幹細胞療法對神經退化性疾病的治療具有高度的潛力，然而此方法應用於治療阿茲海默氏症的發展仍然有限。腦衍生神經滋養因子(BDNF)對於阿茲海默氏症的病理進程與治療相當重要。本研究利用BDNF大量表現的神經幹細胞(BDNF-NSC)來探討一新穎的阿茲海默氏症治療策略。在體外實驗中，BDNF大量表現具有神經保護作用，可減緩類澱粉蛋白對神經幹細胞的毒性作用。將神經幹細胞移植到阿茲海默氏症的基因轉殖小鼠腦部海馬回後，BDNF-NSC所分化的神經細胞不但表現了細胞內鈣離子波動、成熟神經元的電生理特性、嵌入宿主的腦神經迴路，並且改善了阿茲海默氏症基因轉殖小鼠的認知功能。此外，BDNF大量表現可幫助移植後的神經幹細胞的存活、神經元分化、神經軸突外展、電生理特性的成熟、以及突觸的密度。相反地，將BDNF大量表現的神經幹細胞減弱BDNF的表現，其幹細胞移植對阿茲海默氏症的治療效果立即下降。總結，BDNF大量表現可經由神經元方面的影響並取代的受損的神經功能以改善神經幹細胞對阿茲海默氏症的治療潛力，而此研究結果也支持了利用神經幹細胞進行阿茲海默症的體外基因治療。

Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer’s disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. In present study, a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs) was investigated. In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca2+-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells’ viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via more neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD.

Aimone, J.B., J. Wiles, and F.H. Gage. 2009. Computational influence of adult neurogenesis on memory encoding. Neuron. 61:187-202.
Alzheimer's, A. 2016. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 12:459-509.
Arber, C., S.V. Precious, S. Cambray, J.R. Risner-Janiczek, C. Kelly, Z. Noakes, M. Fjodorova, A. Heuer, M.A. Ungless, T.A. Rodriguez, A.E. Rosser, S.B. Dunnett, and M. Li. 2015. Activin A directs striatal projection neuron differentiation of human pluripotent stem cells. Development. 142:1375-1386.
Azzouz, M., G.S. Ralph, E. Storkebaum, L.E. Walmsley, K.A. Mitrophanous, S.M. Kingsman, P. Carmeliet, and N.D. Mazarakis. 2004. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature. 429:413-417.
Barreto-Chang, O.L., and R.E. Dolmetsch. 2009. Calcium imaging of cortical neurons using Fura-2 AM. J Vis Exp.
Benraiss, A., and S.A. Goldman. 2011. Cellular therapy and induced neuronal replacement for Huntington's disease. Neurotherapeutics. 8:577-590.
Benraiss, A., M.J. Toner, Q. Xu, E. Bruel-Jungerman, E.H. Rogers, F. Wang, A.N. Economides, B.L. Davidson, R. Kageyama, M. Nedergaard, and S.A. Goldman. 2013. Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington's disease. Cell Stem Cell. 12:787-799.
Blackburn, D., S. Sargsyan, P.N. Monk, and P.J. Shaw. 2009. Astrocyte function and role in motor neuron disease: a future therapeutic target? Glia. 57:1251-1264.
Blurton-Jones, M., M. Kitazawa, H. Martinez-Coria, N.A. Castello, F.J. Muller, J.F. Loring, T.R. Yamasaki, W.W. Poon, K.N. Green, and F.M. LaFerla. 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.
Blurton-Jones, M., B. Spencer, S. Michael, N.A. Castello, A.A. Agazaryan, J.L. Davis, F.J. Muller, J.F. Loring, E. Masliah, and F.M. LaFerla. 2014. Neural stem cells genetically-modified to express neprilysin reduce pathology in Alzheimer transgenic models. Stem Cell Res Ther. 5:46.
Brannvall, K., K. Bergman, U. Wallenquist, S. Svahn, T. Bowden, J. Hilborn, and K. Forsberg-Nilsson. 2007. Enhanced neuronal differentiation in a three-dimensional collagen-hyaluronan matrix. J Neurosci Res. 85:2138-2146.
Cai, Z., and M. Xiao. 2016. Oligodendrocytes and Alzheimer's disease. Int J Neurosci. 126:97-104.
Campanac, E., C. Gasselin, A. Baude, S. Rama, N. Ankri, and D. Debanne. 2013. Enhanced intrinsic excitability in basket cells maintains excitatory-inhibitory balance in hippocampal circuits. Neuron. 77:712-722.
Chen, W.W., and M. Blurton-Jones. 2012. Concise review: Can stem cells be used to treat or model Alzheimer's disease? Stem Cells. 30:2612-2618.
Coras, R., F.A. Siebzehnrubl, E. Pauli, H.B. Huttner, M. Njunting, K. Kobow, C. Villmann, E. Hahnen, W. Neuhuber, D. Weigel, M. Buchfelder, H. Stefan, H. Beck, D.A. Steindler, and I. Blumcke. 2010. Low proliferation and differentiation capacities of adult hippocampal stem cells correlate with memory dysfunction in humans. Brain. 133:3359-3372.
Dey, N.D., M.C. Bombard, B.P. Roland, S. Davidson, M. Lu, J. Rossignol, M.I. Sandstrom, R.L. Skeel, L. Lescaudron, and G.L. Dunbar. 2010. Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington's disease. Behav Brain Res. 214:193-200.
Dezawa, M., H. Kanno, M. Hoshino, H. Cho, N. Matsumoto, Y. Itokazu, N. Tajima, H. Yamada, H. Sawada, H. Ishikawa, T. Mimura, M. Kitada, Y. Suzuki, and C. Ide. 2004. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest. 113:1701-1710.
Ding, D.C., Y.H. Chang, W.C. Shyu, and S.Z. Lin. 2015. Human umbilical cord mesenchymal stem cells: a new era for stem cell therapy. Cell Transplant. 24:339-347.
Dunnett, S.B., and A. Bjorklund. 1999. Prospects for new restorative and neuroprotective treatments in Parkinson's disease. Nature. 399:A32-39.
Ebert, A.D., A.E. Barber, B.M. Heins, and C.N. Svendsen. 2010. Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington's disease. Exp Neurol. 224:155-162.
Emborg, M.E., A.D. Ebert, J. Moirano, S. Peng, M. Suzuki, E. Capowski, V. Joers, B.Z. Roitberg, P. Aebischer, and C.N. Svendsen. 2008. GDNF-secreting human neural progenitor cells increase tyrosine hydroxylase and VMAT2 expression in MPTP-treated cynomolgus monkeys. Cell Transplant. 17:383-395.
Eucher, J.N., E. Uemura, D.S. Sakaguchi, and M.H. Greenlee. 2007. Amyloid-beta peptide affects viability but not differentiation of embryonic and adult rat hippocampal progenitor cells. Exp Neurol. 203:486-492.
Fargo, K., and L. Bleiler. 2014. 2014 Alzheimer's disease facts and figures. Alzheimer's & Dementia. 10:e47-e92.
Ferraiuolo, L., A. Frakes, and B.K. Kaspar. 2013. Neural stem cells as a therapeutic approach for amyotrophic lateral sclerosis. Mol Ther. 21:503-505.
Figurov, A., L.D. Pozzo-Miller, P. Olafsson, T. Wang, and B. Lu. 1996. Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature. 381:706-709.
Gage, F.H., G. Kempermann, T.D. Palmer, D.A. Peterson, and J. Ray. 1998. Multipotent progenitor cells in the adult dentate gyrus. J Neurobiol. 36:249-266.
Glass, J.D., N.M. Boulis, K. Johe, S.B. Rutkove, T. Federici, M. Polak, C. Kelly, and E.L. Feldman. 2012. Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients. Stem Cells. 30:1144-1151.
Graff, J., D. Rei, J.S. Guan, W.Y. Wang, J. Seo, K.M. Hennig, T.J. Nieland, D.M. Fass, P.F. Kao, M. Kahn, S.C. Su, A. Samiei, N. Joseph, S.J. Haggarty, I. Delalle, and L.H. Tsai. 2012. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature. 483:222-226.
Grillo, F.W., S. Song, L.M. Teles-Grilo Ruivo, L. Huang, G. Gao, G.W. Knott, B. Maco, V. Ferretti, D. Thompson, G.E. Little, and V. De Paola. 2013. Increased axonal bouton dynamics in the aging mouse cortex. Proc Natl Acad Sci U S A. 110:E1514-1523.
Gylys, K.H., J.A. Fein, F. Yang, D.J. Wiley, C.A. Miller, and G.M. Cole. 2004. Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Am J Pathol. 165:1809-1817.
Hardy, J., and D.J. Selkoe. 2002. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297:353-356.
Harper, J.M., C. Krishnan, J.S. Darman, D.M. Deshpande, S. Peck, I. Shats, S. Backovic, J.D. Rothstein, and D.A. Kerr. 2004. Axonal growth of embryonic stem cell-derived motoneurons in vitro and in motoneuron-injured adult rats. Proc Natl Acad Sci U S A. 101:7123-7128.
Haughey, N.J., A. Nath, S.L. Chan, A.C. Borchard, M.S. Rao, and M.P. Mattson. 2002. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 83:1509-1524.
Hester, M.E., M.J. Murtha, S. Song, M. Rao, C.J. Miranda, K. Meyer, J. Tian, G. Boulting, D.V. Schaffer, M.X. Zhu, S.L. Pfaff, F.H. Gage, and B.K. Kaspar. 2011. Rapid and efficient generation of functional motor neurons from human pluripotent stem cells using gene delivered transcription factor codes. Mol Ther. 19:1905-1912.
Hock, C., K. Heese, C. Hulette, C. Rosenberg, and U. Otten. 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. Arch Neurol. 57:846-851.
Hongpaisan, J., M.K. Sun, and D.L. Alkon. 2011. PKC epsilon activation prevents synaptic loss, Abeta elevation, and cognitive deficits in Alzheimer's disease transgenic mice. J Neurosci. 31:630-643.
Hsiao, K., P. Chapman, S. Nilsen, C. Eckman, Y. Harigaya, S. Younkin, F. Yang, and G. Cole. 1996. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 274:99-102.
Hunsberger, J.G., M. Rao, J. Kurtzberg, J.W.M. Bulte, A. Atala, F.M. LaFerla, H.T. Greely, A. Sawa, S. Gandy, L.S. Schneider, and P.M. Doraiswamy. 2016. Accelerating stem cell trials for Alzheimer's disease. The Lancet Neurology. 15:219-230.
Hwang, D.H., H.J. Lee, I.H. Park, J.I. Seok, B.G. Kim, I.S. Joo, and S.U. Kim. 2009. Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice. Gene Ther. 16:1234-1244.
Israel, M.A., S.H. Yuan, C. Bardy, S.M. Reyna, Y. Mu, C. Herrera, M.P. Hefferan, S. Van Gorp, K.L. Nazor, F.S. Boscolo, C.T. Carson, L.C. Laurent, M. Marsala, F.H. Gage, A.M. Remes, E.H. Koo, and L.S. Goldstein. 2012. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 482:216-220.
Jaderstad, J., L.M. Jaderstad, J. Li, S. Chintawar, C. Salto, M. Pandolfo, V. Ourednik, Y.D. Teng, R.L. Sidman, E. Arenas, E.Y. Snyder, and E. Herlenius. 2010. Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host. Proc Natl Acad Sci U S A. 107:5184-5189.
Jandial, R., I. Singec, C.P. Ames, and E.Y. Snyder. 2008. Genetic modification of neural stem cells. Mol Ther. 16:450-457.
Jeronimo-Santos, A., J. Fonseca-Gomes, D.A. Guimaraes, S.R. Tanqueiro, R.M. Ramalho, J.A. Ribeiro, A.M. Sebastiao, and M.J. Diogenes. 2015. Brain-derived neurotrophic factor mediates neuroprotection against Abeta-induced toxicity through a mechanism independent on adenosine 2A receptor activation. Growth Factors. 33:298-308.
Kim, S.U., H.J. Lee, and Y.B. Kim. 2013. Neural stem cell-based treatment for neurodegenerative diseases. Neuropathology. 33:491-504.
Kordower, J.H., C.G. Goetz, T.B. Freeman, and C.W. Olanow. 1997. Dopaminergic transplants in patients with Parkinson's disease: neuroanatomical correlates of clinical recovery. Exp Neurol. 144:41-46.
Kriks, S., J.W. Shim, J. Piao, Y.M. Ganat, D.R. Wakeman, Z. Xie, L. Carrillo-Reid, G. Auyeung, C. Antonacci, A. Buch, L. Yang, M.F. Beal, D.J. Surmeier, J.H. Kordower, V. Tabar, and L. Studer. 2011. Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease. Nature. 480:547-551.
Kumar, A., A. Singh, and Ekavali. 2015. A review on Alzheimer's disease pathophysiology and its management: an update. Pharmacol Rep. 67:195-203.
Laske, C., E. Stransky, T. Leyhe, G.W. Eschweiler, A. Wittorf, E. Richartz, M. Bartels, G. Buchkremer, and K. Schott. 2006. Stage-dependent BDNF serum concentrations in Alzheimer's disease. J Neural Transm. 113:1217-1224.
Lee, J.K., H.K. Jin, S. Endo, E.H. Schuchman, J.E. Carter, and J.S. Bae. 2010. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells. 28:329-343.
Lee, L., E. Dale, A. Staniszewski, H. Zhang, F. Saeed, M. Sakurai, M. Fa, I. Orozco, F. Michelassi, N. Akpan, H. Lehrer, and O. Arancio. 2014. Regulation of synaptic plasticity and cognition by SUMO in normal physiology and Alzheimer's disease. Sci Rep. 4:7190.
Lee, S.T., K. Chu, K.H. Jung, W.S. Im, J.E. Park, H.C. Lim, C.H. Won, S.H. Shin, S.K. Lee, M. Kim, and J.K. Roh. 2009. Slowed progression in models of Huntington disease by adipose stem cell transplantation. Ann Neurol. 66:671-681.
Lewandowski, D., V. Barroca, F. Duconge, J. Bayer, J.T. Van Nhieu, C. Pestourie, P. Fouchet, B. Tavitian, and P.H. Romeo. 2010. In vivo cellular imaging pinpoints the role of reactive oxygen species in the early steps of adult hematopoietic reconstitution. Blood. 115:443-452.
Li, P., A. Tessler, S.S. Han, I. Fischer, M.S. Rao, and M.E. Selzer. 2005. Fate of immortalized human neuronal progenitor cells transplanted in rat spinal cord. Arch Neurol. 62:223-229.
Lindvall, O., P. Brundin, H. Widner, S. Rehncrona, B. Gustavii, R. Frackowiak, K.L. Leenders, G. Sawle, J.C. Rothwell, C.D. Marsden, and et al. 1990. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science. 247:574-577.
Liu, H., and K.M. Guthrie. 2011. Neuronal replacement in the injured olfactory bulb. Exp Neurol. 228:270-282.
Liu, Y., J.P. Weick, H. Liu, R. Krencik, X. Zhang, L. Ma, G.M. Zhou, M. Ayala, and S.C. Zhang. 2013. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol. 31:440-447.
Livesey, M.R., B. Bilican, J. Qiu, N.M. Rzechorzek, G. Haghi, K. Burr, G.E. Hardingham, S. Chandran, and D.J. Wyllie. 2014. Maturation of AMPAR composition and the GABAAR reversal potential in hPSC-derived cortical neurons. J Neurosci. 34:4070-4075.
Lu, B., G. Nagappan, X. Guan, P.J. Nathan, and P. Wren. 2013. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci. 14:401-416.
Lunn, J.S., S.A. Sakowski, and E.L. Feldman. 2014. Concise review: Stem cell therapies for amyotrophic lateral sclerosis: recent advances and prospects for the future. Stem Cells. 32:1099-1109.
Mansuy, I.M., M. Mayford, B. Jacob, E.R. Kandel, and M.E. Bach. 1998. Restricted and regulated overexpression reveals calcineurin as a key component in the transition from short-term to long-term memory. Cell. 92:39-49.
Marutle, A., M. Ohmitsu, M. Nilbratt, N.H. Greig, A. Nordberg, and K. Sugaya. 2007. Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine. Proceedings of the National Academy of Sciences. 104:12506-12511.
Massa, S.M., T. Yang, Y. Xie, J. Shi, M. Bilgen, J.N. Joyce, D. Nehama, J. Rajadas, and F.M. Longo. 2010. Small molecule BDNF mimetics activate TrkB signaling and prevent neuronal degeneration in rodents. J Clin Invest. 120:1774-1785.
Matsuzaki, M., N. Honkura, G.C. Ellis-Davies, and H. Kasai. 2004. Structural basis of long-term potentiation in single dendritic spines. Nature. 429:761-766.
McDole, B., C. Isgor, C. Pare, and K. Guthrie. 2015. BDNF over-expression increases olfactory bulb granule cell dendritic spine density in vivo. Neuroscience. 304:146-160.
Miles, G.B., D.C. Yohn, H. Wichterle, T.M. Jessell, V.F. Rafuse, and R.M. Brownstone. 2004. Functional properties of motoneurons derived from mouse embryonic stem cells. J Neurosci. 24:7848-7858.
Moe, M.C., M. Varghese, A.I. Danilov, U. Westerlund, J. Ramm-Pettersen, L. Brundin, M. Svensson, J. Berg-Johnsen, and I.A. Langmoen. 2005. Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons. Brain. 128:2189-2199.
Mu, Y., and F.H. Gage. 2011. Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol Neurodegener. 6:85.
Mucke, L. 2009. Neuroscience: Alzheimer's disease. Nature. 461:895-897.
Nagahara, A.H., D.A. Merrill, G. Coppola, S. Tsukada, B.E. Schroeder, G.M. Shaked, L. Wang, A. Blesch, A. Kim, J.M. Conner, E. Rockenstein, M.V. Chao, E.H. Koo, D. Geschwind, E. Masliah, A.A. Chiba, and M.H. Tuszynski. 2009. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 15:331-337.
Nagahara, A.H., and M.H. Tuszynski. 2011. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov. 10:209-219.
Nivet, E., M. Vignes, S.D. Girard, C. Pierrisnard, N. Baril, A. Deveze, J. Magnan, F. Lante, M. Khrestchatisky, F. Feron, and F.S. Roman. 2011. Engraftment of human nasal olfactory stem cells restores neuroplasticity in mice with hippocampal lesions. J Clin Invest. 121:2808-2820.
Pagano, S.F., F. Impagnatiello, M. Girelli, L. Cova, E. Grioni, M. Onofri, M. Cavallaro, S. Etteri, F. Vitello, S. Giombini, C.L. Solero, and E.A. Parati. 2000. Isolation and characterization of neural stem cells from the adult human olfactory bulb. Stem Cells. 18:295-300.
Panatier, A., D.T. Theodosis, J.P. Mothet, B. Touquet, L. Pollegioni, D.A. Poulain, and S.H. Oliet. 2006. Glia-derived D-serine controls NMDA receptor activity and synaptic memory. Cell. 125:775-784.
Pascual, O., K.B. Casper, C. Kubera, J. Zhang, R. Revilla-Sanchez, J.Y. Sul, H. Takano, S.J. Moss, K. McCarthy, and P.G. Haydon. 2005. Astrocytic purinergic signaling coordinates synaptic networks. Science. 310:113-116.
Phillips, H.S., J.M. Hains, M. Armanini, G.R. Laramee, S.A. Johnson, and J.W. Winslow. 1991. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron. 7:695-702.
Pickard, L., J. Noel, J.M. Henley, G.L. Collingridge, and E. Molnar. 2000. Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J Neurosci. 20:7922-7931.
Poon, W.W., A.J. Carlos, B.L. Aguilar, N.C. Berchtold, C.K. Kawano, V. Zograbyan, T. Yaopruke, M. Shelanski, and C.W. Cotman. 2013. beta-Amyloid (Abeta) oligomers impair brain-derived neurotrophic factor retrograde trafficking by down-regulating ubiquitin C-terminal hydrolase, UCH-L1. J Biol Chem. 288:16937-16948.
Pre, D., M.W. Nestor, A.A. Sproul, S. Jacob, P. Koppensteiner, V. Chinchalongporn, M. Zimmer, A. Yamamoto, S.A. Noggle, and O. Arancio. 2014. A time course analysis of the electrophysiological properties of neurons differentiated from human induced pluripotent stem cells (iPSCs). PLoS One. 9:e103418.
Ramser, E.M., K.J. Gan, H. Decker, E.Y. Fan, M.M. Suzuki, S.T. Ferreira, and M.A. Silverman. 2013. Amyloid-beta oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons. Mol Biol Cell. 24:2494-2505.
Rantamaki, T., S. Kemppainen, H. Autio, S. Staven, H. Koivisto, M. Kojima, H. Antila, P.O. Miettinen, E. Karkkainen, N. Karpova, L. Vesa, L. Lindemann, M.C. Hoener, H. Tanila, and E. Castren. 2013. The impact of Bdnf gene deficiency to the memory impairment and brain pathology of APPswe/PS1dE9 mouse model of Alzheimer's disease. PLoS One. 8:e68722.
Redmond, D.E., Jr., K.B. Bjugstad, Y.D. Teng, V. Ourednik, J. Ourednik, D.R. Wakeman, X.H. Parsons, R. Gonzalez, B.C. Blanchard, S.U. Kim, Z. Gu, S.A. Lipton, E.A. Markakis, R.H. Roth, J.D. Elsworth, J.R. Sladek, Jr., R.L. Sidman, and E.Y. Snyder. 2007. Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells. Proc Natl Acad Sci U S A. 104:12175-12180.
Reh, T.A. 2002. Neural stem cells: form and function. Nat Neurosci. 5:392-394.
Richetin, K., C. Leclerc, N. Toni, T. Gallopin, S. Pech, L. Roybon, and C. Rampon. 2015. Genetic manipulation of adult-born hippocampal neurons rescues memory in a mouse model of Alzheimer's disease. Brain. 138:440-455.
Shin, J.W., J.K. Lee, J.E. Lee, W.K. Min, E.H. Schuchman, H.K. Jin, and J.S. Bae. 2011. Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1alpha in an Alzheimer's disease mouse model. Stem Cells. 29:1075-1089.
Sholl, D.A. 1953. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat. 87:387-406.
Shors, T.J., G. Miesegaes, A. Beylin, M. Zhao, T. Rydel, and E. Gould. 2001. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 410:372-376.
Song, J., S.T. Lee, W. Kang, J.E. Park, K. Chu, S.E. Lee, T. Hwang, H. Chung, and M. Kim. 2007. Human embryonic stem cell-derived neural precursor transplants attenuate apomorphine-induced rotational behavior in rats with unilateral quinolinic acid lesions. Neurosci Lett. 423:58-61.
Spitzer, N.C., P.A. Kingston, T.J. Manning, and M.W. Conklin. 2002. Outside and in: development of neuronal excitability. Curr Opin Neurobiol. 12:315-323.
Storkebaum, E., D. Lambrechts, M. Dewerchin, M.P. Moreno-Murciano, S. Appelmans, H. Oh, P. Van Damme, B. Rutten, W.Y. Man, M. De Mol, S. Wyns, D. Manka, K. Vermeulen, L. Van Den Bosch, N. Mertens, C. Schmitz, W. Robberecht, E.M. Conway, D. Collen, L. Moons, and P. Carmeliet. 2005. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci. 8:85-92.
Takagane, K., J. Nojima, H. Mitsuhashi, S. Suo, D. Yanagihara, F. Takaiwa, Y. Urano, N. Noguchi, and S. Ishiura. 2015. Abeta induces oxidative stress in senescence-accelerated (SAMP8) mice. Biosci Biotechnol Biochem. 79:912-918.
Terry, R.D., E. Masliah, D.P. Salmon, N. Butters, R. DeTeresa, R. Hill, L.A. Hansen, and R. Katzman. 1991. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 30:572-580.
Tong, L., R. Balazs, P.L. Thornton, and C.W. Cotman. 2004. Beta-amyloid peptide at sublethal concentrations downregulates brain-derived neurotrophic factor functions in cultured cortical neurons. J Neurosci. 24:6799-6809.
Trachtenberg, J.T., B.E. Chen, G.W. Knott, G. Feng, J.R. Sanes, E. Welker, and K. Svoboda. 2002. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature. 420:788-794.
Tsai, K.J., Y.C. Tsai, and C.K. Shen. 2007. G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med. 204:1273-1280.
Tsai, K.J., C.H. Yang, Y.H. Fang, K.H. Cho, W.L. Chien, W.T. Wang, T.W. Wu, C.P. Lin, W.M. Fu, and C.K. Shen. 2010. Elevated expression of TDP-43 in the forebrain of mice is sufficient to cause neurological and pathological phenotypes mimicking FTLD-U. J Exp Med. 207:1661-1673.
Tuszynski, M.H., L. Thal, M. Pay, D.P. Salmon, H.S. U, R. Bakay, P. Patel, A. Blesch, H.L. Vahlsing, G. Ho, G. Tong, S.G. Potkin, J. Fallon, L. Hansen, E.J. Mufson, J.H. Kordower, C. Gall, and J. Conner. 2005. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 11:551-555.
van Velthoven, C.T., L. Braccioli, H.L. Willemen, A. Kavelaars, and C.J. Heijnen. 2014. Therapeutic potential of genetically modified mesenchymal stem cells after neonatal hypoxic-ischemic brain damage. Mol Ther. 22:645-654.
Velasco, I., P. Salazar, A. Giorgetti, V. Ramos-Mejia, J. Castano, D. Romero-Moya, and P. Menendez. 2014. Concise review: Generation of neurons from somatic cells of healthy individuals and neurological patients through induced pluripotency or direct conversion. Stem Cells. 32:2811-2817.
Vivar, C., M.C. Potter, J. Choi, J.Y. Lee, T.P. Stringer, E.M. Callaway, F.H. Gage, H. Suh, and H. van Praag. 2012. Monosynaptic inputs to new neurons in the dentate gyrus. Nat Commun. 3:1107.
Wang, I.F., B.S. Guo, Y.C. Liu, C.C. Wu, C.H. Yang, K.J. Tsai, and C.K. Shen. 2012. Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc Natl Acad Sci U S A. 109:15024-15029.
Watabe, K., T. Ohashi, T. Sakamoto, Y. Kawazoe, T. Takeshima, K. Oyanagi, K. Inoue, Y. Eto, and S.U. Kim. 2000. Rescue of lesioned adult rat spinal motoneurons by adenoviral gene transfer of glial cell line-derived neurotrophic factor. J Neurosci Res. 60:511-519.
Wernig, M., J.P. Zhao, J. Pruszak, E. Hedlund, D. Fu, F. Soldner, V. Broccoli, M. Constantine-Paton, O. Isacson, and R. Jaenisch. 2008. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A. 105:5856-5861.
Wesson, D.W., and D.A. Wilson. 2011. Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein (APP) mice. Behav Brain Res. 216:408-413.
Wichterle, H., I. Lieberam, J.A. Porter, and T.M. Jessell. 2002. Directed differentiation of embryonic stem cells into motor neurons. Cell. 110:385-397.
Yang, H., Z. Xie, L. Wei, H. Yang, S. Yang, Z. Zhu, P. Wang, C. Zhao, and J. Bi. 2013. Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AbetaPP/PS1 transgenic mouse model. Stem Cell Res Ther. 4:76.
Zheng, Z., B. Sabirzhanov, and J. Keifer. 2010. Oligomeric amyloid-{beta} inhibits the proteolytic conversion of brain-derived neurotrophic factor (BDNF), AMPA receptor trafficking, and classical conditioning. J Biol Chem. 285:34708-34717.