drug Targets CNS Neurol Disord 2002;1:59-80.
101. Skaper SD. The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets 2008;7:46-62.
102. Zhang H, Zou K, Tesseur I, Wyss-Coray T. Small molecule tgf-beta mimetics as potential neuroprotective factors. Curr Alzheimer Res 2005;2:183-186.
103. Brinton RD. Impact of estrogen therapy on Alzheimer's disease: A fork in the road? CNS Drugs 2004;18:405-422.
104. Chen S, Nilsen J, Brinton RD. Dose and temporal pattern of estrogen exposure determines neuroprotective outcome in hippocampal neurons: Therapeutic implications. Endocrinology 2006;147:5303-5313.
105. Redondo S, Santos-Gallego CG, Tejerina T. TGF-beta1: A novel target for cardiovascular pharmacology. Cytokine Growth Factor Rev 2007;18:279-286.
106. Broe GA, Grayson DA, Creasey HM, et al. Anti-inflammatory drugs protect against Alzheimer disease at low doses. Arch Neurol 2000;57:1586-1591.
107. Nilsson SE, Johansson B, Takkinen S, et al. Does aspirin protect against Alzheimer's dementia? A study in a Swedish population-based sample aged > or = 80 years. Eur J Clin Pharmacol 2003;59:313-319.
108. Li G, Larson EB, Sonnen JA, et al. Statin therapy is associated with reduced neuropathologic changes of Alzheimer disease. Neurology 2007;69:878-885.
109. Sparks DL, Kryscio RJ, Sabbagh MN, Connor DJ, Sparks LM, Liebsack C. Reduced risk of incident AD with elective statin use in a clinical trial cohort. Curr Alzheimer Res 2008;5:416-421.
110. Redondo S, Santos-Gallego CG, Ganado P, García M, Rico L, Del Rio M, Tejerina T. Acetylsalicylic acid inhibits cell proliferation by involving transforming growth factor-beta. Circulation 2003;107:626-629.
111. Grainger DJ, Kemp PR, Metcalfe JC, et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med 1995;1:174-179.
112. Porreca E, Di Febbo C, Baccante G, Di Nisio M, Cuccurullo F. Increased transforming growth factor-beta(1) circulating levels and production in human monocytes after 3-hydroxy-3-methyl-glutarylcoenzyme a reductase inhibition with pravastatin. J Am Coll Cardiol 2002;39:1752-1757.
113. Nakamura K, Masuda H, Kariyazono H, et al. Effects of atorvastatin and aspirin combined therapy on inflammatory responses in patients undergoing coronary artery bypass grafting. Cytokine 2006;36:201-210.
114. Simpson D, Noble S, Perry C. Glatiramer acetate: A review of its use in relapsing-remitting multiple sclerosis. CNS Drugs 2002;16:825-850.
115. Arnon R, Aharoni R. Mechanism of action of glatiramer acetate in multiple sclerosis and its potential for the development of new applications. Proc Natl Acad Sci U S A 2004;101(Suppl 2):14593-14598.
116. Aharoni R, Eilam R, Domev H, Labunskay G, Sela M, Arnon R. The immunomodulator glatiramer acetate augments the expression of neurotrophic factors in brains of experimental autoimmune encephalomyelitis mice. Proc Natl Acad Sci U S A 2005;102:19045-19050.
117. Breivik T, Gundersen Y, Myhrer T, et al. Enhanced susceptibility to periodontitis in an animal model of depression: Reversed by chronic treatment with the anti-depressant tianeptine. J Clin Periodontol 2006;33:469-477.
118. Sutcigil L, Oktenli C, Musabak U, et al. Pro- and anti-inflammatory cytokine balance in major depression: Effect of sertraline therapy. Clin Dev Immunol 2007; doi:.
119. Vollmar P, Haghikia A, Dermietzel R, Faustmann PM. Venlafaxine exhibits an anti-inflammatory effect in an inflammatory co-culture model. Int J Neuropsychopharmacol 2008;11:111-117.
120. Nelson RL, Guo Z, Halagappa VM, et al. Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol 2007;205:166-176.
121. Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: Systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006;63:530-538.
122. Modrego PJ, Ferrández J. Depression in patients with mild cognitive impairment increases the risk of developing dementia of Alzheimer type: A prospective cohort study. Arch Neurol 2004;61:1290-1293.
123. Myint AM, Leonard BE, Steinbusch HW, Kim YK. Th1, Th2, and Th3 cytokine alterations in major depression. J Affect Disord 2005;88:167-173.
124. Lee KM, Kim YK. The role of IL-12 and TGF-beta1 in the pathophysiology of major depressive Disorder. Int Immunopharmacol 2006;6:1298-1304.
125. Kessing LV, Søndergård L, Forman JL, Andersen PK. Antidepressants and dementia. J Affect Disord 2009;117:24-29.
126. Wada A, Yokoo H, Yanagita T, Kobayashi H. Lithium: Potential therapeutics against acute brain injuries and chronic neurodegenerative diseases. J Pharmacol Sci 2005;99:307-321.
127. Yeh HL, Tsai SJ. Lithium may be useful in the prevention of Alzheimer's disease in individuals at risk of presenile familial Alzheimer's disease. Med Hypotheses 2008;71:948-951.
128. Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer's disease in elderly patients with bipolar disorder. Br J Psychiatry 2007;190:359-360.
129. Liang MH, Wendland JR, Chuang DM. Lithium inhibits Smad 3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling. Mol Cell Neurosc 2008;37:440-453.
130. Bruno V, Battaglia G, Casabona G, Copani A, Caciagli F, Nicoletti F. Neuroprotection by glial metabotropic glutamate receptors is mediated by transforming growth factor-beta. J Neurosci 1998;18:9594-9600.
131. D'Onofrio M, Cuomo L, Battaglia G, et al. Neuroprotection mediated by glial group-II metabotropic glutamate receptors requires the activation of the MAP kinase and the phosphatidylinositol-3-kinase pathways. J Neurochem 2001;78:435-445.
132. Copani A, Bruno V, Battaglia G, et al. Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by beta-amyloid peptide. Mol Pharmacol 1995;47:890-897.
133. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized Phase 2 clinical trial. Nat Med 2007;13:1102-1107.
134. Gill SS, Rochon PA, Herrmann N, et al. Atypical antipsychotic drugs and risk of ischaemic stroke: Population based retrospective cohort study. BMJ 2005; doi:.