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Neurotherapeutics. 2010 October; 7(4): 392–398.
PMCID: PMC2948545

Rebuilding synaptic architecture in HIV-1 associated neurocognitive disease: A therapeutic strategy based on modulation of mixed lineage kinase


Work from our laboratories has validated mixed lineage kinase type 3 (MLK3) as an enzyme pathologically activated in the CNS by human immunodeficiency virus 1 (HIV-1) neurotoxins. In this review, we discuss MLK3 activation in the context of the neuropathogenesis of HIV-1 associated neurocognitive deficits (HAND). We use findings from the literature to substantiate the neuropathologic relevance of MLK3 to neurodegenerative disease, with an emphasis on Parkinson’s disease that shares a number of important phenotypic and neuropathologic characteristics with HAND. We discuss signal transduction pathways downstream from MLK3 activation, with an emphasis on their involvement in microglia and neurons in preclinical models of HAND. Finally, we make a case for pharmacologic intervention targeted at inhibition of MLK3 as a strategy to reverse HAND, in light of the fact that combination antiretroviral therapy, despite successfully managing systemic infection of HIV-1, has been largely unsuccessful in eradicating HAND.

Key Words: HIV-1, HIV-1 associated neurocognitive disease (HAND), microglia, mixed lineage kinase type 3, neuroinflammation, neurotrophins, synapse, tat


1. Heaton R, Clifford D, Woods S, et al. HIV-associated neurocognitive impairment remains prevalent in the era of combination ART: The CHARTER Study. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
2. Neuenburg JK, Brodt HR, Herndier BG, et al. HIV-related neuro-pathology, 1985 to 1999: rising prevalence of HIV encephalopathy in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002;31:171–177. [PubMed]
3. Marra CM, Zhao Y, Clifford DB, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. Aids. 2009;23:1359–1366. doi: 10.1097/QAD.0b013e32832c4152. [PMC free article] [PubMed] [Cross Ref]
4. Brennan TP, Woods JO, Sedaghat AR, Siliciano JD, Siliciano RF, Wilke CO. Analysis of human immunodeficiency virus type 1 viremia and provirus in resting CD4+ T cells reveals a novel source of residual viremia in patients on antiretroviral therapy. J Virol. 2009;83:8470–8481. doi: 10.1128/JVI.02568-08. [PMC free article] [PubMed] [Cross Ref]
5. Dinoso JB, Rabi SA, Blankson JN, et al. A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy. J Virol. 2009;83:9247–9257. doi: 10.1128/JVI.00840-09. [PMC free article] [PubMed] [Cross Ref]
6. Yang HC, Xing S, Shan L, et al. Small-molecule screening using a human primary cell model of HIV latency identifies compounds that reverse latency without cellular activation. J Clin Invest. 2009;119:3473–3486. [PMC free article] [PubMed]
7. Uthman OA, Abdulmalik JO. Adjunctive therapies for AIDS dementia complex. Cochrane Database Syst Rev 2008:CD006496. [PubMed]
8. Chang L, Ernst T, Witt MD, et al. Persistent brain abnormalities in antiretroviral-naive HIV patients 3 months after HAART. Antivir Ther. 2003;8:17–26. [PubMed]
9. Ernst T, Chang L, Jovicich J, Ames N, Arnold S. Abnormal brain activation on functional MRI in cognitively asymptomatic HIV patients. Neurology. 2002;59:1343–1349. [PubMed]
10. Ernst T, Yakupov R, Nakama H, et al. Declined neural efficiency in cognitively stable human immunodeficiency virus patients. Ann Neurol. 2009;65:316–325. doi: 10.1002/ana.21594. [PMC free article] [PubMed] [Cross Ref]
11. Anderson ER, Gendelman HE, Xiong H. Memantine protects hippocampal neuronal function in murine human immunodeficiency virus type 1 encephalitis. J Neurosci. 2004;24:7194–7198. doi: 10.1523/JNEUROSCI.1933-04.2004. [PubMed] [Cross Ref]
12. Schifitto G, Navia BA, Yiannoutsos CT, et al. Memantine and HIV-associated cognitive impairment: a neuropsychological and proton magnetic resonance spectroscopy study. Aids. 2007;21:1877–1886. doi: 10.1097/QAD.0b013e32813384e8. [PubMed] [Cross Ref]
13. Bellizzi MJ, Lu SM, Gelbard HA. Protecting the synapse: evidence for a rational strategy to treat HIV-1 associated neurologic disease. J Neuroimmune Pharmacol. 2006;1:20–31. doi: 10.1007/s11481-005-9006-y. [PubMed] [Cross Ref]
14. Bellizzi MJ, Lu SM, Masliah E, Gelbard HA. Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of plate-let-activating factor. J Clin Invest. 2005;115:3185–3192. doi: 10.1172/JCI25444. [PMC free article] [PubMed] [Cross Ref]
15. Ellis R, Langford D, Masliah E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci. 2007;8:33–44. doi: 10.1038/nrn2040. [PubMed] [Cross Ref]
16. Gallo KA, Johnson GL. Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol. 2002;3:663–672. doi: 10.1038/nrm906. [PubMed] [Cross Ref]
17. Silva RM, Kuan CY, Rakic P, Burke RE. Mixed lineage kinase-c-jun N-terminal kinase signaling pathway: a new therapeutic target in Parkinson’s disease. Mov Disord. 2005;20:653–664. doi: 10.1002/mds.20390. [PubMed] [Cross Ref]
18. Wang LH, Besirli CG, Johnson EM. Mixed-lineage kinases: a target for the prevention of neurodegeneration. Annu Rev Pharmacol Toxicol. 2004;44:451–474. doi: 10.1146/annurev.pharmtox.44.101802.121840. [PubMed] [Cross Ref]
19. Maroney AC, Finn JP, Connors TJ, et al. Cep-1347 (KT7515), a semisynthetic inhibitor of the mixed lineage kinase family. J Biol Chem. 2001;276:25302–25308. doi: 10.1074/jbc.M011601200. [PubMed] [Cross Ref]
20. Handley ME, Rasaiyaah J, Barnett J, et al. Expression and function of mixed lineage kinases in dendritic cells. Int Immunol. 2007;19:923–933. doi: 10.1093/intimm/dxm050. [PubMed] [Cross Ref]
21. Handley ME, Rasaiyaah J, Chain BM, Katz DR. Mixed lineage kinases (MLKs): a role in dendritic cells, inflammation and immunity? Int J Exp Pathol. 2007;88:111–126. doi: 10.1111/j.1365-2613.2007.00531.x. [PubMed] [Cross Ref]
22. Jaeschke A, Davis RI. Metabolic stress signaling mediated by mixed-lineage kinases. Mol Cell. 2007;27:498–508. doi: 10.1016/j.molcel.2007.07.008. [PMC free article] [PubMed] [Cross Ref]
23. Sathyanarayana P, Barthwal MK, Kundu CN, et al. Activation of the drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3. Mol Cell. 2002;10:1527–1533. doi: 10.1016/S1097-2765(02)00734-7. [PubMed] [Cross Ref]
24. Leung IW, Lassam N. Dimerization via tandem leucine zippers is essential for the activation of the mitogen-activated protein kinase kinase kinase, MLK-3. J Biol Chem. 1998;273:32408–32415. doi: 10.1074/jbc.273.49.32408. [PubMed] [Cross Ref]
25. Leung IW, Lassam N. The kinase activation loop is the key to mixed lineage kinase-3 activation via both autophosphorylation and hematopoietic progenitor kinase 1 phosphorylation. J Biol Chem. 2001;276:1961–1967. doi: 10.1074/jbc.M004092200. [PubMed] [Cross Ref]
26. Sui Z, Fan S, Sniderhan L, et al. Inhibition of mixed lineage kinase 3 prevents HIV-1 Tat-mediated neurotoxicity and monocyte activation. J Immunol. 2006;177:702–711. [PubMed]
27. Mishra R, Barthwal MK, Sondarva G, et al. Glycogen synthase kiuase-3beta induces neuronal cell death via direct phosphorylation of mixed lineage kinase 3. J Biol Chem. 2007;282:30393–30405. doi: 10.1074/jbc.M705895200. [PubMed] [Cross Ref]
28. Mota M, Reeder M, Chernoff J, Bazenet CE. Evidence for a role of mixed lineage kinases in neuronal apoptosis. J Neurosci. 2001;21:4949–4957. [PubMed]
29. Savinainen A, Garcia EP, Dorow D, Marshall J, Liu YF. Kainate receptor activation induces mixed lineage kinase-mediated cellular signaling cascades via post-synaptic density protein 95. J Biol Chem. 2001;276:11382–11386. doi: 10.1074/jbc.M100190200. [PubMed] [Cross Ref]
30. Lotharius J, Falsig J, van Beek J, et al. Progressive degeneration of human mesencephalic neuron-derived cells triggered by dopamine-dependent oxidative stress is dependent on the mixed-lineage kinase pathway. J Neurosci. 2005;25:6329–6342. doi: 10.1523/JNEUROSCI.1746-05.2005. [PubMed] [Cross Ref]
31. Mathiasen JR, McKenna BA, Saporito MS, et al. Inhibition of mixed lineage kinase 3 attenuates MPP+-induced neurotoxicity in SH-SY5Y cells. Brain Res. 2004;1003:86–97. doi: 10.1016/j.brainres.2003.11.073. [PubMed] [Cross Ref]
32. Saporito MS, Brown EM, Miller MS, Carswell S. CEP-1347/KT-7515, an inhibitor of c-jun N-terminal ldnase activation, attenuates the 1-methyl-4-phenyl tetrahydropyridine-mediated loss of nigrostriatal dopaminergic neurons in vivo. J Pharmacol Exp Ther. 1999;288:421–427. [PubMed]
33. Saporito MS, Hudkins RL, Maroney AC. Discovery of CEP-1347/ KT-7515, an inhibitor of the JNK/S APK pathway for the treatment of neurodegenerative diseases. Prog Med Chem. 2002;40:23–62. doi: 10.1016/S0079-6468(08)70081-X. [PubMed] [Cross Ref]
34. Bodner A, Maroney AC, Finn JP, Ghadge G, Roos R, Miller RJ. Mixed lineage kinase 3 mediates gp120IIIB-induced neurotoxicity. J Neurochem. 2002;82:1424–1434. doi: 10.1046/j.1471-4159.2002.01088.x. [PubMed] [Cross Ref]
35. Bodner A, Toth PT, Miller RJ. Activation of c-Jun N-terminal kinase mediates gpl20IIIB- and nucleoside analogue-induced sensory neuron toxicity. Exp Neurol. 2004;188:246–253. doi: 10.1016/j.expneurol.2004.04.009. [PubMed] [Cross Ref]
36. Parkinson Study Group PRECEPT Investigators Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology. 2007;69:1480–1490. doi: 10.1212/01.wnl.0000277648.63931.c0. [PubMed] [Cross Ref]
37. Wang J, Gigliotti F, Bhagwat SP, Maggirwar SB, Wright TW. Pneumocystis stimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism. Am J Physiol Lung Cell Mol Physiol. 2007;292:L1495–L1505. doi: 10.1152/ajplung.00452.2006. [PubMed] [Cross Ref]
38. Saporito MS, Thomas BA, Scott RW. MPTP activates c-Jun NH(2)-terminal ldnase (JNK) and its upstream regulatory ldnase MKK4 in nigrostriatal neurons in vivo. J Neurochem. 2000;75:1200–1208. doi: 10.1046/j.1471-4159.2000.0751200.x. [PubMed] [Cross Ref]
39. Wang LH, Johnson EM. Mixed lineage kinase inhibitor CEP-1347 fails to delay disability in early Parkinson disease. Neurology. 2008;71:462–463. doi: 10.1212/01.wnl.0000324506.93877.5e. [PubMed] [Cross Ref]
40. Eggert D, Dash PK, Gorantla S, et al. Neuroprotective activities of CEP-1347 in models of neuroAIDS. J Immunol. 2010;184:746–756. doi: 10.4049/jimmunol.0902962. [PMC free article] [PubMed] [Cross Ref]
41. Glass JD, Fedor H, Wesselingh SL, McArthur JC. Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol. 1995;38:755–762. doi: 10.1002/ana.410380510. [PubMed] [Cross Ref]
42. Borda JT, Alvarez X, Mohan M, et al. CD163, a marker of perivascular macrophages, is up-regulated by microglia in simian immunodeficiency virus encephalitis after haptoglobin-hemoglobin complex stimulation and is suggestive of breakdown of the blood-brain barrier. Am J Pathol. 2008;172:725–737. doi: 10.2353/ajpath.2008.070848. [PubMed] [Cross Ref]
43. Fabriek BO, Van Haastert ES, Galea I, et al. CD163-positive perivascular macrophages in the human CNS express molecules for antigen recognition and presentation. Glia. 2005;51:297–305. doi: 10.1002/glia.20208. [PubMed] [Cross Ref]
44. Kim WK, Alvarez X, Fisher J, et al. CD163 identifies perivascular macrophages in normal and viral encephalitic brains and potential precursors to perivascular macrophages in blood. Am J Pathol. 2006;168:822–834. doi: 10.2353/ajpath.2006.050215. [PubMed] [Cross Ref]
45. Marcondes MC, Lanigan CM, Burdo TH, Watry DD, Fox HS. Increased expression of monocyte CD44v6 correlates with the deveopment of encephalitis in rhesus macaques infected with simian immunodeficiency virus. J Infect Dis. 2008;197:1567–1576. doi: 10.1086/588002. [PMC free article] [PubMed] [Cross Ref]
46. Pulliam L, Gascon R, Stubblebine M, Mcguire D, McGrath MS. Unique monocyte subset in patients with AIDS dementia. Lancet. 1997;349:692–695. doi: 10.1016/S0140-6736(96)10178-1. [PubMed] [Cross Ref]
47. Roberts ES, Masliah E, Fox HS. CD163 identifies a unique population of ramified microglia in HIV encephalitis (HIVE) J Neuropathol Exp Neurol. 2004;63:1255–1264. [PubMed]
48. Roberts ES, Zandonatti MA, Watry DD, et al. Induction of pathogenic sets of genes in macrophages and neurons in NeuroAIDS. Am J Pathol. 2003;162:2041–2057. doi: 10.1016/S0002-9440(10)64336-2. [PubMed] [Cross Ref]
49. Anthony IC, Bell JE. The Neuropathology of HIV/AIDS. Int Rev Psychiatry. 2008;20:15–24. doi: 10.1080/09540260701862037. [PubMed] [Cross Ref]
50. Anthony IC, Ramage SN, Garnie FW, Simmonds P, Bell JE. Influence of HAART on HIV-related CNS disease and neuroinflammation. J Neuropathol Exp Neurol. 2005;64:529–536. [PubMed]
51. Everall IP, Hansen LA, Masliah E. The shifting patterns of HIV encephalitis neuropathology. Neurotox Res. 2005;8:51–61. doi: 10.1007/BF03033819. [PubMed] [Cross Ref]
52. Gray F, Chretien F, Vallat-Decouvelaere AV, Scaravilli F. The changing pattern of HIV neuropathology in the FIAART era. J Neuropathol Exp Neurol. 2003;62:429–440. [PubMed]
53. Abraham S, Sawaya BE, Safak M, Batuman O, Khalili K, Amini S. Regulation of MCP-1 gene transcription by Smads and HIV-1 Tat in human glial cells. Virology. 2003;309:196–202. doi: 10.1016/S0042-6822(03)00112-0. [PubMed] [Cross Ref]
54. Conant K, Garzino-Demo A, Nath A, et al. Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci U S A. 1998;95:3117–3121. doi: 10.1073/pnas.95.6.3117. [PubMed] [Cross Ref]
55. D’Aversa TG, Yu KO, Berman JW. Expression of chemokines by human fetal microglia after treatment with the human immunodeficiency virus type 1 protein Tat. J Neurovirol. 2004;10:86–97. doi: 10.1080/13550280490279807. [PubMed] [Cross Ref]
56. El-Hage N, Wu G, Ambati J, Brace-Keller AJ, Knapp PE, Hauser KF. CCR2 mediates increases in glial activation caused by exposure to HIV-1 Tat and opiates. J Neuroimmunol. 2006;178:9–16. doi: 10.1016/j.jneuroim.2006.05.027. [PMC free article] [PubMed] [Cross Ref]
57. El-Hage N, Wu G, Wang J, et al. HIV-1 Tat and opiate-induced changes in astrocytes promote chemotaxis of microglia through the expression of MCP-1 and alternative chemokines. Glia. 2006;53:132–146. doi: 10.1002/glia.20262. [PMC free article] [PubMed] [Cross Ref]
58. Eugenin EA, D’Aversa TG, Lopez L, Calderon TM, Berman JW. MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. J Neurochem. 2003;85:1299–1311. doi: 10.1046/j.1471-4159.2003.01775.x. [PubMed] [Cross Ref]
59. Eugenin EA, Dyer G, Calderon TM, Berman JW. HIV-1 tat protein induces a migratory phenotype in human fetal microglia by a CCL2 (MCP-l)-dependent mechanism: possible role in NeuroAIDS. Glia. 2005;49:501–510. doi: 10.1002/glia.20137. [PMC free article] [PubMed] [Cross Ref]
60. Lim SP, Garzino-Demo A. The human immunodeficiency viras type 1 Tat protein up-regulates the promoter activity of the beta-chemokine monocyte chemoattractant protein 1 in the human astrocytoma cell line U-87 MG: role of SP-1, AP-1, and NF-kappaB consensus sites. J Virol. 2000;74:1632–1640. doi: 10.1128/JVI.74.4.1632-1640.2000. [PMC free article] [PubMed] [Cross Ref]
61. McManus CM, Weidenheim K, Woodman SE, et al. Chemokine and chemokine-receptor expression in human glial elements: induction by the HIV protein, Tat, and chemokine autoregulation. Am J Pathol. 2000;156:1441–1453. doi: 10.1016/S0002-9440(10)65013-4. [PubMed] [Cross Ref]
62. Sodhi A, Biswas SK. Monocyte chemoattractant protein-1-induced activation of p42/44 MAPK and c-Jun in murine peritoneal macrophages: a potential pathway for macrophage activation. J Interferon Cytokine Res. 2002;22:517–526. doi: 10.1089/10799900252981990. [PubMed] [Cross Ref]
63. Toborek M, Lee YW, Pu H, et al. HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J Neurochem. 2003;84:169–179. doi: 10.1046/j.1471-4159.2003.01543.x. [PubMed] [Cross Ref]
64. Weiss JM, Nath A, Major EO, Berman JW. HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood-brain barrier and up-regulates CCR5 expression on human monocytes. J Immunol. 1999;163:2953–2959. [PubMed]
65. Zheng JC, Huang Y, Tang K, et al. HIV-1-infected and/or immune-activated macrophages regulate astrocyte CXCL8 production through IL-1beta and TNF-alpha: involvement of mitogen-activated protein kinases and protein kinase R. J Neuroimmunol. 2008;200:100–10. doi: 10.1016/j.jneuroim.2008.06.015. [PMC free article] [PubMed] [Cross Ref]
66. Gouwy M, Struyf S, Noppen S, et al. Synergy between coproduced CC and CXC chemokines in monocyte chemotaxis through receptor-mediated events. Mol Pharmacol. 2008;74:485–495. doi: 10.1124/mol.108.045146. [PubMed] [Cross Ref]
67. Gouwy M, Struyf S, Verbeke H, et al. CC chemokine ligand-2 synergizes with the nonchemokine G protein-coupled receptor ligand fMLP in monocyte chemotaxis, and it cooperates with the TLR ligand LPS via induction of CXCL8. J Leukoc Biol. 2009;86:671–680. doi: 10.1189/jlb.1008638. [PubMed] [Cross Ref]
68. Ahmed RA, Murao K, Imachi H, et al. c-Jun N-terminal kinases inhibitor suppresses the TNF-alpha induced MCP-1 expression in human umbilical vein endothelial cells. Endocrine. 2009;35:184–188. doi: 10.1007/s12020-008-9136-0. [PubMed] [Cross Ref]
69. Arndt PG, Suzuki N, Avdi NJ, Malcolm KC, Worthen GS. Lipopolysaccharide-induced c-Jun NH2-terminal kinase activation in human neutrophils: role of phosphatidylinositol 3-Kinase and Sykmediated pathways. J Biol Chem. 2004;279:10883–10891. doi: 10.1074/jbc.M309901200. [PubMed] [Cross Ref]
70. Gao YJ, Zhang L, Samad OA, et al. JNK-mduced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 2009;29:4096–4108. doi: 10.1523/JNEUROSCI.3623-08.2009. [PMC free article] [PubMed] [Cross Ref]
71. Wolter S, Doerrie A, Weber A, et al. c-Jun controls histone modifications, NF-kappaB recruitment, and RNA polymerase II function to activate the ccl2 gene. Mol Cell Biol. 2008;28:4407–4423. doi: 10.1128/MCB.00535-07. [PMC free article] [PubMed] [Cross Ref]
72. Young SK, Arndt PG. c-Jun NH2-terminal kinase regulates lipopolysaccharide-induced pulmonary mononuclear cell recruitment via CCL2. Exp Lung Res. 2009;35:682–700. doi: 10.3109/01902140902853168. [PubMed] [Cross Ref]
73. Cambien B, Pomeranz M, Millet MA, Rossi B, Schmid-Alliana A. Signal transduction involved in MCP-1-mediated monocytic transendothelial migration. Blood. 2001;97:359–366. doi: 10.1182/blood.V97.2.359. [PubMed] [Cross Ref]
74. Werle M, Schmal U, Hanna K, Kreuzer J. MCP-1 induces activation of MAP-kinases ERK, JNK and p38 MAPK in human endothelial cells. Cardiovasc Res. 2002;56:284–292. doi: 10.1016/S0008-6363(02)00600-4. [PubMed] [Cross Ref]
75. Sui Z, Kovacs AD, Maggirwar SB. Recruitment of active glycogen synthase kinase-3 into neuronal lipid rafts. Biochem Biophys Res Commun. 2006;345:1643–1648. doi: 10.1016/j.bbrc.2006.05.087. [PubMed] [Cross Ref]
76. New DR, Maggirwar SB, Epstein LG, Dewhurst S, Gelbard HA. HIV-1 Tat induces neuronal death via tumor necrosis factor-alpha and activation of non-N-methyl-D-aspartate receptors by a NFkappaB-independent mechanism. J Biol Chem. 1998;273:17852–17858. doi: 10.1074/jbc.273.28.17852. [PubMed] [Cross Ref]
77. Asami T, Ito T, Fukumitsu H, Nomoto H, Furukawa Y, Furakawa S. Autocrine activation of cultured macrophages by brain-derived neurotrophic factor. Biochem Biophys Res Commun. 2006;344:941–947. doi: 10.1016/j.bbrc.2006.03.228. [PubMed] [Cross Ref]
78. Batchelor PE, Liberatore GT, Wong JY, et al. Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. J Neurosci. 1999;19:1708–1716. [PubMed]
79. Lai AY, Todd KG. Differential regulation of trophic and proin-flammatory microglial effectors is dependent on severity of neuronal injury. Glia. 2008;56:259–270. doi: 10.1002/glia.20610. [PubMed] [Cross Ref]
80. Nakajima K, Honda S, Tohyama Y, Imai Y, Kohsaka S, Kurihara T. Neurotrophin secretion from cultured microglia. J Neurosci Res. 2001;65:322–331. doi: 10.1002/jnr.1157. [PubMed] [Cross Ref]
81. Mizoguchi Y, Monji A, Kato T, et al. Brain-derived neurotrophic factor induces sustained elevation of intracellular Ca2+ in rodent microglia. J Immunol. 2009;183:7778–7786. doi: 10.4049/jimmunol.0901326. [PubMed] [Cross Ref]
82. Nakajima K, Kikuchi Y, Ikoma E, et al. Neurotrophins regulate the function of cultured microglia. Glia. 1998;24:272–289. doi: 10.1002/(SICI)1098-1136(199811)24:3<272::AID-GLIA2>3.0.CO;2-4. [PubMed] [Cross Ref]
83. Pedraza N, Rafel M, Navarro I, Encinas M, Aldea M, Gallego C. Mixed lineage kinase phosphorylates transcription factor E47 and inhibits TrκB expression to link neuronal death and survival pathways. J Biol Chem. 2009;284:32980–32988. doi: 10.1074/jbc.M109.038729. [PMC free article] [PubMed] [Cross Ref]
84. Wang LH, Paden AJ, Johnson EM. Mixed-lineage kinase inhibitors require the activation of Trk receptors to maintain long-term neuronal trophism and survival. J Pharmacol Exp Ther. 2005;312:1007–1019. doi: 10.1124/jpet.104.077800. [PubMed] [Cross Ref]
85. Nosheny RL, Ahmed F, Yakovlev A, et al. Brain-derived neurotrophic factor prevents the nigrostriatal degeneration induced by human immunodeficiency virus-1 glycoprotein 120 in vivo. Eur J Neurosci. 2007;25:2275–2284. doi: 10.1111/j.1460-9568.2007.05506.x. [PubMed] [Cross Ref]
86. Mocchetti I, Bachis A. Brain-derived neurotrophic factor activation of TrκB protects neurons from HIV-1/gp120-induced cell death. Crit Rev Neurobiol. 2004;16:51–57. doi: 10.1615/CritRevNeurobiol.v16.i12.50. [PubMed] [Cross Ref]

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