Rapamycin and interleukin-1β impair brain-derived neurotrophic factor-dependent neuron survival by modulating autophagy

Journal of Biological Chemistry

Volumn 289, Issue 30, 2014, Pages 20615-20629

  Smith, Erica D ^a   Prieto, G Aleph ^a   Tong, Liqi ^a   Sears Kraxberger, Ilse ^b   Rice, Jeffrey D ^a   Steward, Oswald ^b   Cotman, Carl W ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTICS; BRAIN; CELL DEATH; CELL SIGNALING; CHEMICAL ACTIVATION; MACHINERY; PHYSIOLOGY;

BRAIN-DERIVED NEUROTROPHIC FACTORS; CASPASE-3 ACTIVATION; CASPASE-INDEPENDENT; CHRONIC INFLAMMATION; GENETIC MANIPULATIONS; MAMMALIAN TARGET OF RAPAMYCIN (MTOR); PHYSIOLOGICAL FUNCTIONS; PROTECTION MECHANISMS;

NEURONS;

ATG5 PROTEIN, RAT; ATG7 PROTEIN, RAT; BRAIN DERIVED NEUROTROPHIC FACTOR; CASP3 PROTEIN, RAT; CASPASE 3; IL1B PROTEIN, RAT; IMMUNOSUPPRESSIVE AGENT; INTERLEUKIN 1BETA; MTOR PROTEIN, RAT; PROTEIN; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE; UBIQUITIN PROTEIN LIGASE;

ANIMAL; AUTOPHAGY; CELL CULTURE; CELL SURVIVAL; DEGENERATIVE DISEASE; DRUG EFFECTS; MALE; METABOLISM; NERVE CELL; PATHOLOGY; RAT; SIGNAL TRANSDUCTION; SPRAGUE DAWLEY RAT;

ANIMALS; AUTOPHAGY; BRAIN-DERIVED NEUROTROPHIC FACTOR; CASPASE 3; CELL SURVIVAL; CELLS, CULTURED; IMMUNOSUPPRESSIVE AGENTS; INTERLEUKIN-1BETA; MALE; NEURODEGENERATIVE DISEASES; NEURONS; PROTEINS; RATS; RATS, SPRAGUE-DAWLEY; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES; UBIQUITIN-ACTIVATING ENZYMES;

EID: 84905398277     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.568659     Document Type: Article

References (86)

1. Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N. A., Müller, F.-J., Loring, J. F., Yamasaki, T. R., Poon, W. W., Green, K. N., and LaFerla, F. M. (2009) Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 106, 13594-13599
2. Ploughman, M., Windle, V., MacLellan, C. L., White, N., Doré, J. J., and Corbett, D. (2009) Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke 40, 1490-1495
3. Nagahara, A. H., Merrill, D. A., Coppola, G., Tsukada, S., Schroeder, B. E., Shaked, G. M., Wang, L., Blesch, A., Kim, A., Conner, J. M., Rockenstein, E., Chao, M. V., Koo, E. H., Geschwind, D., Masliah, E., Chiba, A. A., and Tuszynski, M. H. (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat. Med. 15, 331-337
4. Hetman, M., Kanning, K., Cavanaugh, J. E., and Xia, Z. (1999) Neuroprotection by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase. J. Biol. Chem. 274, 22569-22580
5. Tong, L., Balazs, R., Soiampornkul, R., Thangnipon, W., and Cotman, C. W. (2008) Interleukin-1β impairs brain derived neurotrophic factorinduced signal transduction. Neurobiol. Aging 29, 1380-1393
6. Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., and Greenberg, M. E. (1999) Cell survival promoted by the ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358-1362
7. Pastor, M. D., García-Yébenes, I., Fradejas, N., Pérez-Ortiz, J. M., Mora-Lee, S., Tranque, P., Moro, M. A., Pende, M., and Calvo, S. (2009) mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J. Biol. Chem. 284, 22067-22078
8. Shaw, R. J., and Cantley, L. C. (2006) Ras, PI (3) K, and mTOR signalling controls tumour cell growth. Nature 441, 424-430
9. Wullschleger, S., Loewith, R., and Hall, M. N. (2006) TOR signaling in growth and metabolism. Cell 124, 471-484
10. Edinger, A. L., and Thompson, C. B. (2004) An activated mTOR mutant supports growth factor-independent, nutrient-dependent cell survival. Oncogene 23, 5654-5663
11. Sato, T., Nakashima, A., Guo, L., Coffman, K., and Tamanoi, F. (2010) Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene 29, 2746-2752
12. Bekinschtein, P., Cammarota, M., Igaz, L. M., Bevilaqua, L. R., Izquierdo, I., and Medina, J. H. (2007) Persistence of long-term memory storage requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Neuron 53, 261-277
13. Cammalleri, M., Lütjens, R., Berton, F., King, A. R., Simpson, C., Francesconi, W., and Sanna, P. P. (2003) Time-restricted role for dendritic activation of the mTOR-p70S6K pathway in the induction of late-phase long-term potentiation in the CA1. Proc. Natl. Acad. Sci. U. S. A. 100, 14368-14373
14. Stoica, L., Zhu, P. J., Huang, W., Zhou, H., Kozma, S. C., and Costa-Mattioli, M. (2011) Selective pharmacogenetic inhibition of mammalian target of rapamycin complex I (mTORC1) blocks long-term synaptic plasticity and memory storage. Proc. Natl. Acad. Sci. U. S. A. 108, 3791-3796
15. Malagelada, C., Jin, Z. H., Jackson-Lewis, V., Przedborski, S., and Greene, L. A. (2010) Rapamycin protects against neuron death in in vitro and in vivo models of Parkinson's disease. J. Neurosci. 30, 1166-1175
16. Kapahi, P., Zid, B. M., Harper, T., Koslover, D., Sapin, V., and Benzer, S. (2004) Regulation of life span in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885-890
17. Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., Pahor, M., Javors, M. A., Fernandez, E., and Miller, R. A. (2009) Rapamycin fed late in life extends life span in genetically heterogeneous mice. Nature 460, 392-395
18. Miller, R. A., Harrison, D. E., Astle, C. M., Baur, J. A., Boyd, A. R., de Cabo, R., Fernandez, E., Flurkey, K., Javors, M. A., Nelson, J. F., Orihuela, C. J., Pletcher, S., Sharp, Z. D., Sinclair, D., Starnes, J. W., Wilkinson, J. E., Nadon, N. L., and Strong, R. (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J. Gerontol. A Biol. Sci. Med. Sci. 66, 191-201
19. Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., Yokoyama, M., Mishima, K., Saito, I., Okano, H., and Mizushima, N. (2006) Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889
20. Komatsu, M., Waguri, S., Chiba, T., Murata, S., Iwata, J., Tanida, I., Ueno, T., Koike, M., Uchiyama, Y., Kominami, E., and Tanaka, K. (2006) Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884
21. Koike, M., Shibata, M., Tadakoshi, M., Gotoh, K., Komatsu, M., Waguri, S., Kawahara, N., Kuida, K., Nagata, S., Kominami, E., Tanaka, K., and Uchiyama, Y. (2008) Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am. J. Pathol. 172, 454-469
22. Jaeger, P. A., and Wyss-Coray, T. (2009) All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol. Neurodegener. 4, 16-16
23. Lee, J.-A., and Gao, F.-B. (2009) Inhibition of autophagy induction delays neuronal cell loss caused by dysfunctional ESCRT-III in frontotemporal dementia. J. Neurosci. 29, 8506-8511
24. Higgins, G. C., Devenish, R. J., Beart, P. M., and Nagley, P. (2011) Autophagic activity in cortical neurons under acute oxidative stress directly contributes to cell death. Cell. Mol. Life Sci. 68, 3725-3740
25. Ma, T., Hoeffer, C. A., Capetillo-Zarate, E., Yu, F., Wong, H., Lin, M. T., Tampellini, D., Klann, E., Blitzer, R. D., and Gouras, G. K. (2010) Dysregulation of themTORpathway mediates impairment of synaptic plasticity in a mouse model of Alzheimer's disease. PLoS ONE 5, e12845
26. Yamamoto, A., Cremona, M. L., and Rothman, J. E. (2006) Autophagymediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J. Cell Biol. 172, 719-731
27. Mitra, S., Tsvetkov, A. S., and Finkbeiner, S. (2009) Protein turnover differences between neurons and other cells. Autophagy 5, 1037-1038
28. Hoeffer, C. A., and Klann, E. (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 33, 67-75
29. Pike, C. J., Burdick, D., Walencewicz, A. J., Glabe, C. G., and Cotman, C. W. (1993) Neurodegeneration induced by β-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13, 1676-1687
30. Caceres, A., Binder, L. I., Payne, M. R., Bender, P., Rebhun, L., and Steward, O. (1984) Differential subcellular localization of tubulin and the microtubuleassociated protein MAP2 in brain tissue as revealed by immunocytochemistry with monoclonal hybridoma antibodies. J. Neurosci. 4, 394-410
31. Caceres, A., Banker, G., Steward, O., Binder, L., and Payne, M. (1984) MAP2is localized to the dendrites of hippocampal neurons which develop in culture. Brain Res. 315, 314-318
32. Schalm, S. S., and Blenis, J. (2002) Identification of a conserved motif required for mTOR signaling. Curr. Biol. 12, 632-639
33. Dieterich, D. C., Lee, J. J., Link, A. J., Graumann, J., Tirrell, D. A., and Schuman, E. M. (2007) Labeling, detection and identification of newly synthesized proteomes with bioorthogonal non-canonical amino-acid tagging. Nat. Protoc. 2, 532-540
34. Mizushima, N. (2009) in Methods in Enzymology (Daniel J. Klionsky, ed) pp. 13-23, Academic Press, New York
35. Huang, E. J., and Reichardt, L. F. (2001) Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677-736
36. Navé, B. T., Ouwens, M., Withers, D. J., Alessi, D. R., and Shepherd, P. R. (1999) Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem. J. 344, 427-431
37. Sekulić, A., Hudson, C. C., Homme, J. L., Yin, P., Otterness, D. M., Karnitz, L. M., and Abraham, R. T. (2000) A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells. Cancer Res. 60, 3504-3513
38. Wu, X., Reiter, C. E., Antonetti, D. A., Kimball, S. R., Jefferson, L. S., and Gardner, T. W. (2004) Insulin promotes rat retinal neuronal cell survival in a p70S6K-dependent manner. J. Biol. Chem. 279, 9167-9175
39. Harada, H., Andersen, J. S., Mann, M., Terada, N., and Korsmeyer, S. J. (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc. Natl. Acad. Sci. U. S. A. 98, 9666-9670
40. Cunningham, J. T., Rodgers, J. T., Arlow, D. H., Vazquez, F., Mootha, V. K., and Puigserver, P. (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1[agr] transcriptional complex. Nature 450, 736-740
41. Armour, S. M., Baur, J. A., Hsieh, S. N., Land-Bracha, A., Thomas, S. M., and Sinclair, D. A. (2009) Inhibition of mammalian S6 kinase by resveratrol suppresses autophagy. Aging 1, 515-528
42. Kim, D.-H., Sarbassov, D. D., Ali, S. M., King, J. E., Latek, R. R., Erdjument-Bromage, H., Tempst, P., and Sabatini, D. M. (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163-175
43. Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J. L., Bonenfant, D., Oppliger, W., Jenoe, P., and Hall, M. N. (2002) Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control. Mol. Cell 10, 457-468
44. Zhao, P., Meng, Q., Liu, L.-Z., You, Y.-P., Liu, N., and Jiang, B.-H. (2010) Regulation of survivin by PI3K/Akt/p70S6K1 pathway. Biochem. Biophys. Res. Commun. 395, 219-224
45. Vega, F., Medeiros, L. J., Leventaki, V., Atwell, C., Cho-Vega, J. H., Tian, L., Claret, F.-X., and Rassidakis, G. Z. (2006) Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res. 66, 6589-6597
46. Snigdha, S., Smith, E. D., Prieto, G. A., and Cotman, C. W. (2012) Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci. Bull. 28, 14-24
47. Meijer, A. J., and Codogno, P. (2004) Regulation and role of autophagy in mammalian cells. Int. J. Biochem. Cell Biol. 36, 2445-2462
48. Klionsky, D. J., Abdalla, F. C., Abeliovich, H., Abraham, R. T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J. A., Ahn, H. J., Ait-Mohamed, O., Ait-Si-Ali, S., Akematsu, T., Akira, S., Al-Younes, H. M., Al-Zeer, M. A., Albert, M. L., Albin, R. L., Alegre-Abarrategui, J., Aleo, M. F., Alirezaei, M., Almasan, A., Almonte-Becerril, M., Amano, A., Amaravadi, R., et al. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445-544.
49. Tanida, I., Ueno, T., and Kominami, E. (2004) Human light chain 3/MAP1LC3B is cleaved at its carboxyl-terminal Met-121 to expose Gly-120 for lipidation and targeting to autophagosomal membranes. J. Biol. Chem. 279, 47704-47710
50. Petralia, R. S., Schwartz, C. M., Wang, Y.-X., Kawamoto, E. M., Mattson, M. P., and Yao, P. J. (2013) Sonic hedgehog promotes autophagy in hippocampal neurons. Biol. Open 2, 499-504
51. Boland, B., Kumar, A., Lee, S., Platt, F. M., Wegiel, J., Yu, W. H., and Nixon, R. A. (2008) Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J. Neurosci. 28, 6926-6937
52. Mizushima, N., Yoshimori, T., and Levine, B. (2010) Methods in mammalian autophagy research. Cell 140, 313-326
53. Bains, M., Florez-McClure, M. L., and Heidenreich, K. A. (2009) Insulinlike growth factor-I prevents the accumulation of autophagic vesicles and cell death in Purkinje neurons by increasing the rate of autophagosometolysosome fusion and degradation. J. Biol. Chem. 284, 20398-20407
54. Neely, K. M., Green, K. N., and LaFerla, F. M. (2011) Presenilin is necessary for efficient proteolysis through the autophagy-lysosome system in a α-secretase-independent manner. J. Neurosci. 31, 2781-2791
55. Scott, R. C., Schuldiner, O., and Neufeld, T. P. (2004) Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev. Cell 7, 167-178
56. Tremblay, F., Krebs, M., Dombrowski, L., Brehm, A., Bernroider, E., Roth, E., Nowotny, P., Waldhäusl, W., Marette, A., and Roden, M. (2005) Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54, 2674-2684
57. Zhang, J., Gao, Z., Yin, J., Quon, M. J., and Ye, J. (2008) S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-α signaling through IKK2. J. Biol. Chem. 283, 35375-35382
58. Chang, Y.-Y., Juhász, G., Goraksha-Hicks, P., Arsham, A. M., Mallin, D. R., Muller, L. K., and Neufeld, T. P. (2009) Nutrient-dependent regulation of autophagy through the target of rapamycin pathway. Biochem. Soc. Trans 37, 232-326
59. Yu, L., McPhee, C. K., Zheng, L., Mardones, G. A., Rong, Y., Peng, J., Mi, N., Zhao, Y., Liu, Z., Wan, F., Hailey, D. W., Oorschot, V., Klumperman, J., Baehrecke, E. H., and Lenardo, M. J. (2010) Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature 465, 942-946
60. Klionsky, D. J., Meijer, A. J., and Codogno, P. (2005) Autophagy and p70S6 kinase. Autophagy 1, 59-60
61. Du, L., Hickey, R. W., Bayir, H., Watkins, S. C., Tyurin, V. A., Guo, F., Kochanek, P. M., Jenkins, L. W., Ren, J., Gibson, G., Chu, C. T., Kagan, V. E., and Clark, R. S. (2009) Starving neurons show sex difference in autophagy. J. Biol. Chem. 284, 2383-2396
62. Walls, K. C., Ghosh, A. P., Franklin, A. V., Klocke, B. J., Ballestas, M., Shacka, J. J., Zhang, J., and Roth, K. A. (2010) Lysosome dysfunction triggers Atg7-dependent neural apoptosis. J. Biol. Chem. 285, 10497-10507
63. Shehata, M., Matsumura, H., Okubo-Suzuki, R., Ohkawa, N., and Inokuchi, K. (2012) Neuronal stimulation induces autophagy in hippocampal neurons that is involved in AMPA receptor degradation after chemical long-term depression. J. Neurosci. 32, 10413-10422
64. Yamada, M., Ohnishi, H., Sano, S. i, Nakatani, A., Ikeuchi, T., and Hatanaka, H. (1997) Insulin receptor substrate (IRS)-1 and IRS-2 are tyrosinephosphorylated and associated with phosphatidylinositol 3-kinase in response to brain-derived neurotrophic factor in cultured cerebral cortical neurons. J. Biol. Chem. 272, 30334-30339
65. Sun, J., Conn, C. S., Han, Y., Yeung, V., and Qian, S.-B. (2011) PI3KmTORC1 attenuates stress response by inhibiting cap-independent Hsp70 translation. J. Biol. Chem. 286, 6791-6800
66. Qin, X., and Sarnow, P. (2004) Preferential translation of internal ribosome entry site-containing mRNAs during the mitotic cycle in mammalian cells. J. Biol. Chem. 279, 13721-13728
67. Jaeger, P. A., and Wyss-Coray, T. (2010) Beclin 1 complex in autophagy and Alzheimer disease. Arch. Neurol. 67, 1181-1184
68. Sarkar, S., Floto, R. A., Berger, Z., Imarisio, S., Cordenier, A., Pasco, M., Cook, L. J., and Rubinsztein, D. C. (2005) Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101-1111
69. Levine, B., and Yuan, J. (2005) Autophagy in cell death: an innocent convict? J. Clin. Invest. 115, 2679-2688
70. Hyman, B. T. (2011) Caspase activation without apoptosis: insight into Aβ initiation of neurodegeneration. Nat. Neurosci. 14, 5-6
71. Yu, L., Alva, A., Su, H., Dutt, P., Freundt, E., Welsh, S., Baehrecke, E. H., and Lenardo, M. J. (2004) Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304, 1500-1502
72. Puyal, J., Vaslin, A., Mottier, V., and Clarke, P. G. (2009) Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann. Neurol. 66, 378-389
73. Dziedzic, S. A., and Caplan, A. B. (2012) Autophagy proteins play cytoprotective and cytocidal roles in leucine starvation-induced cell death in Saccharomyces cerevisiae. Autophagy 8, 731-738
74. Shimizu, S., Kanaseki, T., Mizushima, N., Mizuta, T., Arakawa-Kobayashi, S., Thompson, C. B., and Tsujimoto, Y. (2004) Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat. Cell Biol. 6, 1221-1228
75. Peng, S., Wuu, J., Mufson, E. J., and Fahnestock, M. (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease. J. Neurochem. 93, 1412-1421
76. Francis, B. M., Kim, J., Barakat, M. E., Fraenkl, S., Yücel, Y. H., Peng, S., Michalski, B., Fahnestock, M., McLaurin, J., and Mount, H. T. (2012) Object recognition memory and BDNF expression are reduced in young TgCRND8 mice. Neurobiol. Aging 33, 555-563
77. Tong, L., Prieto, G. A., Kramár, E. A., Smith, E. D., Cribbs, D. H., Lynch, G., and Cotman, C. W. (2012) Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1β via p38 mitogen-activated protein kinase. J. Neurosci. 32, 17714-17724
78. Delgado, M. A., Elmaoued, R. A., Davis, A. S., Kyei, G., and Deretic, V. (2008) Toll-like receptors control autophagy. EMBO J. 27, 1110-1121
79. Sanjuan, M. A., Dillon, C. P., Tait, S. W., Moshiach, S., Dorsey, F., Connell, S., Komatsu, M., Tanaka, K., Cleveland, J. L., Withoff, S., and Green, D. R. (2007) Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature 450, 1253-1257
80. Ost, A., Svensson, K., Ruishalme, I., Brännmark, C., Franck, N., Krook, H., Sandström, P., Kjolhede, P., and Strålfors, P. (2010) Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Mol. Med. 16, 235-246
81. Lee, D.-F., Kuo, H.-P., Chen, C.-T., Hsu, J.-M., Chou, C.-K., Wei, Y., Sun, H.-L., Li, L.-Y., Ping, B., Huang, W.-C., He, X., Hung, J.-Y., Lai, C.-C., Ding, Q., Su, J.-L., Yang, J.-Y., Sahin, A. A., Hortobagyi, G. N., Tsai, F.-J., Tsai, C.-H., and Hung, M.-C. (2007) IKKβ suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell 130, 440-455
82. Fischer, W., Wictorin, K., Björklund, A., Williams, L. R., Varon, S., and Gage, F. H. (1987) Amelioration of cholinergic neuron atrophy and spatial memory impairment in aged rats by nerve growth factor. Nature 329, 65-68
83. Autry, A. E., and Monteggia, L. M. (2012) Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol. Rev. 64, 238-258
84. Park, H.-Y., Kim, J. H., Sun Kim, H., and Park, C. K. (2012) Stem cell-based delivery of brain-derived neurotrophic factor gene in the rat retina. Brain Res. 1469, 10-23
85. Alirezaei, M., Kemball, C. C., Flynn, C. T., Wood, M. R., Whitton, J. L., and Kiosses, W. B. (2010) Short-term fasting induces profound neuronal autophagy. Autophagy 6, 702-710
86. He, C., Sumpter, R., Jr., and Levine, B. (2012) Exercise induces autophagy in peripheral tissues and in the brain. Autophagy 8, 1548-1551