Targeting Fyn Kinase in Alzheimer's Disease

Biological Psychiatry

Volumn 83, Issue 4, 2018, Pages 369-376

  Nygaard, Haakon B ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

Alzheimer's disease; Amyloid beta; Cellular prion protein; Fyn; Saracatinib

Indexed keywords

AMYLOID BETA PROTEIN; CELL PROTEIN; OLIGOMER; PRION PROTEIN; PROTEIN KINASE FYN; SARACATINIB; TAU PROTEIN; 1,3 BENZODIOXOLE DERIVATIVE; ENZYME INHIBITOR; QUINAZOLINE DERIVATIVE;

ALZHEIMER DISEASE; CEREBROSPINAL FLUID; DOWNSTREAM PROCESSING; DRUG TARGETING; ENZYME INHIBITION; HUMAN; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; DRUG EFFECT; METABOLISM;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BENZODIOXOLES; ENZYME INHIBITORS; HUMANS; PRION PROTEINS; PROTO-ONCOGENE PROTEINS C-FYN; QUINAZOLINES;

EID: 85021887170     PISSN: 00063223     EISSN: 18732402     Source Type: Journal    
DOI: 10.1016/j.biopsych.2017.06.004     Document Type: Review

References (99)

1. Satizabal, C.L., Beiser, A.S., Chouraki, V., Chene, G., Dufouil, C., Seshadri, S., Incidence of dementia over three decades in the Framingham Heart Study. N Engl J Med 374 (2016), 523–532.
2. Alzheimer's Association. 2016 Alzheimer's disease facts and figures. Alzheimer's Dement 12 (2016), 459–509.
3. Nygaard, H.B., Current and emerging therapies for Alzheimer's disease. Clin Ther 35 (2013), 1480–1489.
4. Doody, R.S., Thomas, R.G., Farlow, M., Iwatsubo, T., Vellas, B., Joffe, S., et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 370 (2014), 311–321.
5. Salloway, S., Sperling, R., Fox, N.C., Blennow, K., Klunk, W., Raskind, M., et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 370 (2014), 322–333.
6. Sevigny, J., Chiao, P., Bussiere, T., Weinreb, P.H., Williams, L., Maier, M., et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 537 (2016), 50–56.
7. Laurén, J., Gimbel, D., Nygaard, H., Gilbert, J., Strittmatter, S., Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457 (2009), 1128–1132.
8. Nygaard, H.B., Strittmatter, S.M., Cellular prion protein mediates the toxicity of beta-amyloid oligomers: Implications for Alzheimer disease. Arch Neurol 66 (2009), 1325–1328.
9. Um, J.W., Nygaard, H.B., Heiss, J.K., Kostylev, M.A., Stagi, M., Vortmeyer, A., et al. Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat Neurosci 15 (2012), 1227–1235.
10. Bliss, T.V., Lomo, T., Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232 (1973), 331–356.
11. Malenka, R.C., Nicoll, R.A., Long-term potentiation—A decade of progress?. Science 285 (1999), 1870–1874.
12. O'Dell, T.J., Kandel, E.R., Grant, S.G., Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors. Nature 353 (1991), 558–560.
13. Bading, H., Greenberg, M.E., Stimulation of protein tyrosine phosphorylation by NMDA receptor activation. Science 253 (1991), 912–914.
14. Grant, S.G., O'Dell, T.J., Karl, K.A., Stein, P.L., Soriano, P., Kandel, E.R., Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science 258 (1992), 1903–1910.
15. Yu, X.M., Askalan, R., Keil, G.J. 2nd, Salter, M.W., NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275 (1997), 674–678.
16. Suzuki, T., Okumura-Noji, K., NMDA receptor subunits epsilon 1 (NR2A) and epsilon 2 (NR2B) are substrates for Fyn in the postsynaptic density fraction isolated from the rat brain. Biochem Biophys Res Commun 216 (1995), 582–588.
17. Nakazawa, T., Komai, S., Tezuka, T., Hisatsune, C., Umemori, H., Semba, K., et al. Characterization of Fyn-mediated tyrosine phosphorylation sites on GluR epsilon 2 (NR2B) subunit of the N-methyl-D-aspartate receptor. J Biol Chem 276 (2001), 693–699.
18. Tezuka, T., Umemori, H., Akiyama, T., Nakanishi, S., Yamamoto, T., PSD-95 promotes Fyn-mediated tyrosine phosphorylation of the N-methyl-D-aspartate receptor subunit NR2A. Proc Natl Acad Sci U S A 96 (1999), 435–440.
19. Trepanier, C.H., Jackson, M.F., MacDonald, J.F., Regulation of NMDA receptors by the tyrosine kinase Fyn. FEBS J 279 (2012), 12–19.
20. Xia, D., Gotz, J., Premature lethality, hyperactivity, and aberrant phosphorylation in transgenic mice expressing a constitutively active form of Fyn. Front Mol Neurosci, 7, 2014, 40.
21. Oda, T., Wals, P., Osterburg, H.H., Johnson, S.A., Pasinetti, G.M., Morgan, T.E., et al. Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1–42) and forms slowly sedimenting A beta complexes that cause oxidative stress. Exp Neurol 136 (1995), 22–31.
22. Lambert, M.P., Barlow, A.K., Chromy, B.A., Edwards, C., Freed, R., Liosatos, M., et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 95 (1998), 6448–6453.
23. Shankar, G.M., Li, S., Mehta, T.H., Garcia-Munoz, A., Shepardson, N.E., Smith, I., et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 14 (2008), 837–842.
24. Walsh, D.M., Klyubin, I., Fadeeva, J.V., Cullen, W.K., Anwyl, R., Wolfe, M.S., et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416 (2002), 535–539.
25. Barry, A.E., Klyubin, I., Mc Donald, J.M., Mably, A.J., Farrell, M.A., Scott, M., et al. Alzheimer's disease brain-derived amyloid-beta-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci 31 (2011), 7259–7263.
26. Chin, J., Palop, J.J., Yu, G.Q., Kojima, N., Masliah, E., Mucke, L., Fyn kinase modulates synaptotoxicity, but not aberrant sprouting, in human amyloid precursor protein transgenic mice. J Neurosci 24 (2004), 4692–4697.
27. Chin, J., Palop, J.J., Puolivali, J., Massaro, C., Bien-Ly, N., Gerstein, H., et al. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J Neurosci 25 (2005), 9694–9703.
28. Luo, Y.Q., Hirashima, N., Li, Y.H., Alkon, D.L., Sunderland, T., Etcheberrigaray, R., et al. Physiological levels of beta-amyloid increase tyrosine phosphorylation and cytosolic calcium. Brain Res 681 (1995), 65–74.
29. Bamberger, M.E., Harris, M.E., McDonald, D.R., Husemann, J., Landreth, G.E., A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 23 (2003), 2665–2674.
30. Grace, E.A., Busciglio, J., Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy. J Neurosci 23 (2003), 493–502.
31. Shirazi, S.K., Wood, J.G., The protein tyrosine kinase, fyn, in Alzheimer's disease pathology. NeuroReport 4 (1993), 435–437.
32. Bhaskar, K., Hobbs, G.A., Yen, S.H., Lee, G., Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy. Neuropathol Appl Neurobiol 36 (2010), 462–477.
33. Bhaskar, K., Yen, S.H., Lee, G., Disease-related modifications in tau affect the interaction between Fyn and tau. J Biol Chem 280 (2005), 35119–35125.
34. Lee, G., Thangavel, R., Sharma, V.M., Litersky, J.M., Bhaskar, K., Fang, S.M., et al. Phosphorylation of tau by fyn: Implications for Alzheimer's disease. J Neurosci 24 (2004), 2304–2312.
35. Lee, G., Newman, S.T., Gard, D.L., Band, H., Panchamoorthy, G., Tau interacts with Src-family non-receptor tyrosine kinases. J Cell Sci 111:Pt 21 (1998), 3167–3177.
36. Roberson, E.D., Halabisky, B., Yoo, J.W., Yao, J., Chin, J., Yan, F., et al. Amyloid-beta/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease. J Neurosci 31 (2011), 700–711.
37. Roberson, E.D., Scearce-Levie, K., Palop, J.J., Yan, F., Cheng, I.H., Wu, T., et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 316 (2007), 750–754.
38. Ittner, L.M., Ke, Y.D., Delerue, F., Bi, M., Gladbach, A., van Eersel, J., et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 142 (2010), 387–397.
39. Ittner, A., Chua, S.W., Bertz, J., Volkerling, A., van der Hoven, J., Gladbach, A., et al. Site-specific phosphorylation of tau inhibits amyloid-beta toxicity in Alzheimer's mice. Science 354 (2016), 904–908.
40. Lacor, P.N., Buniel, M.C., Furlow, P.W., Clemente, A.S., Velasco, P.T., Wood, M., et al. Aβ oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci 27 (2007), 796–807.
41. Jarosz-Griffiths, H.H., Noble, E., Rushworth, J.V., Hooper, N.M., Amyloid-beta receptors: The good, the bad, and the prion protein. J Biol Chem 291 (2016), 3174–3183.
42. Harris, D.A., Lele, P., Snider, W.D., Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc Natl Acad Sci U S A 90 (1993), 4309–4313.
43. Gimbel, D.A., Nygaard, H.B., Coffey, E.E., Gunther, E.C., Lauren, J., Gimbel, Z.A., et al. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30 (2010), 6367–6374.
44. Kostylev, M.A., Kaufman, A.C., Nygaard, H.B., Patel, P., Haas, L.T., Gunther, E.C., et al. Prion-protein-interacting amyloid-beta oligomers of high molecular weight are tightly correlated with memory impairment in multiple Alzheimer mouse models. J Biol Chem 290 (2015), 17415–17438.
45. Haas, L.T., Salazar, S.V., Kostylev, M.A., Um, J.W., Kaufman, A.C., Strittmatter, S.M., Metabotropic glutamate receptor 5 couples cellular prion protein to intracellular signalling in Alzheimer's disease. Brain 139 (2016), 526–546.
46. c –Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J Neurosci 32 (2012), 16857–16871.
47. Um, J.W., Kaufman, A.C., Kostylev, M., Heiss, J.K., Stagi, M., Takahashi, H., et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 79 (2013), 887–902.
48. Haas, L.T., Strittmatter, S.M., Oligomers of amyloid beta prevent physiological activation of the cellular prion protein–metabotropic glutamate receptor 5 complex by glutamate in Alzheimer disease. J Biol Chem 291 (2016), 17112–17121.
49. Park, S., Park, J.M., Kim, S., Kim, J.A., Shepherd, J.D., Smith-Hicks, C.L., et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59 (2008), 70–83.
50. Ma, T., Chen, Y., Vingtdeux, V., Zhao, H., Viollet, B., Marambaud, P., et al. Inhibition of AMP-activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid beta. J Neurosci 34 (2014), 12230–12238.
51. Jan, A., Jansonius, B., Delaidelli, A., Somasekharan, S.P., Bhanshali, F., Vandal, M., et al. eEF2K inhibition blocks Aβ42 neurotoxicity by promoting an NRF2 antioxidant response. Acta Neuropathol 133 (2017), 101–119.
52. Huang, Y., Lu, W., Ali, D.W., Pelkey, K.A., Pitcher, G.M., Lu, Y.M., et al. CAKβ/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus. Neuron 29 (2001), 485–496.
53. Collins, M., Tremblay, M., Chapman, N., Curtiss, M., Rothman, P.B., Houtman, J.C., The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol 87 (2010), 691–701.
54. Qian, D., Lev, S., van Oers, N.S., Dikic, I., Schlessinger, J., Weiss, A., Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling. J Exp Med 185 (1997), 1253–1259.
55. Kaufman, A.C., Salazar, S.V., Haas, L.T., Yang, J., Kostylev, M.A., Jeng, A.T., et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol 77 (2015), 953–971.
56. Nguyen, T.H., Liu, J., Lombroso, P.J., Striatal enriched phosphatase 61 dephosphorylates Fyn at phosphotyrosine 420. J Biol Chem 277 (2002), 24274–24279.
57. Lau, D.H., Hogseth, M., Phillips, E.C., O'Neill, M.J., Pooler, A.M., Noble, W., et al. Critical residues involved in tau binding to fyn: Implications for tau phosphorylation in Alzheimer's disease. Acta Neuropathol Commun, 4, 2016, 49.
58. Zahratka, J.A., Shao, Y., Shaw, M., Todd, K., Formica, S.V., Khrestian, M., et al. Regulatory region genetic variation is associated with FYN expression in Alzheimer's disease. Neurobiol Aging 51 (2017), 43–53.
59. Yang, K., Belrose, J., Trepanier, C.H., Lei, G., Jackson, M.F., MacDonald, J.F., Fyn, a potential target for Alzheimer's disease. J Alzheimer's Dis 27 (2011), 243–252.
60. Nygaard, H.B., van Dyck, C.H., Strittmatter, S.M., Fyn kinase inhibition as a novel therapy for Alzheimer's disease. Alzheimer's Res Ther, 6, 2014, 8.
61. Boggon, T.J., Eck, M.J., Structure and regulation of Src family kinases. Oncogene 23 (2004), 7918–7927.
62. Thomas, S.M., Brugge, J.S., Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol 13 (1997), 513–609.
63. Martin, G.S., The hunting of the Src. Nat Rev Mol Cell Biol 2 (2001), 467–475.
64. Goldsmith, J.F., Hall, C.G., Atkinson, T.P., Identification of an alternatively spliced isoform of the fyn tyrosine kinase. Biochem Biophys Res Commun 298 (2002), 501–504.
65. Cooke, M.P., Perlmutter, R.M., Expression of a novel form of the fyn proto-oncogene in hematopoietic cells. New Biol 1 (1989), 66–74.
66. Ohnishi, H., Murata, Y., Okazawa, H., Matozaki, T., Src family kinases: Modulators of neurotransmitter receptor function and behavior. Trends Neurosci 34 (2011), 629–637.
67. Schenone, S., Brullo, C., Musumeci, F., Biava, M., Falchi, F., Botta, M., Fyn kinase in brain diseases and cancer: The search for inhibitors. Curr Med Chem 18 (2011), 2921–2942.
68. Hennequin, L.F., Allen, J., Breed, J., Curwen, J., Fennell, M., Green, T.P., et al. N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem 49 (2006), 6465–6488.
69. Green, T.P., Fennell, M., Whittaker, R., Curwen, J., Jacobs, V., Allen, J., et al. Preclinical anticancer activity of the potent, oral Src inhibitor AZD0530. Mol Oncol 3 (2009), 248–261.
70. Nygaard, H.B., Wagner, A.F., Bowen, G.S., Good, S.P., MacAvoy, M.G., Strittmatter, K.A., et al. A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease. Alzheimer's Res Ther, 7, 2015, 35.
71. Piette, F., Belmin, J., Vincent, H., Schmidt, N., Pariel, S., Verny, M., et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer's disease: A randomised, placebo-controlled phase 2 trial. Alzheimer's Res Ther, 3, 2011, 16.
72. Dubreuil, P., Letard, S., Ciufolini, M., Gros, L., Humbert, M., Casteran, N., et al. Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. PLoS One, 4, 2009, e7258.
73. Hermine O, Moussy A, Mansfield C, Dubreuil P (2015): Masitinib for the treatment of severe systemic mastocytosis: Pooled phase 2 study simulation of phase 3 population and response criteria. Presented at the 7th EMBRN International Mast Cell and Basophil Meeting, October 21–23, Marseille, France.
74. Trias, E., Ibarburu, S., Barreto-Nunez, R., Babdor, J., Maciel, T.T., Guillo, M., et al. Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis. J Neuroinflammation, 13, 2016, 177.
75. Folch, J., Petrov, D., Ettcheto, M., Pedros, I., Abad, S., Beas-Zarate, C., et al. Masitinib for the treatment of mild to moderate Alzheimer's disease. Expert Rev Neurother 15 (2015), 587–596.
76. European Medicines Agency (2014): Assessment report, Masiviera—International non-propietary name: MASITINIB. Procedure No. EMEA/H/C/002659/0000.
77. Das, J., Chen, P., Norris, D., Padmanabha, R., Lin, J., Moquin, R.V., et al. 2-Aminothiazole as a novel kinase inhibitor template: Structure–activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J Med Chem 49 (2006), 6819–6832.
78. Dhawan, G., Combs, C.K., Inhibition of Src kinase activity attenuates amyloid associated microgliosis in a murine model of Alzheimer's disease. J Neuroinflammation, 9, 2012, 117.
79. Hanke, J.H., Gardner, J.P., Dow, R.L., Changelian, P.S., Brissette, W.H., Weringer, E.J., et al. Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor: Study of Lck- and FynT-dependent T cell activation. J Biol Chem 271 (1996), 695–701.
80. Boschelli, D.H., Ye, F., Wang, Y.D., Dutia, M., Johnson, S.L., Wu, B., et al. Optimization of 4-phenylamino-3-quinolinecarbonitriles as potent inhibitors of Src kinase activity. J Med Chem 44 (2001), 3965–3977.
81. Boschelli, F., Arndt, K., Gambacorti-Passerini, C., Bosutinib: A review of preclinical studies in chronic myelogenous leukaemia. Eur J Cancer 46 (2010), 1781–1789.
82. O'Hare, T., Shakespeare, W.C., Zhu, X., Eide, C.A., Rivera, V.M., Wang, F., et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16 (2009), 401–412.
83. 6 -Fyn signaling promotes oral cancer progression. J Biol Chem 278 (2003), 41646–41653.
84. Fresno Vara, J.A., Caceres, M.A., Silva, A., Martin-Perez, J., Src family kinases are required for prolactin induction of cell proliferation. Mol Biol Cell 12 (2001), 2171–2183.
85. Appleby, M.W., Gross, J.A., Cooke, M.P., Levin, S.D., Qian, X., Perlmutter, R.M., Defective T cell receptor signaling in mice lacking the thymic isoform of p59fyn. Cell 70 (1992), 751–763.
86. Tamura, T., Igarashi, O., Hino, A., Yamane, H., Aizawa, S., Kato, T., et al. Impairment in the expression and activity of Fyn during differentiation of naive CD4+ T cells into the Th2 subset. J Immunol 167 (2001), 1962–1969.
87. Sugie, K., Kawakami, T., Maeda, Y., Kawabe, T., Uchida, A., Yodoi, J., Fyn tyrosine kinase associated with Fc epsilon RII/CD23: Possible multiple roles in lymphocyte activation. Proc Natl Acad Sci U S A 88 (1991), 9132–9135.
88. Sugie, K., Jeon, M.S., Grey, H.M., Activation of naive CD4 T cells by anti-CD3 reveals an important role for Fyn in Lck-mediated signaling. Proc Natl Acad Sci U S A 101 (2004), 14859–14864.
89. Umemori, H., Sato, S., Yagi, T., Aizawa, S., Yamamoto, T., Initial events of myelination involve Fyn tyrosine kinase signalling. Nature 367 (1994), 572–576.
90. Sperber, B.R., McMorris, F.A., Fyn tyrosine kinase regulates oligodendroglial cell development but is not required for morphological differentiation of oligodendrocytes. J Neurosci Res 63 (2001), 303–312.
91. Laursen, L.S., Chan, C.W., ffrench-Constant, C., An integrin–contactin complex regulates CNS myelination by differential Fyn phosphorylation. J Neurosci 29 (2009), 9174–9185.
92. 3 –integrin signaling. J Cell Sci 121 (2008), 1641–1648.
93. Horak, I.D., Corcoran, M.L., Thompson, P.A., Wahl, L.M., Bolen, J.B., Expression of p60fyn in human platelets. Oncogene 5 (1990), 597–602.
94. Hannon, R.A., Clack, G., Rimmer, M., Swaisland, A., Lockton, J.A., Finkelman, R.D., et al. Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: A randomized, double-blind, placebo-controlled, multiple-ascending-dose phase I trial. J Bone Min Res 25 (2010), 463–471.
95. Kreutzman, A., Ladell, K., Koechel, C., Gostick, E., Ekblom, M., Stenke, L., et al. Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation. Leukemia 25 (2011), 1587–1597.
96. Takai, S., Sabzevari, H., Farsaci, B., Schlom, J., Greiner, J.W., Distinct effects of saracatinib on memory CD8+ T cell differentiation. J Immunol 188 (2012), 4323–4333.
97. Baselga, J., Cervantes, A., Martinelli, E., Chirivella, I., Hoekman, K., Hurwitz, H.I., et al. Phase I safety, pharmacokinetics, and inhibition of SRC activity study of saracatinib in patients with solid tumors. Clin Cancer Res 16 (2010), 4876–4883.
98. Jankowsky, J.L., Fadale, D.J., Anderson, J., Xu, G.M., Gonzales, V., Jenkins, N.A., et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: Evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13 (2004), 159–170.
99. Oddo, S., Caccamo, A., Shepherd, J.D., Murphy, M.P., Golde, T.E., Kayed, R., et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: Intracellular Aβ and synaptic dysfunction. Neuron 39 (2003), 409–421.