Early intervention with a small molecule inhibitor for tumor nefosis factor-α prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease

Journal of Neuroinflammation

Volumn 9, Issue , 2012, Pages

  Gabbita, S P ^a   Srivastava, Minu K ^b   Eslami, Pirooz ^b   Johnson, Ming F ^b   Kobritz, Naomi K ^b   Tweedie, David ^c   Greig, Nigel H ^c   Zemlan, Frank P ^a   Sharma, Sherven P ^b   Harris White, Marni E ^b  

^a P2D Inc   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

^c NATIONAL INSTITUTES OF HEALTH   (United States)

Author keywords

Alzheimer's disease; Memory; Neuroinflammation; Thalidomide; Thiothalidomide; Tumor necrosis factor alpha

Indexed keywords

3,6' DITHIOTHALIDOMIDE; AMYLOID BETA PROTEIN; AMYLOID PRECURSOR PROTEIN; MESSENGER RNA; TAU PROTEIN; THALIDOMIDE; TUMOR NECROSIS FACTOR ALPHA; TUMOR NECROSIS FACTOR ALPHA INHIBITOR; UNCLASSIFIED DRUG;

ALZHEIMER DISEASE; AMYLOID PLAQUE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOCHEMISTRY; BRAIN LEVEL; CELL INFILTRATION; COGNITIVE DEFECT; CONTROLLED STUDY; CYTOKINE PRODUCTION; CYTOPLASM; DRUG EFFICACY; DRUG SAFETY; DRUG STRUCTURE; EARLY INTERVENTION; FLOW CYTOMETRY; GENE EXPRESSION; HIPPOCAMPUS; HISTOPATHOLOGY; IMMUNOHISTOCHEMISTRY; IMMUNOMODULATION; LEUKOCYTE COUNT; LONG TERM CARE; MALE; MAZE TEST; MENTAL PERFORMANCE; MICROGLIA; MOUSE; NERVOUS SYSTEM INFLAMMATION; NEUROPATHOLOGY; NONHUMAN; PROTEIN EXPRESSION; PROTEIN SYNTHESIS INHIBITION; SINGLE DRUG DOSE; TRANSGENIC MOUSE; TREATMENT DURATION; WORKING MEMORY;

EID: 84861411831     PISSN: None     EISSN: 17422094     Source Type: Journal    
DOI: 10.1186/1742-2094-9-99     Document Type: Article

References (81)

1. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin- induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975, 72:3666-3670. 10.1073/pnas.72.9.3666, 433057, 1103152.
2. Sedel F, Bechade C, Vyas S, Triller A. Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death. J Neurosci 2004, 24:2236-2246. 10.1523/JNEUROSCI.4464-03.2004, 14999074.
3. Bernardino L, Agasse F, Silva B, Ferreira R, Grade S, Malva JO. Tumor necrosis factor-alpha modulates survival, proliferation, and neuronal differentiation in neonatal subventricular zone cell cultures. Stem Cell 2008, 26:2361-2371.
4. Keohane A, Ryan S, Maloney E, Sullivan AM, Nolan YM. Tumour necrosis factor- alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: role of Hes1. Mol Cell Neurosci 2010, 43:127-135. 10.1016/j.mcn.2009.10.003, 19840854.
5. Obregon E, Punzon C, Fernandez-Cruz E, Fresno M, Munoz-Fernandez MA. HIV-1 infection induces differentiation of immature neural cells through autocrine tumor necrosis factor and nitric oxide production. Virology 1999, 261:193-204. 10.1006/viro.1999.9848, 10497105.
6. Neumann H, Schweigreiter R, Yamashita T, Rosenkranz K, Wekerle H, Barde YA. Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J Neurosci 2002, 22:854-862.
7. Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science 2002, 295:2282-2285. 10.1126/science.1067859, 11910117.
8. Fujii S, Matsumoto M, Igarashi K, Kato H, Mikoshiba K. Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors. Learn Mem 2000, 7:312-320. 10.1101/lm.34100, 311349, 11040263.
9. Park KM, Yule DI, Bowers WJ. Tumor necrosis factor-alpha potentiates intraneuronal Ca2+ signaling via regulation of the inositol 1,4,5 -trisphosphate receptor. J Biol Chem 2008, 283:33069-33079. 10.1074/jbc.M802209200, 2586262, 18838384.
10. Steinmetz CC, Turrigiano GG. Tumor necrosis factor-alpha signaling maintains the ability of cortical synapses to express synaptic scaling. J Neurosci 2010, 30:14685-14690. 10.1523/JNEUROSCI.2210-10.2010, 3063078, 21048125.
11. Wheeler D, Knapp E, Bandaru VV, Wang Y, Knorr D, Poirier C, Mattson MP, Geiger JD, Haughey NJ. Tumor necrosis factor-alpha-induced neutral sphingomyelinase-2 modulates synaptic plasticity by controlling the membrane insertion of NMDA receptors. J Neurochem 2009, 109:1237-1249. 10.1111/j.1471-4159.2009.06038.x, 2688711, 19476542.
12. Montgomery SL, Bowers WJ. Tumor necrosis factor-alpha and the roles it plays in homeostatic and degenerative processes within the central nervous system. J Neuroimmune Pharmacol 2012, 7:42-59. 10.1007/s11481-011-9287-2, 21728035.
13. McGeer EG, McGeer PL. Inflammatory processes in Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatr 2003, 27:741-749.
14. Standridge JB. Pharmacotherapeutic approaches to the prevention of Alzheimer's disease. Am J Geriatr Pharmacother 2004, 2:119-132. 10.1016/S1543-5946(04)90017-7, 15555488.
15. Craft JM, Watterson DM, van Eldik LJ. Neuroinflammation: a potential therapeutic target. Expert Opin Ther Targets 2005, 9:887-900. 10.1517/14728222.9.5.887, 16185146.
16. Hu W, Ralay Ranaivo H, Craft JM, van Eldik LJ, Watterson DM. Validation of the neuroinflammation cycle as a drug discovery target using integrative chemical biology and lead compound development with an Alzheimer's disease -related mouse model. Curr Alzheimer Res 2005, 2:197-205. 10.2174/1567205053585828, 15974919.
17. Jacobsen JS, Reinhart P, Pangalos MN. Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease. NeuroRx 2005, 2:612-626. 10.1602/neurorx.2.4.612, 1201319, 16489369.
18. Kelleher-Andersson J. Discovery of neurogenic, Alzheimer's disease therapeutics. Curr Alzheimer Res 2006, 3:55-62. 10.2174/156720506775697179, 16472204.
19. Ralay Ranaivo H, Craft JM, Hu W, Guo L, Wing LK, Van Eldik LJ, Watterson DM. Glia as a therapeutic target: selective suppression of human amyloid -beta-induced upregulation of brain proinflammatory cytokine production attenuates neurodegeneration. J Neurosci 2006, 26:662-670. 10.1523/JNEUROSCI.4652-05.2006, 16407564.
20. Rosenberg PB. Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatr 2005, 17:503-514.
21. Combs CK, Karlo JC, Kao SC, Landreth GE. beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J Neurosci 2001, 21:1179-1188.
22. Griffin WS, Sheng JG, Royston MC, Gentleman SM, McKenzie JE, Graham DI, Roberts GW, Mrak RE. Glial-neuronal interactions in Alzheimer's disease: the potential role of a 'cytokine cycle' in disease progression. Brain Pathol 1998, 8:65-72.
23. Zhao M, Cribbs DH, Anderson AJ, Cummings BJ, Su JH, Wasserman AJ, Cotman CW. The induction of the TNFalpha death domain signaling pathway in Alzheimer's disease brain. Neurochem Res 2003, 28:307-318.
24. Alvarez S, Blanco A, Fresno M, Munoz-Fernandez MA. TNF-alpha contributes to caspase-3 independent apoptosis in neuroblastoma cells: role of NFAT. PLoS One 2011, 6:e16100. 10.1371/journal.pone.0016100, 3029262, 21298033.
25. Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 1999, 19:223-230. 10.1023/A:1020568013953, 10471976.
26. Tarkowski E, Andreasen N, Tarkowski A, Blennow K. Intrathecal inflammation precedes development of Alzheimer's disease. J Neurol Neurosurg Psychiatry 2003, 74:1200-1205. 10.1136/jnnp.74.9.1200, 1738668, 12933918.
27. Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M. Serum TNF- alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 2007, 28:533-536. 10.1016/j.neurobiolaging.2006.02.012, 16569464.
28. Medeiros R, Prediger RD, Passos GF, Pandolfo P, Duarte FS, Franco JL, Dafre AL, Di Giunta G, Figueiredo CP, Takahashi RN, et al. Connecting TNF-alpha signaling pathways to iNOS expression in a mouse model of Alzheimer's disease: relevance for the behavioral and synaptic deficits induced by amyloid beta protein. J Neurosci 2007, 27:5394-5404. 10.1523/JNEUROSCI.5047-06.2007, 17507561.
29. Mehlhorn G, Hollborn M, Schliebs R. Induction of cytokines in glial cells surrounding cortical beta-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology. Int J Dev Neurosci 2000, 18:423-431. 10.1016/S0736-5748(00)00012-5, 10817926.
30. Ruan L, Kang Z, Pei G, Le Y. Amyloid deposition and inflammation in APPswe/PS1dE9 mouse model of Alzheimer's disease. Curr Alzheimer Res 2009, 6:531-540. 10.2174/156720509790147070, 19747158.
31. Janelsins MC, Mastrangelo MA, Oddo S, LaFerla FM, Federoff HJ, Bowers WJ. Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation 2005, 2:23. 10.1186/1742-2094-2-23, 1276812, 16232318.
32. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 2005, 45:675-688. 10.1016/j.neuron.2005.01.040, 15748844.
33. Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging 2003, 24:1063-1070. 10.1016/j.neurobiolaging.2003.08.012, 14643377.
34. Franklin KBJ, Paxinos G. The mouse brain in stereotaxic coordinates 2007, Academic, San Diego, CA, 3.
35. Pino PA, Cardona AE. Isolation of brain and spinal cord mononuclear cells using percoll gradients. J Vis Exp 2011, 48:e2348.
36. Baratz R, Tweedie D, Rubovitch V, Luo W, Yoon JS, Hoffer BJ, Greig NH, Pick CG. Tumor necrosis factor-alpha synthesis inhibitor, 3,6'-dithiothalidomide, reverses behavioral impairments induced by minimal traumatic brain injury in mice. J Neurochem 2011, 118:1032-1042. 10.1111/j.1471-4159.2011.07377.x, 21740439.
37. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 2003, 39:409-421. 10.1016/S0896-6273(03)00434-3, 12895417.
38. Rothwell NJ, Relton JK. Involvement of interleukin-1 and lipocortin-1 in ischaemic brain damage. Cerebrovasc Brain Metab Rev 1993, 5:178-198.
39. 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, Streit W, Strohmeyer R, Tooyoma I, et al. Inflammation and Alzheimer's disease. Neurobiol Aging 2000, 21:383-421. 10.1016/S0197-4580(00)00124-X, 10858586.
40. Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP. TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 2001, 4:1116-1122. 10.1038/nn738, 11600888.
41. Shi JQ, Shen W, Chen J, Wang BR, Zhong LL, Zhu YW, Zhu HQ, Zhang QQ, Zhang YD, Xu J. Anti-TNF-alpha reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res 2011, 1368:239-247.
42. Calingasan NY, Erdely HA, Altar CA. Identification of CD40 ligand in Alzheimer's disease and in animal models of Alzheimer's disease and brain injury. Neurobiol Aging 2002, 23:31-39. 10.1016/S0197-4580(01)00246-9, 11755016.
43. Tan J, Town T, Paris D, Mori T, Suo Z, Crawford F, Mattson MP, Flavell RA, Mullan M. Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation. Science 1999, 286:2352-2355. 10.1126/science.286.5448.2352, 10600748.
44. Giuliani F, Vernay A, Leuba G, Schenk F. Decreased behavioral impairments in an Alzheimer mice model by interfering with TNF-alpha metabolism. Brain Res Bull 2009, 80:302-308. 10.1016/j.brainresbull.2009.07.009, 19622386.
45. Scherbel U, Raghupathi R, Nakamura M, Saatman KE, Trojanowski JQ, Neugebauer E, Marino MW, McIntosh TK. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury. Proc Natl Acad Sci U S A 1999, 96:8721-8726. 10.1073/pnas.96.15.8721, 17583, 10411942.
46. Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed 2006, 8:25. 1781291, 17415933.
47. Tobinick EL, Gross H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer's disease. BMC Neurol 2008, 8:27. 10.1186/1471-2377-8-27, 2500042, 18644112.
48. Tobinick EL, Gross H. Rapid cognitive improvement in Alzheimer's disease following perispinal etanercept administration. J Neuroinflammation 2008, 5:2. 10.1186/1742-2094-5-2, 2211476, 18184433.
49. Kruys V, Marinx O, Shaw G, Deschamps J, Huez G. Translational blockade imposed by cytokine-derived UA-rich sequences. Science 1989, 245:852-855. 10.1126/science.2672333, 2672333.
50. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor alpha by enhancing mRNA degradation. J Exp Med 1993, 177:1675-1680. 10.1084/jem.177.6.1675, 2191046, 8496685.
51. Sampaio EP, Sarno EN, Galilly R, Cohn ZA, Kaplan G. Thalidomide selectively inhibits tumor necrosis factor alpha production by stimulated human monocytes. J Exp Med 1991, 173:699-703. 10.1084/jem.173.3.699, 2118820, 1997652.
52. Alkam T, Nitta A, Mizoguchi H, Saito K, Seshima M, Itoh A, Yamada K, Nabeshima T. Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice. Behav Brain Res 2008, 189:100-106. 10.1016/j.bbr.2007.12.014, 18325608.
53. Tariman JD. Thalidomide: current therapeutic uses and management of its toxicities. Clin J Oncol Nurs 2003, 7:143-147. 10.1188/03.CJON.143-147, 12696209.
54. Zhu X, Giordano T, Yu QS, Holloway HW, Perry TA, Lahiri DK, Brossi A, Greig NH. Thiothalidomides: novel isosteric analogues of thalidomide with enhanced TNF-alpha inhibitory activity. J Med Chem 2003, 46:5222-5229. 10.1021/jm030152f, 14613324.
55. Greig NH, Giordano T, Zhu X, Yu QS, Perry TA, Holloway HW, Brossi A, Rogers JT, Sambamurti K, Lahiri DK. Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases. Acta Neurobiol Exp (Wars) 2004, 64:1-9.
56. Luo W, Yu QS, Salcedo I, Holloway HW, Lahiri DK, Brossi A, Tweedie D, Greig NH. Design, synthesis and biological assessment of novel N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines and 3-substituted 2,6- dioxopiperidines for TNF-alpha inhibitory activity. Bioorg Med Chem 2011, 19:3965-3972. 10.1016/j.bmc.2011.05.029, 21658960.
57. Kadiu I, Glanzer JG, Kipnis J, Gendelman HE, Thomas MP. Mononuclear phagocytes in the pathogenesis of neurodegenerative diseases. Neurotox Res 2005, 8:25-50. 10.1007/BF03033818, 16260384.
58. Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10:1387-1394. 10.1038/nn1997, 17965659.
59. Streit WJ. Microglial senescence: does the brain's immune system have an expiration date?. Trends Neurosci 2006, 29:506-510. 10.1016/j.tins.2006.07.001, 16859761.
60. Glanzer JG, Enose Y, Wang T, Kadiu I, Gong N, Rozek W, Liu J, Schlautman JD, Ciborowski PS, Thomas MP, Gendelman HE. Genomic and proteomic microglial profiling: pathways for neuroprotective inflammatory responses following nerve fragment clearance and activation. J Neurochem 2007, 102:627-645. 10.1111/j.1471-4159.2007.04568.x, 17442053.
61. Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 2012, 87:10-20. 10.1016/j.brainresbull.2011.10.004, 22024597.
62. Streit WJ. Microglia and Alzheimer's disease pathogenesis. J Neurosci Res 2004, 77:1-8. 10.1002/jnr.20093, 15197750.
63. Streit WJ, Mrak RE, Griffin WS. Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 2004, 1:14. 10.1186/1742-2094-1-14, 509427, 15285801.
64. Chen ML, Yan BS, Bando Y, Kuchroo VK, Weiner HL. Latency-associated peptide identifies a novel CD4 + CD25+ regulatory T cell subset with TGFbeta -mediated function and enhanced suppression of experimental autoimmune encephalomyelitis. J Immunol 2008, 180:7327-7337. 2771858, 18490732.
65. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol 2008, 8:958-969. 10.1038/nri2448, 2724991, 19029990.
66. Pichlmair A, RE Sousa C. Innate recognition of viruses. Immunity 2007, 27:370-383. 10.1016/j.immuni.2007.08.012, 17892846.
67. Engelhardt B. The blood-central nervous system barriers actively control immune cell entry into the central nervous system. Curr Pharm Des 2008, 14:1555-1565. 10.2174/138161208784705432, 18673197.
68. Mildner A, Schmidt H, Nitsche M, Merkler D, Hanisch UK, Mack M, Heikenwalder M, Bruck W, Priller J, Prinz M. Microglia in the adult brain arise from Ly -6ChiCCR2+ monocytes only under defined host conditions. Nat Neurosci 2007, 10:1544-1553. 10.1038/nn2015, 18026096.
69. Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, Frotscher M, Kreutzberg GW, Persons DA, Dirnagl U. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 2001, 7:1356-1361. 10.1038/nm1201-1356, 11726978.
70. Butovsky O, Koronyo-Hamaoui M, Kunis G, Ophir E, Landa G, Cohen H, Schwartz M. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A 2006, 103:11784-11789. 10.1073/pnas.0604681103, 1544247, 16864778.
71. Fiala M, Liu QN, Sayre J, Pop V, Brahmandam V, Graves MC, Vinters HV. Cyclooxygenase-2-positive macrophages infiltrate the Alzheimer's disease brain and damage the blood-brain barrier. Eur J Clin Invest 2002, 32:360-371. 10.1046/j.1365-2362.2002.00994.x, 12027877.
72. Malm TM, Koistinaho M, Parepalo M, Vatanen T, Ooka A, Karlsson S, Koistinaho J. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis 2005, 18:134-142. 10.1016/j.nbd.2004.09.009, 15649704.
73. Malm TM, Magga J, Kuh GF, Vatanen T, Koistinaho M, Koistinaho J. Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer's disease. Glia 2008, 56:1767-1779. 10.1002/glia.20726, 18649403.
74. Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 2006, 49:489-502. 10.1016/j.neuron.2006.01.022, 16476660.
75. Stalder AK, Ermini F, Bondolfi L, Krenger W, Burbach GJ, Deller T, Coomaraswamy J, Staufenbiel M, Landmann R, Jucker M. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci 2005, 25:11125-11132. 10.1523/JNEUROSCI.2545-05.2005, 16319312.
76. Sharief MK, Thompson EJ. In vivo relationship of tumor necrosis factor-alpha to blood-brain barrier damage in patients with active multiple sclerosis. J Neuroimmunol 1992, 38:27-34. 10.1016/0165-5728(92)90087-2, 1577950.
77. Angelucci F, Gruber SH, El Khoury A, Tonali PA, Mathe AA. Chronic amphetamine treatment reduces NGF and BDNF in the rat brain. Eur Neuropsychopharmacol 2007, 17:756-762. 10.1016/j.euroneuro.2007.03.002, 17434716.
78. Butovsky O, Kunis G, Koronyo-Hamaoui M, Schwartz M. Selective ablation of bone marrow-derived dendritic cells increases amyloid plaques in a mouse Alzheimer's disease model. Eur J Neurosci 2007, 26:413-416. 10.1111/j.1460-9568.2007.05652.x, 17623022.
79. Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 2008, 14:681-687. 2649699, 18516051.
80. Subramanian S, Ayala P, Wadsworth TL, Harris CJ, Vandenbark AA, Quinn JF, Offner H. CCR6: a biomarker for Alzheimer's-like disease in a triple transgenic mouse model. J Alzheimers Dis 2010, 22:619-629. 2988888, 20847401.
81. Ringman JM, Schulman H, Becker C, Jones T, Bai Y, Immermann F, Cole G, Sokolow S, Gylys K, Geschwind DH, Cummings JL, Wan HI. Proteomic changes in cerebrospinal fluid of presymptomatic and affected persons carrying familial Alzheimer disease mutations. Arch Neurol 2012, 69:96-104. 10.1001/archneurol.2011.642, 22232349.