Document Type : Original Article
Authors
Department of Exercise Physiology, Faculty of Physical Education and Sport Sciences, University of Tehran, Tehran, Iran.
Abstract
Background and Aim: Alzheimer’s disease is a progressive disorder of the nervous system. Inflammation plays an important role in neurological dysfunction and loss of neuronal cells in Alzheimer’s disease. Previous studies have shown that cAMP response element-binding protein (CREB) activity decreases with beta amyloid and inflammation. Therefore, the purpose of this study was to investigate the effect of aerobic training before and after induction of Alzheimer on interleukin-1β (IL-1β) and CREB gene expression of Wistar male rats. Materials and Methods: The number of 115 male adult rats (eight-week old) with an average weight of 250±17.20 grams in the pre-Alzheimer’s stage were randomly divided into two equal resting (55 heads) and exercise (55 heads) groups. After four weeks and after induction of Alzheimer’s disease, the rats of each group were divided into three subgroups including Amyloid injection, injecting the placebo, and without injection groups. Before the start of the study, animals were killed (5 heads in each group) and their hippocampus removed after four weeks of training (before and after Alzheimer’s induction). IL-1β and CREB expression were measured by Real Time-PCR method and data were analyzed in two stages before and after Alzheimer’s induction with one way- analysis of variance and least significant difference (LSD) tests at the significant level of p≤0.05. Results: Both in the pre and post-Alzheimer’s stages, IL-1β and CREB expression decreased and increased significantly (p<0.05) in the training group compared to the resting group, respectively. Conclusion: Aerobic exercise can increase of CREB expression and reduction of inflammation before and after Alzheimer’s induction, and it probably contributes to hippocampal plasticity in this way and has cognitive or functional benefits.
Keywords
Aguiar, A. S., Castro, A. A., Moreira, E. L., Glaser, V., Santos, A. R., Tasca, C. I., ... & Prediger, R. D. (2011). Short bouts of mild-intensity physical exercise improve spatial learning and memory in aging rats: involvement of hippocampal plasticity via AKT, CREB and BDNF signaling. Mechanisms of Ageing and Development, 132(11), 560-567.
Barrientos, R. M., Sprunger, D. B., Campeau, S., Watkins, L. R., Rudy, J. W., & Maier, S. F. (2004). BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. Journal of Neuroimmunology, 155, 119–126.
Bauer, J., Berkenbosch, F., Van Dam, A.M., & Dijkstra, C.D. (1993). Demonstration of interleukin-1β in Lewis rat brain during experimental allergic encephalomyelitis by immunocytochemistry at the light and ultrastructural level. Journal of Neuroimmunology, 48(1), 13-21.
Buchanan, J. B., Sparkman, N. L., Chen, J., & Johnson, R. W. (2008). Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology, 33, 755–765.
Buchner, D. M., Beresford, S. A., Larson, E. B., LaCroix, A. Z., & Wagner, E. H. (1992). Effects of physical activity on health status in older adults II: Intervention studies. Annual Review of Public Health, 13(1), 469-488.
Burger, C. (2010). Region-specific genetic alterations in the aging hippocampus: implications for cognitive aging. Frontiers in Aging Neuroscience, 2, 140.
Cassilhas, R. C., Lee, K. S., Fernandes, J., Oliveira, M. G. M., Tufik, S., Meeusen, R., & De Mello, M. T. (2012). Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience, 202, 309-317.
Chae, C. H., & Kim, H. T. (2009). Forced, moderate-intensity treadmill exercise suppresses apoptosis by increasing the level of NGF and stimulating phosphatidylinositol 3-kinase signaling in the hippocampus of induced aging rats. Neurochemistry International, 55(4), 208-213.
Chen, M. J., & Russo-Neustadt, A. A. (2009). Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus, 19(10), 962-972.
Chennaoui, M., Drogou, C., & Gomez-Merino, D. (2008). Effects of physical training on IL-1β, IL-6 and IL-1ra concentrations in various brain areas of the rat. European Cytokine Network, 19(1), 8-14.
Chennaoui, M., Gomez Merino, D., Lesage, J., Drogou, C., & Guezennec, C. (2002). Effects of moderate and intensive training on the hypothalamo–pituitary–adrenal axis in rats. Acta Physiologica, 175(2), 113-121.
Cotman, C. W., & Berchtold, N. C. (2002). Exercise: a behavioral intervention to enhance brain health and plasticity. Trends in Neurosciences, 25(6), 295-301.
Dao, A. T., Zagaar, M. A., & Alkadhi, K. A. (2015). Moderate treadmill exercise protects synaptic plasticity of the dentate gyrus and related signaling cascade in a rat model of Alzheimer’s disease. Molecular Neurobiology, 52(3), 1067-1076.
Da Silva, S. G., Simões, P. S. R., Mortara, R. A., Scorza, F. A., Cavalheiro, E. A., da Graça Naffah-Mazzacoratti, M., & Arida, R. M. (2013). Exercise-induced hippocampal anti-inflammatory response in aged rats. Journal of Neuroinflammation, 10(1), 827.
Depino, A.M., Alonso, M., Ferrari, C., del Rey, A., Anthony, D., Besedovsky, H., … & Pittosi, F. (2004). Learning modulation by endogenous Hippocampal IL-1: Blockade of endogenous IL-1 facilitates memory formation. Hippocampus, 14, 526–535.
Donovan, D. C., Jackson, C. A., Colahan, P. T., Norton, N., & Hurley, D. J. (2007). Exercise-induced alterations in pro-inflammatory cytokines and prostaglandin F2α in horses. Veterinary Immunology and Immunopathology, 118(3), 263-269.
Farmer, J., Zhao, X. V., Van Praag, H., Wodtke, K., Gage, F. H., & Christie, B. R. (2004). Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo. Neuroscience, 124(1), 71-79.
Finkbeiner, S. (2000). CREB couples neurotrophin signals to survival messages. Neuron, 25(1), 11-14.
Frank, D. A., & Greenberg, M. E. (1994). CREB: a mediator of long-term memory from mollusks to mammals. Cell, 79(1), 5-8.
García-Mesa, Y., Pareja-Galeano, H., Bonet-Costa, V., Revilla, S., Gómez-Cabrera, M. C., Gambini, J., … & Sanfeliu, C. (2014). Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms. Psychoneuroendocrinology, 31(45), 154-66.
Gong, B., Vitolo, O. V., Trinchese, F., Liu, S., Shelanski, M., & Arancio, O. (2004). Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. Journal of Clinical Investigation, 114(11), 1624.
Gooney, M., Shaw, K., Kelly, A., O’Mara, S. M., & Lynch, M. A. (2002). Long-term potentiation and spatial learning are associated with increased phosphorylation of TrkB and extracellular signal-regulated kinase (ERK) in the dentate gyrus: evidence for a role for brain-derived neurotrophic factor. Behavioral Neuroscience, 116(3), 455.
Griffin, W. S., Stanley, L. C., Ling, C. H. E. N., White, L., MacLeod, V., Perrot, L. J., ... & Araoz, C. (1989). Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proceedings of the National Academy of Sciences, 86(19), 7611-7615.
Guzowski, J. F., & McGaugh, J. L. (1997). Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proceedings of the National Academy of Sciences, 94(6), 2693-2698.
Impey, S., Mark, M., Villacres, E. C., Poser, S., Chavkin, C., & Storm, D. R. (1996). Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron, 16(5), 973-982.
Kang, E. B., Kwon, I. S., Koo, J. H., Kim, E. J., Kim, C. H., Lee, J., ... & Cho, J. Y. (2013). Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis, 18(11), 1332-1347.
Leem, Y.H., Lee, Y., Son, H., & Lee, S. (2011). Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochemical and Biophysical Research Communications, 406, 359–365.
Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., ... & Cole, G. M. (2000). Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. Journal of Neuroscience, 20(15), 5709-5714.
Lynch, M. A. (2004). Long-term potentiation and memory. Physiological Reviews, 84(1), 87-136.
Meda, L., Baron, P., Prat, E., Scarpini, E., Scarlato, G., Cassatella, M.A., & Rossi, F. (1999). Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with β-amyloid [25–35]. Journal of Neuroimmunology, 93(1), 45-52.
Moore, A. H., Wu, M., Shaftel, S. S., Graham, K. A., & O’Banion, M. K. (2009). Sustained expression of interleukin-1 in mouse hippocampus impairs spatial memory. Neuroscience, 164, 1484–1495.
Morgan, D. (2009). The role of microglia in antibody-mediated clearance of amyloid-beta from the brain. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 8(1), 7-15.
Morris, K. A., & Gold, P. E. (2012). Age-related impairments in memory and in CREB and pCREB expression in hippocampus and amygdala following inhibitory avoidance training. Mechanisms of Ageing and Development, 133(5), 291-299.
Moyna, N. M., Acker, G. R., Fulton, J. R., Weber, K., Goss, F. L., Robertson, R. J., ... & Rabin, B. S. (1996). Lymphocyte function and cytokine production during incremental exercise in active and sedentary males and females. InternationalJournal of Sports medicine, 17(08), 585-591.
Mrak, R. E., & Griffin, W. S. T. (2005). Glia and their cytokines in progression of neurodegeneration. Neurobiology of Aging, 26(3), 349-354.
Nichol, K. E., Poon, W. W., Parachikova, A. I., Cribbs, D. H., Glabe, C. G., & Cotman, C. W. (2008). Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. Journal of Neuroinflammation, 5, 13.
Parachikova, A., Nichol, K. E., & Cotman, C. W. (2008). Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiology of Disease, 30(1), 121-129.
Puzzo, D., Staniszewski, A., Deng, S. X., Privitera, L., Leznik, E., Liu, S ... & Arancio, O. (2009). Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-β load in an Alzheimer’s disease mouse model. Journal of Neuroscience, 29(25), 8075-8086.
Qin, L., Wu, X., Block, M.L., Liu, Y., Breese, G.R., Hong, J. S ... & Crews, F. T. (2007). Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55(5), 453-462.
Shaftel, S. S., Griffin, W. S. T., & O’Banion, M. K. (2008). The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. Journal of Neuroinflammation, 5(1), 7.
Sheng, J. G., Ito, K., Skinner, R. D., Mrak, R. E., Rovnaghi, C. R., Van Eldik, L. J., & Griffin, W. S. T. (1996). In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiology of Aging, 17(5), 761-766.
Souza, L. C., Carlos Filho, B., Goes, A.T., Del Fabbro, L., de Gomes, M. G., Savegnago, L., ... & Jesse, C. R. (2013). Neuroprotective effect of physical exercise in a mouse model of Alzheimer’s disease induced by β-amyloid1–40 peptide. Neurotoxicity Research, 24(2), 148-163.
Stranahan, A. M., Lee, K., Becker, K. G., Zhang, Y., Maudsley, S., Martin, B ... & Mattson, M. P. (2010). Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice. Neurobiology of Aging, 31(11), 1937-1949.
Tong, L., Balazs, R., Soiampornkul, R., Thangnipon, W., & Cotman, C. W. (2008). Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction. Neurobiology of Aging, 29(9), 1380-1393.
Tong, L., Balazs, R., Thornton, P.L., & Cotman, C. W. (2004). β-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. Journal of Neuroscience, 24(30), 6799-6809.
Vilela, T. C., Muller, A. P., Damiani, A. P., Macan, T. P., da Silva, S., Canteiro, P. B., … & de Pinho, R. A. (2017). Strength and aerobic exercises improve spatial memory in aging rats through stimulating distinct neuroplasticity mechanisms. Molecular Neurobiology, 54(10), 7928-7937.
Vitolo, O. V., Sant’Angelo, A., Costanzo, V., Battaglia, F., Arancio, O., & Shelanski, M. (2002). Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proceedings of the National Academy of Sciences, 99(20), 13217-13221.
Wang, Q., Wu, J., Rowan, M. J., & Anwyl, R. (2005). β‐amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor. European Journal of Neuroscience, 22(11), 2827-2832.
Wei, Z., Belal, C., Tu, W., Chigurupati, S., Ameli, N.J., Lu, Y., & Chan, S.L. (2011). Chronic nicotine administration impairs activation of cyclic AMP-response element binding protein and survival of newborn cells in the dentate gyrus. Stem Cells and Development, 21(3), 411-422.
Wu, M. D., Hein, A. M., Moravan, M. J., Shaftel, S. S., Olschowka, J. A., & O’Banion, M. K. (2012). Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running. Brain, Behavior, and Immunity, 26(2), 292-300.
Wyss-Coray, T., & Mucke, L. (2002). Inflammation in neurodegenerative disease—a double-edged sword. Neuron, 35(3), 419-432.
Zagaar, M., Alhaider, I., Dao, A., Levine, A., Alkarawi, A., Alzubaidy, M., & Alkadhi, K. (2012). The beneficial effects of regular exercise on cognition in REM sleep deprivation: behavioral, electrophysiological and molecular evidence. Neurobiology of Disease, 45(3), 1153-1162.
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Barrientos, R. M., Sprunger, D. B., Campeau, S., Watkins, L. R., Rudy, J. W., & Maier, S. F. (2004). BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. Journal of Neuroimmunology, 155, 119–126.
Bauer, J., Berkenbosch, F., Van Dam, A.M., & Dijkstra, C.D. (1993). Demonstration of interleukin-1β in Lewis rat brain during experimental allergic encephalomyelitis by immunocytochemistry at the light and ultrastructural level. Journal of Neuroimmunology, 48(1), 13-21.
Buchanan, J. B., Sparkman, N. L., Chen, J., & Johnson, R. W. (2008). Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice. Psychoneuroendocrinology, 33, 755–765.
Buchner, D. M., Beresford, S. A., Larson, E. B., LaCroix, A. Z., & Wagner, E. H. (1992). Effects of physical activity on health status in older adults II: Intervention studies. Annual Review of Public Health, 13(1), 469-488.
Burger, C. (2010). Region-specific genetic alterations in the aging hippocampus: implications for cognitive aging. Frontiers in Aging Neuroscience, 2, 140.
Cassilhas, R. C., Lee, K. S., Fernandes, J., Oliveira, M. G. M., Tufik, S., Meeusen, R., & De Mello, M. T. (2012). Spatial memory is improved by aerobic and resistance exercise through divergent molecular mechanisms. Neuroscience, 202, 309-317.
Chae, C. H., & Kim, H. T. (2009). Forced, moderate-intensity treadmill exercise suppresses apoptosis by increasing the level of NGF and stimulating phosphatidylinositol 3-kinase signaling in the hippocampus of induced aging rats. Neurochemistry International, 55(4), 208-213.
Chen, M. J., & Russo-Neustadt, A. A. (2009). Running exercise-induced up-regulation of hippocampal brain-derived neurotrophic factor is CREB-dependent. Hippocampus, 19(10), 962-972.
Chennaoui, M., Drogou, C., & Gomez-Merino, D. (2008). Effects of physical training on IL-1β, IL-6 and IL-1ra concentrations in various brain areas of the rat. European Cytokine Network, 19(1), 8-14.
Chennaoui, M., Gomez Merino, D., Lesage, J., Drogou, C., & Guezennec, C. (2002). Effects of moderate and intensive training on the hypothalamo–pituitary–adrenal axis in rats. Acta Physiologica, 175(2), 113-121.
Cotman, C. W., & Berchtold, N. C. (2002). Exercise: a behavioral intervention to enhance brain health and plasticity. Trends in Neurosciences, 25(6), 295-301.
Dao, A. T., Zagaar, M. A., & Alkadhi, K. A. (2015). Moderate treadmill exercise protects synaptic plasticity of the dentate gyrus and related signaling cascade in a rat model of Alzheimer’s disease. Molecular Neurobiology, 52(3), 1067-1076.
Da Silva, S. G., Simões, P. S. R., Mortara, R. A., Scorza, F. A., Cavalheiro, E. A., da Graça Naffah-Mazzacoratti, M., & Arida, R. M. (2013). Exercise-induced hippocampal anti-inflammatory response in aged rats. Journal of Neuroinflammation, 10(1), 827.
Depino, A.M., Alonso, M., Ferrari, C., del Rey, A., Anthony, D., Besedovsky, H., … & Pittosi, F. (2004). Learning modulation by endogenous Hippocampal IL-1: Blockade of endogenous IL-1 facilitates memory formation. Hippocampus, 14, 526–535.
Donovan, D. C., Jackson, C. A., Colahan, P. T., Norton, N., & Hurley, D. J. (2007). Exercise-induced alterations in pro-inflammatory cytokines and prostaglandin F2α in horses. Veterinary Immunology and Immunopathology, 118(3), 263-269.
Farmer, J., Zhao, X. V., Van Praag, H., Wodtke, K., Gage, F. H., & Christie, B. R. (2004). Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague–Dawley rats in vivo. Neuroscience, 124(1), 71-79.
Finkbeiner, S. (2000). CREB couples neurotrophin signals to survival messages. Neuron, 25(1), 11-14.
Frank, D. A., & Greenberg, M. E. (1994). CREB: a mediator of long-term memory from mollusks to mammals. Cell, 79(1), 5-8.
García-Mesa, Y., Pareja-Galeano, H., Bonet-Costa, V., Revilla, S., Gómez-Cabrera, M. C., Gambini, J., … & Sanfeliu, C. (2014). Physical exercise neuroprotects ovariectomized 3xTg-AD mice through BDNF mechanisms. Psychoneuroendocrinology, 31(45), 154-66.
Gong, B., Vitolo, O. V., Trinchese, F., Liu, S., Shelanski, M., & Arancio, O. (2004). Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. Journal of Clinical Investigation, 114(11), 1624.
Gooney, M., Shaw, K., Kelly, A., O’Mara, S. M., & Lynch, M. A. (2002). Long-term potentiation and spatial learning are associated with increased phosphorylation of TrkB and extracellular signal-regulated kinase (ERK) in the dentate gyrus: evidence for a role for brain-derived neurotrophic factor. Behavioral Neuroscience, 116(3), 455.
Griffin, W. S., Stanley, L. C., Ling, C. H. E. N., White, L., MacLeod, V., Perrot, L. J., ... & Araoz, C. (1989). Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proceedings of the National Academy of Sciences, 86(19), 7611-7615.
Guzowski, J. F., & McGaugh, J. L. (1997). Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. Proceedings of the National Academy of Sciences, 94(6), 2693-2698.
Impey, S., Mark, M., Villacres, E. C., Poser, S., Chavkin, C., & Storm, D. R. (1996). Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus. Neuron, 16(5), 973-982.
Kang, E. B., Kwon, I. S., Koo, J. H., Kim, E. J., Kim, C. H., Lee, J., ... & Cho, J. Y. (2013). Treadmill exercise represses neuronal cell death and inflammation during Aβ-induced ER stress by regulating unfolded protein response in aged presenilin 2 mutant mice. Apoptosis, 18(11), 1332-1347.
Leem, Y.H., Lee, Y., Son, H., & Lee, S. (2011). Chronic exercise ameliorates the neuroinflammation in mice carrying NSE/htau23. Biochemical and Biophysical Research Communications, 406, 359–365.
Lim, G. P., Yang, F., Chu, T., Chen, P., Beech, W., Teter, B., ... & Cole, G. M. (2000). Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer’s disease. Journal of Neuroscience, 20(15), 5709-5714.
Lynch, M. A. (2004). Long-term potentiation and memory. Physiological Reviews, 84(1), 87-136.
Meda, L., Baron, P., Prat, E., Scarpini, E., Scarlato, G., Cassatella, M.A., & Rossi, F. (1999). Proinflammatory profile of cytokine production by human monocytes and murine microglia stimulated with β-amyloid [25–35]. Journal of Neuroimmunology, 93(1), 45-52.
Moore, A. H., Wu, M., Shaftel, S. S., Graham, K. A., & O’Banion, M. K. (2009). Sustained expression of interleukin-1 in mouse hippocampus impairs spatial memory. Neuroscience, 164, 1484–1495.
Morgan, D. (2009). The role of microglia in antibody-mediated clearance of amyloid-beta from the brain. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 8(1), 7-15.
Morris, K. A., & Gold, P. E. (2012). Age-related impairments in memory and in CREB and pCREB expression in hippocampus and amygdala following inhibitory avoidance training. Mechanisms of Ageing and Development, 133(5), 291-299.
Moyna, N. M., Acker, G. R., Fulton, J. R., Weber, K., Goss, F. L., Robertson, R. J., ... & Rabin, B. S. (1996). Lymphocyte function and cytokine production during incremental exercise in active and sedentary males and females. InternationalJournal of Sports medicine, 17(08), 585-591.
Mrak, R. E., & Griffin, W. S. T. (2005). Glia and their cytokines in progression of neurodegeneration. Neurobiology of Aging, 26(3), 349-354.
Nichol, K. E., Poon, W. W., Parachikova, A. I., Cribbs, D. H., Glabe, C. G., & Cotman, C. W. (2008). Exercise alters the immune profile in Tg2576 Alzheimer mice toward a response coincident with improved cognitive performance and decreased amyloid. Journal of Neuroinflammation, 5, 13.
Parachikova, A., Nichol, K. E., & Cotman, C. W. (2008). Short-term exercise in aged Tg2576 mice alters neuroinflammation and improves cognition. Neurobiology of Disease, 30(1), 121-129.
Puzzo, D., Staniszewski, A., Deng, S. X., Privitera, L., Leznik, E., Liu, S ... & Arancio, O. (2009). Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-β load in an Alzheimer’s disease mouse model. Journal of Neuroscience, 29(25), 8075-8086.
Qin, L., Wu, X., Block, M.L., Liu, Y., Breese, G.R., Hong, J. S ... & Crews, F. T. (2007). Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia, 55(5), 453-462.
Shaftel, S. S., Griffin, W. S. T., & O’Banion, M. K. (2008). The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective. Journal of Neuroinflammation, 5(1), 7.
Sheng, J. G., Ito, K., Skinner, R. D., Mrak, R. E., Rovnaghi, C. R., Van Eldik, L. J., & Griffin, W. S. T. (1996). In vivo and in vitro evidence supporting a role for the inflammatory cytokine interleukin-1 as a driving force in Alzheimer pathogenesis. Neurobiology of Aging, 17(5), 761-766.
Souza, L. C., Carlos Filho, B., Goes, A.T., Del Fabbro, L., de Gomes, M. G., Savegnago, L., ... & Jesse, C. R. (2013). Neuroprotective effect of physical exercise in a mouse model of Alzheimer’s disease induced by β-amyloid1–40 peptide. Neurotoxicity Research, 24(2), 148-163.
Stranahan, A. M., Lee, K., Becker, K. G., Zhang, Y., Maudsley, S., Martin, B ... & Mattson, M. P. (2010). Hippocampal gene expression patterns underlying the enhancement of memory by running in aged mice. Neurobiology of Aging, 31(11), 1937-1949.
Tong, L., Balazs, R., Soiampornkul, R., Thangnipon, W., & Cotman, C. W. (2008). Interleukin-1β impairs brain derived neurotrophic factor-induced signal transduction. Neurobiology of Aging, 29(9), 1380-1393.
Tong, L., Balazs, R., Thornton, P.L., & Cotman, C. W. (2004). β-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. Journal of Neuroscience, 24(30), 6799-6809.
Vilela, T. C., Muller, A. P., Damiani, A. P., Macan, T. P., da Silva, S., Canteiro, P. B., … & de Pinho, R. A. (2017). Strength and aerobic exercises improve spatial memory in aging rats through stimulating distinct neuroplasticity mechanisms. Molecular Neurobiology, 54(10), 7928-7937.
Vitolo, O. V., Sant’Angelo, A., Costanzo, V., Battaglia, F., Arancio, O., & Shelanski, M. (2002). Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proceedings of the National Academy of Sciences, 99(20), 13217-13221.
Wang, Q., Wu, J., Rowan, M. J., & Anwyl, R. (2005). β‐amyloid inhibition of long-term potentiation is mediated via tumor necrosis factor. European Journal of Neuroscience, 22(11), 2827-2832.
Wei, Z., Belal, C., Tu, W., Chigurupati, S., Ameli, N.J., Lu, Y., & Chan, S.L. (2011). Chronic nicotine administration impairs activation of cyclic AMP-response element binding protein and survival of newborn cells in the dentate gyrus. Stem Cells and Development, 21(3), 411-422.
Wu, M. D., Hein, A. M., Moravan, M. J., Shaftel, S. S., Olschowka, J. A., & O’Banion, M. K. (2012). Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running. Brain, Behavior, and Immunity, 26(2), 292-300.
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