Abstract
The accumulation of amyloid-β is widely considered the primary neurotoxic insult leading to Alzheimer’s disease. Although the precise mechanism of this toxicity is not well understood, amyloid-β-induced downregulation of brain-derived neurotrophic factor may be one of the most important contributors to amyloid-β toxicity. Brain-derived neurotrophic factor has diverse neurotrophic effects on the nervous system, including promoting synaptic plasticity and neurogenesis, and it is essential for cognition and memory. Early in the progression of Alzheimer’s disease, prior to significant plaque and tangle deposition, declining brain-derived neurotrophic factor expression induced by amyloid-β is associated with mounting impairments in cognition and memory. A variety of approaches have demonstrated that increasing brain-derived neurotrophic factor levels improves learning and memory, highlighting the possibility that therapeutically restoring brain-derived neurotrophic factor levels may prevent or reverse the memory impairments and cognitive decline seen in Alzheimer’s disease.
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Aggarwal, N. T., Wilson, R. S., Beck, T. L., Bienias, J. L., & Bennett, D. A. (2005). Mild cognitive impairment in different functional domains and incident Alzheimer’s disease. Journal of Neurology, Neurosurgery, and Psychiatry, 76(11), 1479–84.
Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., Wyss-Coray, T. (2000). Inflammation and Alzheimer’s disease. Neurobiology of Aging, 21, 383–421.
Alderson, R. F., Alterman, A. L., Barde, Y.-A., & Lindsay, R. M. (1990). Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture. Neuron, 5, 297–306.
Anderson, K. D., Alderson, R. F., Altar, C. A., DiStefano, P. S., Corcoran, T. L., Lindsay, R. M., & Wiegand, S. J. (1995). Differential distribution of exogenous BDNF, NGF, and NT-3 in the brain corresponds to the relative abundance and distribution of high-affinity and low-affinity neurotrophin receptors. The Journal of comparative neurology, 357, 296–317.
Ando, S., Kobayashi, S., Waki, H., Kon, K., Fukui, F., Tadenuma, T., Iwamoto, M., Takeda, Y., Izumiyama, N., Watanabe, K., & Nakamura, H. (2002). Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine. Journal of neuroscience research, 70, 519–527.
Aronoff, J. M., Gonnerman, L. M., Almor, A., Arunchalam, S., Kempler, D., & Andersen, E. S. (2006). Information content versus relational knowledge: Semantic deficits in patients with Alzheimer’s disease. Neuropsychologia, 44(1), 21–35.
Atwal, J. K., Massie, B., Miller, F. D., & Kaplan, D. R. (2000). The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase. Neuron, 27(2), 265–277.
Barco, A., Patterson, S. L., Alarcon, J. M., Gromova, P., Mata-Roig, M., Morozov, A., & Kandel, E. R. (2005). Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron, 48(1), 123–137.
Barco, A., Pittenger, C., & Kandel, E. R. (2003). CREB, memory enhancement and the treatment of memory disorders: Promises, pitfalls and prospects. Expert Opinion on Therapeutic Targets, 7(1), 101–114.
Baxter, M. G., & Chiba, A. A. (1999). Cognitive functions of the basal forebrain. Current Opinion in Neurobiology, 9(2), 178–183.
Berchtold, N. C., Kessiak, J. P., & Cotman, C. W. (2002). Hippocampal brain-derived neurotrophic factor gene regulation by exercise and the medial septum. Journal of neuroscience research, 68(5), 511–521.
Berninger, B., García, D. E., Inagaki, N., Hahnel, C., & Lindholm, D. (1993). BDNF and NT-3 induce intracellular Ca2+ elevation in hippocampal neurones. Neuroreport, 4(12), 1303–1306.
Blanquet, P. R., & Lamour, Y. (1997). Brain-derived neurotrophic factor increases Ca2+/calmodulin-dependent protein kinase 2 activity in hippocampus. The Journal of biological chemistry, 272(39), 24133–24136.
Blurton-Jones, M., Kitazawa, M., Martinez-Coria, H., Castello, N. A., Muller, F.-J., Loring, J. F., Yamasaki, T. R., Poon, W. W., Green, K. N., & LaFerla, F. M. (2009). Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proceedings of the National Academy of Sciences U S A., 106(32), 13594–13599.
Boado, R. J., Zhang, Y., Zhang, Y., & Pardridge, W. M. (2007). Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular trojan horse for delivery across the human blood–brain barrier. Biotechnology and Bioengineering, 97(6), 1376–1386.
Boekhoorn, K., Joels, M., & Lucassen, P. J. (2006). Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiology of Disease, 24(1), 1–14.
Burdick, D., Soreghan, B., Kwon, M., Kosmoski, J., Knauer, M., Henschen, A., Yates, J., Cotman, C., & Glabe, C. (1992). Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. The Journal of biological chemistry, 265(1), 546–554.
Caccamo, A., Maldonado, M. A., Bokov, A. F., Majumder, S., & Oddo, S. (2010). CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer’s disease. PNAS, 107(52), 22687–22692.
Chen, Q.-S., Kagan, B., Hirakura, Y., & Xie, C.-W. (2000). Impairment of hippocampal long-term potentiation by Alzheimer amyloid β-peptides. Journal of Neuroscience Research, 60, 65–72.
Citron, M., Oltersdorf, T., Haass, C., McConlogue, L., Hung, A. Y., Seubert, P., Vigo-Pelfrey, C., Lieberburg, I., & Selkoe, D. J. (1992). Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature, 360(6405), 673–674.
Coleman, P. D., & Flood, D. G. (1987). Neuron numbers and dendritic extent in normal aging and Alzheimer’s disease. Neurobiology of Aging, 8, 521–545.
Coleman, P. D., & Yao, P. J. (2003). Synaptic slaughter in Alzheimer’s disease. Neurobiology of Aging, 24, 1023–1027.
Connor, B., Young, D., Yan, Q., Faull, R. L., Synek, B., & Dragunow, M. (1997). Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Brain research. Molecular brain research, 49, 71–81.
Cotman, C. W., & Berchtold, N. C. (2002). Exercise: A behavioral intervention to enhance brain health and plasticity. Trends in neurosciences, 25(6), 295–301.
Cotman, C., & Head, E. (2008). The canine (dog) model of human aging and disease: Dietary, environmental and immunotherapy approaches. Journal of Alzheimer’s disease, 15(4), 685–707.
Coyle, J., Price, D., & DeLong, M. (1983). Alzheimer’s disease: A disorder of cortical cholinergic innervation. Science, 219(4589), 1184–90.
Crews, L., Adame, A., Patrick, C., Delaney, A., Pham, E., Rockenstein, E., Hansen, L., & Masliah, E. (2010). Increased BMP6 levels in the brains of Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. The Journal of neuroscience, 30(37), 12252–62.
Cullen, W., Suh, Y., Anwyl, R., & Rowan, M. (1997). Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments. Neuroreport, 8(15), 3213–3217.
DaRocha-Souto, B., Coma, M., Pérez-Nievas, B. G., Scotton, T. C., Siao, M., Sánchez-Ferrer, P., Hashimoto, T., Fan, Z., Hudry, E., Barroeta, I., Serenó, L., Rodríguez, M., Sánchez, M. B., Hyman, B. T., & Gómez-Isla, T. (2012). Activation of glycogen synthase kinase-3 beta mediates β-amyloid induced neuritic damage in Alzheimer’s disease. Neurobiology of disease, 45(1), 425–437.
Davis, K. E., Easton, A., Eacott, M. J., Gigg, J. (2012) Episodic-like memory for what-where-which occasion is selectively impaired in the 3xTgAD mouse model of Alzheimer’s disease. Journal of Alzheimer’s disease. In press.
DeFelice, F., Velasco, P., Lambert, M., Viola, K., Fernandez, S., Ferreira, S., & Klein, W. (2007). Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. Journal of Biological. Chemistry, 282(15), 11590–11601.
DeMarch, Z., Giampà, C., Patassini, S., Bernardi, G., & Fusco, F. R. (2008). Beneficial effects of rolipram in the R6/2 mouse model of huntington’s disease. Neurobiology of Disease, 30(3), 375–387.
Demuro, A., Mina, E., Kayed, R., Milton, S., Parker, I., & Glabe, C. (2005). Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. The Journal of biological chemistry, 280(17), 17294–17300.
DeStrooper, B., & Annaert, W. (2000). Proteolytic processing and cell biological functions of the amyloid precursor protein. Journal of cell science, 113, 1857–1870.
Devanand, D. P., Pradhaban, G., Liu, X., Khandji, A., De Santi, S., Segal, S., & de Leon, M. J. (2007). Hippocampal and entorhinal atrophy in mild cognitive impairment: prediction of Alzheimer disease. Neurology, 68(11), 828–836.
Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., Zaitsev, E., Gold, B., Goldman, D., Dean, M., Lu, B., & Weinberger, D. R. (2003). The BDNF Val66Met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257–269.
España, J., Valero, J., Miñano-Molina, A. J., Masgrau, R., Martín, E., Guardia-Laguarta, C., Lleó, A., Giménez-Llort, L., Rodríguez-Alvarez, J., & Saura, C. A. (2010). beta-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. The Journal of neuroscience, 30(28), 9402–9410.
Fahnestock, M., Garzon, D., Holsinger, R. M. D., & Michalski, B. (2002). Neurotrophic factors and Alzheimer’s disease: Are we focusing on the wrong molecule? Journal of Neural Transmission. Supplementa, 62, 241–252.
Fahnestock, M., Marchese, M., Head, E., Pop, V., Michalski, B., Milgram, W., & Cotman, C. (2012). BDNF increases with behavioral enrichment and an antioxidant diet in the aged dog. Neurobiology of Aging, 33, 546–554.
Falkenberg, T., Mohammed, A. K., Henriksson, B., Persson, H., Winblad, B., & Lindefors, N. (1992). Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment. Neuroscience Letters, 138(1), 153–156.
Fayard, B., Loeffler, S., Weis, J., Vögelin, E., & Krüttgen, A. (2005). The secreted brain-derived neurotrophic factor precursor pro-BDNF binds to TrkB and p75NTR but not to TrkA or TrkC. Journal of neuroscience research, 80(1), 18–28.
Ferreira, S. T., Vieira, M. N., & De Felice, F. G. (2007). Soluble protein oligomers as emerging toxins in Alzheimer’s and other amyloid diseases. IUBMB Life, 59, 332–345.
Ferreiro, E., Resende, R., Costa, R., Oliveira, C., & Pereira, C. (2006). An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiology of Disease, 23, 669–678.
Ferrer, I., Marín, C., Rey, M. J., Ribalta, T., Goutan, E., Blanco, R., Tolosa, E., & Martí, E. (1999). BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies. Journal of neuropathology and experimental neurology, 58, 729–739.
Figurov, A., Pozzo-Miller, L. D., Olafsoon, P., Wang, T., & Lu, B. (1996). Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature, 381(6584), 706–709.
Finkbeiner, S., Tavazoie, S. F., Maloratsky, A., Jacobs, K. M., Harris, K. M., & Greenberg, M. E. (1997). CREB: A major mediator of neuronal neurotrophin responses. Neuron, 19(5), 1031–1047.
Francis, B. M., Kim, J., Barakat, M. E., Fraenkl, S., Yücel, Y. H., Peng, S., Michalski, B., Fahnestock, M., McLaurin, J., & Mount, H. T. (2012). Object recognition memory and BDNF expression are reduced in young TgCRND8 mice. Neurobiology of Aging, 33(3), 555–563.
Fujioka, T., Fujioka, A., & Duman, R. S. (2004). Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus. The Journal of neuroscience, 24, 319–328.
Garzon, D. J., & Fahnestock, M. (2007). Oligomeric amyloid decreases basal levels of brain-derived neurotrophic factor (BDNF) mRNA via specific downregulation of BDNF transcripts IV and V in differentiated human neuroblastoma cells. The Journal of neuroscience, 27, 2628–2635.
Garzon, D. J., Yu, G., & Fahnestock, M. (2002). A new BDNF transcript and decrease in BDNF transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex. Journal of Neurochemistry, 82, 1058–1064.
Ghosh, A., Carnahan, J., & Greenberg, M. E. (1994). Requirement for BDNF in activity- dependent survival of cortical neurons. Science, 263, 1618–1623.
Giovannini, M., Scali, C., Prosperi, C., Bellucci, A., Vannucchi, M., Rosi, S., & Casamenti, F. (2002). β-Amyloid-induced inflammation and cholinergic hypofunction in the rat brain in vivo: Involvement of the p38MAPK pathway. Neurobiology of Disease, 11, 257–274.
Glabe, C. (2001). Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. Journal of Molecular Neuroscience, 17, 137–145.
Glabe, C. (2004). Conformation-dependent antibodies target diseases of protein misfolding. Trends in biochemical sciences, 29(10), 542–547.
Gomez-Isla, T., Price, J. L., McKeel, D. W., Jr., Morris, J. C., Growdon, J. H., & Hyman, B. T. (1996). Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. The journal of neuroscience, 16, 4491–4500.
Gong, Y., Chang, L., Viola, K. L., Lacor, P. N., Lambert, M., Finch, C., Krafft, G., & Klein, W. L. (2003). Alzheimer’s disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proceedings National Academy of Sciences USA, 100, 10417–10422.
Gonzalez, G. A., & Montminy, M. R. (1989). Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell, 59, 675–680.
Gorski, J. A., Balogh, S. A., Wehner, J. M., & Jones, K. R. (2003). Learning deficits in forebrain-restricted brain-derived neurotrophic factor mutant mice. Neuroscience, 121(2), 341–354.
Gotz, J., Chen, F., van Dorpe, J., & Nitsch, R. M. (2001). Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science, 293, 1491–1495.
Green, K. N., Smith, I. F., & Laferla, F. M. (2007). Role of calcium in the pathogenesis of Alzheimer’s disease and transgenic models. Sub-cellular biochemistry, 45, 507–21.
Guillozet, A. L., Weintraub, S., Mash, D. C., & Mesulam, M. M. (2003). Neurofibrillary tangles, amyloid, and memory in aging and mild cognitive impairment. Archives of neurology, 60, 729–736.
Guzowski, J. F., Lyford, G. L., Stevenson, G. D., Houston, F. P., McGaugh, J. L., Worley, P. F., & Barnes, C. A. (2000). Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. The Journal of neuroscience, 20(11), 3993–4001.
Haass, C., Koo, E., Mellon, A., Hung, A., & Selkoe, D. (1992). Targeting of cell-surface beta-amyloid precursor protein to lysosomes: Alternative processing into amyloid-bearing fragments. Nature, 357(6378), 500–503.
Haass, C., Hung, A., Selkoe, D., & Teplow, D. (1994). Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid beta-protein precursor. The Journal of biological chemistry, 269(26), 17741–17748.
Hanna, A., Horne, P., Yager, D., Eckman, C., Eckman, E., & Janus, C. (2009). Amyloid beta and impairment in multiple memory systems in older transgenic APP TgCRND8 mice. Genes, brain, and behavior, 8(7), 676–684.
Hardy, J., & Selkoe, D. J. (2002). The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science, 297, 353–356.
Hariri, A. R., Goldberg, T. E., Mattay, V. S., Kolachana, B. S., Callicott, J. H., Egan, M. F., & Weinberger, D. R. (2003). Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. The Journal of neuroscience, 23(17), 6690–6694.
Heldt, S. A., Stanek, L., Chhatwal, J. P., & Ressler, K. J. (2007). Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Molecular psychiatry, 12(7), 656–670.
Heneka, M., & O’Banion, M. (2007). Inflammatory processes in Alzheimer’s disease. Journal of Neuroimmunology, 184, 69–91.
Hock, C., Heese, K., Hulette, C., Rosenberg, C., & Otten, U. (2000). Region-specific neurotrophin imbalances in Alzheimer disease: Decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Archives of neurology, 57, 846–851.
Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O'Campo, K., Hardy, J., Prada, C. M., Eckman, C., Younkin, S., Hsiao, K., & Duff, K. (1998). Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes. Nature medicine, 4(1), 97–100.
Holsinger, R. M. D., Schnarr, J., Henry, P., Castelo, V. T., & Fahnestock, M. (2000). Quantitation of BDNF mRNA in human parietal cortex by competitive reverse transcription-polymerase chain reaction: Decreased levels in Alzheimer’s disease. Molecular Brain Research, 76, 347–354.
Hutton, M., & Hardy, J. (1997). The presenilins and Alzheimer’s disease. Human molecular genetics, 6(10), 1639–1646.
Hyman, B. T. (1997). The neuropathological diagnosis of Alzheimer’s disease: Clinical-pathological studies. Neurobiology of Aging, 18(4 Suppl), S27–32.
Hyman, B. T., Van Horsen, G. W., Damasio, A. R., & Barnes, C. L. (1984). Alzheimer’s disease: Cell-specific pathology isolates the hippocampal formation. Science, 225, 1168–1170.
Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., Mirra, S. S., Nelson, P. T., Schneider, J. A., Thal, D. R., Thies, B., Trojanowski, J. Q., Vinters, H. V., & Montine, T. J. (2012). National Institute on Aging-Alzheimer’s Association guidelines for the neuropathological assessment of Alzheimer’s disease. Alzheimers Dement, 8(1), 1–13.
Iqbal, K., & Grundke-Iqbal, I. (2008). Alzheimer neurofibrillary degeneration: Significance, etiopathogenesis, therapeutics and prevention. Journal of Cellular and Molecular Medicine, 12(1), 38–55.
Jacobsen, J. S., Wu, C.-C., Redwine, J. M., Comery, T. A., Arias, R., Bowlby, M., Martone, R., Morrison, J. H., Pangalos, M. N., Reinhart, P. H., & Bloom, F. E. (2006). Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease. Proceedings of National Academy of Sciences USA, 103(13), 5161–6.
Jagasia, R., Steib, K., Englberger, E., Herold, S., Faus-Kessler, T., Saxe, M., Gage, F. H., Song, H., & Lie, D. C. (2009). GABA-cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. The Journal of Neuroscience, 29(25), 7966–7977.
Jang, S. W., Liu, X., Yepes, M., Shepherd, K. R., Miller, G. W., Liu, Y., Wilson, W. D., Xiao, G., Blanchi, B., Sun, Y. E., & Ye, K. (2010). A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proceedings of the National Academy of Sciences of the USA, 107(6), 2687–2692.
Jarrett, J., Berger, E., & Lansbury, P., Jr. (1993). The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer’s disease. Biochemistry, 32(18), 4693–4697.
Jin, K., Peel, A. L., Mao, X. O., Xie, L., Cottrell, B. A., Henshall, D. C., & Greenberg, D. A. (2004). Increased hippocampal neurogenesis in Alzheimer’s disease. Proceedings of the National Academy of Sciences of the USA, 101(1), 343–7.
Knusel, B., Winslow, J. W., Rosenthal, A., Burton, L. E., Seid, D. P., Nikolics, K., & Hefti, F. (1991). Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin-3. Proceedings of the National Academy of Sciences of the USA, 88, 961–965.
Korte, M., Carroll, P., Wolf, E., Brem, G., Thoenen, H., & Bonhoeffer, T. (1995). Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proceedings of the National Academy of Sciences of the USA, 92, 8856–8860.
Koshimizu, H., Kiyosue, K., Hara, T., Hazama, S., Suzuki, S., Uegaki, K., Nagappan, G., Zaitsev, E., Hirokawa, T., Tatsu, Y., Ogura, A., Lu, B., & Kojima, M. (2009). Multiple functions of precursor BDNF to CNS neurons: Negative regulation of neurite outgrowth, spine formation and cell survival. Molecular Brain, 2, 27. doi:10.1186/1756-6606-2-27.
Kumar, V., Zhang, M.-X., Swank, M. W., Kunz, J., & Gang-Yi, W. (2005). Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. Journal of Neuroscience, 25(49), 11288–11299.
Kuruvilla, R., Ye, H., & Ginty, D. D. (2000). Spatially and functionally distinct roles of the PI3-K effector pathway during NGF signaling in sympathetic neurons. Neuron, 27(3), 499–512.
Lacor, P. N., Buniel, M. C., Furlow, P. W., Clemente, A. S., Velasco, P. T., Wood, M., Viola, K. L., & Klein, W. L. (2007). Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. Journal of Neuroscience, 27(4), 796–807.
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., & Klein, W. L. (1998). Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proceedings of the National Academy of Sciences USA, 95, 6448–6453.
Lee, R., Kermani, P., Teng, K. K., & Hempstead, B. L. (2001). Regulation of cell survival by secreted proneurotrophins. Science, 294(5548), 1945–1948.
Lewis, J., Dickson, D. W., Wen-Lang, L., Chisholm, L., Corral, A., Jones, G., Shu-Hui, Y., Sahara, N., Skipper, L., Yager, D., Eckman, C., Hardy, J., Hutton, M., & McGowan, E. (2001). Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science, 293, 1487–1491.
Li, L., Orozco, I. J., Planel, E., Yi, W., Bretteville, A., Krishnamurthy, P., Wang, L., Herman, M., Figueroa, H., Haung Yu, W., Arancio, O., & Duff, K. (2008). A transgenic rat that develops Alzheimer’s disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment. Neurobiology of Disease, 31(1), 46–57.
Lindholm, D., Carroll, P., Tzimagiorgis, G., & Thoenen, H. (1996). Autocrine-paracrine regulation of hippocampal neuron survival by IGF-1 and the neurotrophins BDNF, NT-3 and NT-4. The European Journal of Neuroscience, 8(7), 1452–1460.
Linnarsson, S., Björklund, A., & Ernfors, P. (1997). Learning deficit in BDNF mutant mice. The European Journal of Neuroscience, 9(12), 2581–2587.
Lowenstein, D. H., & Arsenault, L. (1996). The effects of growth factors on the survival and differentiation of cultured dentate gyrus neurons. Journal of Neuroscience, 16(5), 1759–1769.
Lu, B. (2003). BDNF and activity-dependent synaptic modulation. Learning and memory, 10, 86–98.
Lu, B., Pang, P. T., & Woo, N. H. (2005). The yin and yang of neurotrophin action. Nature Reviews Neuroscience, 6(8), 603–614.
Lue, L. F., Kuo, Y. M., Roher, A. E., Brachova, L., Shen, Y., Sue, L., Beach, T., Kurth, J. H., Rydel, R. E., & Rogers, J. (1999). Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. The American Journal of Pathology, 155(3), 853–862.
Lukiw, W., & Bazan, N. (2000). Neuroinflammatory signaling upregulation in Alzheimer’s disease. Neurochemical Research, 25(9/10), 1173–1184.
Lynch, M. A. (2004). Long-term potentiation and memory. Physiological Reviews, 84, 87–136.
Maher, P., Akaishi, T., & Abe, K. (2006). Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proceedings of the National Academy of Sciences USA, 103, 16568–16573.
Markus, A., Zhong, J., & Snider, W. D. (2002). Raf and akt mediate distinct aspects of sensory axon growth. Neuron, 35, 65–76.
Masliah, E., Sisk, A., Mallory, M., & Games, D. (2001). Neurofibrillary pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Journal of Neuropathology and Experimental Neurology, 60, 357–368.
Massa, S. M., Yang, T., Xie, Y., Shi, J., Bilgen, M., Joyce, J. N., Nehama, D., Rajadas, J., & Longo, F. M. (2010). Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. The Journal of Clinical Investigation, 120(5), 1774–1785.
Massey, P. V., Johnson, B. E., Moult, P. R., Auberson, Y. P., Brown, M. W., Molnar, E., Collingridge, G. L., & Bashir, Z. I. (2004). Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. The Journal of Neuroscience, 24(36), 7821–7828.
Mattson, M. (2004). Pathways towards and away from Alzheimer’s disease. Nature, 430, 631–640.
Mattson, M., Barger, S., Cheng, B., Lieberburg, I., Smith-Swintosky, V., & Rydel, R. (1993). β-amyloid precursor protein metabolites and loss of neuronal Ca2+ homeostasis in Alzheimer’s disease. TINS, 16(10), 409–414.
Mattson, M. P., Duan, W., Wan, R., & Guo, Z. (2004). Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations. NeuroRx, 1(1), 111–116.
McKhann, G., Drachman, D. A., Folstein, M., Katzman, R., Price, D. L., Stadlan, E. M. (1984). Clinical diagnosis of Alzheimer’s disease – report of the NINCDS–ADRDA work group under the auspices of department of health and human services task force on Alzheimer’s disease. Neurology 34, 939–944.
Merz, K., Herold, S., & Lie, C. (2012). CREB in adult neurogenesis – master and partner in development of adult-born neurons? The European Journal of Neuroscience, 33, 1078–1086.
Michalski, B., & Fahnestock, M. (2003). Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Molecular Brain Research, 111, 148–154.
Minichiello, L., Korte, M., Wolfer, D., Kühn, R., Unsicker, K., Cestari, V., Rossi-Arnaud, C., Lipp, H. P., Bonhoeffer, T., & Klein, R. (1999). Essential role for TrkB receptors in hippocampus-mediated learning. Neuron, 24(2), 401–414.
Mitchell, A. J., & Shiri-Feshki, M. (2009). Rate of progression of mild cognitive impairment to dementia–meta-analysis of 41 robust inception cohort studies. Acta Psychiatrica Scandinavica, 119(4), 252–265.
Mowla, S., Farhadi, H., Pareek, S., Atwal, J., Morris, S., Seidah, N., & Murphy, R. (2001). Biosynthesis and post-translational processing of the precursor to brain-derived neurotrophic factor. The Journal of Biological Chemistry, 276(16), 12660–12666.
Mu, Y., & Gage, F. H. (2011). Adult hippocampal neurogenesis and its role in Alzheimer’s disease. Molecular Neurodegeneration, 6, 85.
Murray, K. D., Gall, C. M., Jones, E. G., & Isackson P. J. (1994). Differential regulation of brain-derived neurotrophic factor and type II calcium/calmodulin-dependent protein kinase messenger RNA expression in Alzheimer’s disease. Neuroscience, 60(1), 37–48.
Murray, C. A., & Lynch, M. A. (1998). Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. The Journal of Neuroscience, 18, 2974–2981.
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., & Tuszynski, M. H. (2009). Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nature Medicine, 15(3), 331–337.
Nakagawa, S., Kim, J. E., Chen, J., Fujioka, T., Malberg, J., Tsuji, S., & Duman, R. S. (2002a). Localization of phosphorylated cAMP response element-binding protein in immature neurons of adult hippocampus. Journal of the Neuroscience, 22(22), 9868–9876.
Nakagawa, S., Kim, J. E., Lee, R., Malberg, J. E., Chen, J., Steffen, C., Zhang, Y. J., Nestler, E. J., & Duman, R. S. (2002b). Regulation of neurogenesis in adult mouse hippocampus by cAMP and cAMP response element-binding protein. Journal of Neuroscience, 22(9), 3673–3682.
Narisawa-Saito, M., Wakabayashi, K., Tsuji, S., Takahashi, H., & Nawa, H. (1996). Regional specificity of alterations in NGF, BDNF and NT-3 levels in Alzheimer’s disease. Neuroreport, 7(18), 2925–2928.
Nikoletopoulou, V., Lickert, H., Frade, J. M., Rencurel, C., Giallonardo, P., Zhang, L., Bibel, M., & Barde, Y. A. (2010). Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not. Nature, 467(7311), 59–63.
Pang, P. T., Teng, H. K., Zaitsev, E., Woo, N. T., Sakata, K., Zhen, S., Teng, K. K., Yung, W. H., Hempstead, B. L., & Lu, B. (2004). Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science, 306, 487–491.
Patterson, S. L., Abel, T., Deuel, T. A., Martin, K. C., Rose, J. C., & Kandel, E. R. (1996). Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron, 16, 1137–1145.
Peng, S., Wuu, J., Mufson, E. J., & 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. Journal of Neurochemistry, 93, 1412–1421.
Peng, S., Garzon, D. J., Marchese, M., Klein, W., Ginsberg, S. D., Francis, B. M., Mount, H. T., Mufson, E. J., Salehi, A., & Fahnestock, M. (2009). Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease. The Journal of Neuroscience, 29(29), 9321–9329.
Pennanen, L., & Gotz, J. (2005). Different tau epitopes define Abeta(42)-mediated tau insolubility. Biochemical and Biophysical Research Communications, 337(4), 1097–1101.
Phillips, H. S., Hains, J. M., Armanini, M., Laramee, G. R., Johnson, S. A., & Winslow, J. W. (1991). BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron, 7, 695–702.
Pietropaolo, S., Paterna, J. C., Büeler, H., Feldon, H., & Yee, B. K. (2007). Bidirectional changes in water-maze learning following recombinant adenovirus-associated viral vector (rAAV)-mediated brain-derived neurotrophic factor expression in the rat hippocampus. Behavioural Pharmacology, 18(5–6), 533–547.
Pittenger, C., & Kandel, E. (1998). A genetic switch for long-term memory. C. R. Acad. Sci. III, 321(2–3), 91–96.
Pruunsild, P., Kazantseva, A., Aid, T., Palm, K., & Timmusk, T. (2007). Dissecting the human BDNF locus: Bidirectional transcription, complex splicing, and multiple promoters. Genomics, 90(3), 397–406.
Rauskolb, S., Zagrebelsky, M., Dreznjak, A., Deogracias, R., Matsumoto, T., Wiese, S., Erne, B., Sendtner, M., Schaeren-Wiemers, N., Korte, M., & Barde, Y. A. (2010). Global deprivation of brain-derived neurotrophic factor in CNS reveals an area-specific requirement for dendritic growth. Journal of Neuroscience, 30(5), 1739–1749.
Resende, R., Pereira, C., Agostinho, P., Vieira, A., Malva, J., & Oliveira, C. (2007). Susceptibility of hippocampal neurons to Aβ peptide toxicity is associate with perturbation of Ca2+ homeostasis. Brain Research, 1143, 11–21.
Scharfman, H. E. (1997). Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. Journal of Neurophysiology, 78, 1082–1095.
Scharfman, H., Goodman, J., Macleod, A., Phani, S., Antonelli, C., & Croll, S. (2004). Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Experimental Neurology, 192(2), 348–356.
Scheff, S. W., & Price, D. A. (2003). Synaptic pathology in Alzheimer’s disease: A review of ultrastructural studies. Neurobiology of Aging, 24, 1029–1046.
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., Larson, E., Levy-Lahad, E., Viitanen, M., Peskind, E., Poorkaj, P., Schellenberg, G., Tanzi, R., Wasco, W., Lannfelt, L., Selkoe, D., & Younkin, S. (1996). Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nature Medicine, 2(8), 864–870.
Selkoe, D. J. (1994). Amyloid beta-protein precursor: New clues to the genesis of Alzheimer’s disease. Current Opinion in Neurobiology, 4(5), 708–716.
Shieh, P. B., Hu, S. C., Bobb, K., Timmusk, T., & Ghosh, A. (1998). Identification of a signaling pathway involved in calcium regulation of BDNF expression. Neuron, 20(4), 727–740.
Shoji, M., Golde, T. E., Ghiso, J., Cheung, T. T., Estus, S., Shaffer, L. M., Cai, X. D., McKay, D. M., Tintner, R., Frangione, B., et al. (1992). Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science, 258(5079), 126–129.
Singh, K. K., Park, K. J., Hong, E. J., Kramer, B. M., Greenberg, M. E., Kaplan, D. R., & Miller, F. D. (2008). Developmental axon pruning mediated by BDNF-p75NTR-dependent axon degeneration. Nature Neuroscience, 11(6), 64–658.
Soscia, S., Kirby, J., Washicosky, K., Tucker, S., Ingelsson, M., Hyman, B., Burton, M. A., Goldstein, L. E., Duong, S., Tanzi, R. E., Moir R. D. (2010). The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS ONE, 5(3) e9505. doi: 10.1371/journal.pone.0009505.
Sponne, I., Fifre, A., Drouet, B., Klein, C., Koziel, V., Pinçon-Raymond, M., Olivier, J. L., Chambaz, J., & Pillot, T. (2003). Apoptotic neuronal cell death induced by the non-fibrillar amyloid-β peptide proceeds through an early reactive oxygen species-dependent cytoskeleton perturbation. The Journal of Biological Chemistry, 278(5), 3437–3445.
Sun, Y., Lim, Y., Li, F., Liu, S., Lu, J.-J., Haberberger, R., Zhong, J.-H., & Zhou, X. F. (2012). ProBDNF collapses neurite outgrowth of primary neurons by activating RhoA. PLOS ONE, 7(4), e35883. doi:10.1371/journal.pone.0035883.
Tabaton, M., Zhu, X., Perry, G., Smith, M., & Giliberto, L. (2010). Signaling effect of amyloid-β42 on the processing of AβPP. Experimental Neurology, 221(1), 18–25.
Tancredi, V., D’Arcangelo, G., Grassi, F., Tarroni, P., Palmieri, G., Santoni, A., & Eusebi, F. (1992). Tumor necrosis factor alters synaptic transmission in rat hippocampal slices. Neuroscience Letters, 146(2), 176–178.
Tancredi, V., D’Antuono, M., Cafè, C., Giovedì, S., Buè, M. C., D’Arcangelo, G., Onofri, F., & Benfenati, F. (2000). The inhibitory effects of interleukin-6 on synaptic plasticity in the rat hippocampus are associated with an inhibition of mitogen-activated protein kinase ERK. Journal of Neurochemistry, 75(2), 634–643.
Teng, H. K., Teng, K. K., Lee, R., Wright, S., Tevar, S., Almeida, R. D., Kermani, P., Torkin, R., Chen, Z. Y., Lee, F. S., Kraemer, R. T., Nykjaer, A., & Hempstead, B. L. (2005). ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. The Journal of Neuroscience, 25(22), 5455–5463.
Terry, R. D., & Katzman, R. (2001). Life span and synapses: Will there be a primary senile dementia? Neurobiology of Aging, 22, 347–348.
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., Hansen, L. A., & Katzman, R. (1991). Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Annals of Neurology, 30(4), 572–580.
Timmusk, T., Palm, K., Metsis, M., Reintam, T., Paalme, V., Saarma, M., & Persson, H. (1993). Multiple promoters direct tissue-specific expression of the rate BDNF gene. Neuron, 10, 475–489.
Timmusk, T., Lendahl, U., Funakoshi, H., Arenas, E., Persson, H., & Metsis, M. (1995). Identification of brain-derived neurotrophic factor promoter regions mediating tissue-specific, axotomy-, and neuronal activity-induced expression in transgenic mice. The Journal of Cell Biology, 128, 185–199.
Tong, L., Thornton, P. L., Balazs, R., & Cotman, C. W. (2001). Beta-amyloid-(1–42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival is not compromised. Journal of Biological Chemistry, 276, 17301–17306.
Tong, L., Balazs, R., Thornton, P. L., & Cotman, C. W. (2004). Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. The Journal of Neuroscience, 24, 6799–6809.
Van Dam, D., D’Hooge, R., Staufenbiel, M., Van Ginneken, C., Van Meir, F., & De Deyn, P. P. (2003). Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. European Journal of Neuroscience, 17(2), 388–396.
Van Hoesen, G. W., Hyman, B. T., & Damasio, A. R. (1991). Entorhinal cortex pathology in Alzheimer’s disease. Hippocampus, 1(1), 1–8.
Vitolo, O. V., Sant’Angelo, A., Costanzo, V., Battaglia, F., Arancio, O., & Shelanski, M. (2002). Amyloid beta 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 of the USA, 99(20), 13217–13221.
Walsh, D. M., & Selkoe, D. J. (2007). A beta oligomers – a decade of discovery. Journal of Neurochemistry, 101, 1172–1184.
Walsh, D. M., Klyubin, I., Fadeeva, J. V., Cullen, W. K., Anwyl, R., Wolfe, M. S., Rowan, M. J., & Selkoe, D. J. (2002). Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature, 416, 535–539.
Westerman, M. A., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L. H., Carlson, G. A., Younkin, S. G., & Ashe, K. H. (2002). The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J. Neurosci, 22(5), 1858–1867.
Woo, N. H., Teng, H. K., Siao, C. J., Chiaruttini, C., Pang, P. T., Milner, T. A., Hempstead, B. L., & Lu, B. (2005). Activation of p75 NTR by proBDNF facilitates hippocampal long-term depression. Nature Neuroscience, 8(8), 1069–1077.
Xu, B., Michalski, B., Racine, R. J., & Fahnestock, M. (2004). The effects of brain-derived neurotrophic factor (BDNF) administration on kindling induction, Trk expression and seizure-related morphological changes. Neuroscience, 126(3), 521–531.
Xu, Y., Shen, J., Lou, X., Zhu, W., Chen, K., Ma, J., & Jiang, H. (2005). Conformational transition of amyloid beta-peptide. Proceedings of the National Academy of Sciences of the USA, 102(15), 5403–5407.
Yamamoto-Sasaki, M., Ozawa, H., Saito, T., Rosler, M., & Riederer, P. (1999). Impaired phosphorylation of cyclic AMP response element binding protein in the hippocampus of dementia of the Alzheimer’s type. Brain Research, 842(2), 300–303.
Yamashita, T., & Tohyama, M. (2003). The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI. Nature Neuroscience, 6(5), 461–467.
Yamashita, T., Tucker, K. L., & Barde, Y.-A. (1999). Neurotrophin binding to the p75 receptor modulates Rho activity and axonal outgrowth. Neuron, 24, 585–593.
Yamin, G. (2009). NMDA receptor-dependent signaling pathways that underlie amyloid beta-protein disruption of LTP in the hippocampus. Journal of Neuroscience Research, 87(8), 1729–36.
Ying, S. W., Futter, M., Rosenblum, K., Webber, M. J., Hunt, S. P., Bliss, T. V., & Bramham, C. R. (2002). Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: Requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. Journal of Neuroscience, 22(5), 1532–1540.
Ypsilanti, A. R., Girão da Cruz, M. T., Burgess, A., & Aubert, I. (2008). The length of hippocampal cholinergic fibers is reduced in the aging brain. Neurobiology Aging, 29(11), 1666–1679.
Zagrebelsky, M., Holz, A., Dechant, G., Barde, Y.-A., Bonhoeffer, T., & Korte, M. (2005). The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. Journal of Neuroscience, 25(43), 9989–9999.
Zajac, M. S., Pang, T. Y., Wong, N., Weinrich, B., Leang, L. S., Craig, J. M., Saffery, R., & Hannan, A. J. (2010). Wheel running and environmental enrichment differentially modify exon-specific BDNF expression in the hippocampus of wild-type and pre-motor symptomatic male and female Huntington’s disease mice. Hippocampus, 20(5), 621–636.
Ze-F, W., Li, H.-L., Li, X.-C., Zhang, Q., Tian, Q., Wang, Q., Xu, H., & Wang, J.-Z. (2006). Effects of endogenous beta-amyloid overproduction on tau phosphorylation in cell culture. Journal of Neurochemistry, 98, 1167–1175.
Zeng, Y., Zhao, D., & Xie, C. W. (2010). Neurotrophins enhance CaMKII activity and rescue amyloid-β-induced deficits in hippocampal synaptic plasticity. Journal of Alzheimer’s Disease, 21, 823–831.
Zhang, Y., & Pardridge, W. M. (2001a). Conjugation of brain-derived neurotrophic factor to a blood–brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin. Brain Research, 889(1–2), 49–56.
Zhang, Y., & Pardridge, W. M. (2001b). Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood–brain barrier drug targeting system. Stroke, 32(6), 1378–1384.
Zhang, Y., & Pardridge, W. M. (2006). Blood–brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion. Brain Research, 1111(1), 227–229.
Zhao, C., Deng, W., & Gage, F. H. (2008). Mechanisms and functional implications of adult neurogenesis. Cell, 132, 645–660.
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Rosa, E., Fahnestock, M. (2014). Amyloid-Beta, BDNF, and the Mechanism of Neurodegeneration in Alzheimer’s Disease. In: Kostrzewa, R. (eds) Handbook of Neurotoxicity. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5836-4_43
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