Alzheimer's disease, dementia, and stem cell therapy

Thomas Duncan, Michael Valenzuela, Thomas Duncan, Michael Valenzuela

Abstract

Alzheimer's disease (AD) represents arguably the most significant social, economic, and medical crisis of our time. Characterized by progressive neurodegenerative pathology, AD is first and foremost a condition of neuronal and synaptic loss. Repopulation and regeneration of depleted neuronal circuitry by exogenous stem cells is therefore a rational therapeutic strategy. This review will focus on recent advances in stem cell therapies utilizing animal models of AD, as well as detailing the human clinical trials of stem cell therapies for AD that are currently undergoing development.

Keywords: Alzheimer’s disease; Embryonic stem cells; Induced pluripotent stem cells; Mesenchymal stem cells; Neural stem cells.

References

    1. Alzheimers Association 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015;11:332. doi: 10.1016/j.jalz.2015.02.003.
    1. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014;370:322–33. doi: 10.1056/NEJMoa1304839.
    1. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG. A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369:341–50. doi: 10.1056/NEJMoa1210951.
    1. Walker D, Lue LF. Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer’s disease and other neurodegenerative diseases. J Neurosci Res. 2005;81:412–25. doi: 10.1002/jnr.20484.
    1. Delbeuck X, Van der Linden M, Collette F. Alzheimer’s disease as a disconnection syndrome? Neuropsychol Rev. 2003;13:79–92. doi: 10.1023/A:1023832305702.
    1. Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9:1. doi: 10.1186/1478-811X-9-12.
    1. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76. doi: 10.1016/j.cell.2006.07.024.
    1. Jin K, Zhu Y, Sun Y, Mao XO, Xie L, Greenberg DA. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci. 2002;99:11946–50. doi: 10.1073/pnas.182296499.
    1. Lopez-Toledano MA, Shelanski ML. Increased neurogenesis in young transgenic mice overexpressing human APP. J Alzheimers Dis. 2007;12:229–40. doi: 10.3233/JAD-2007-12304.
    1. Donovan MH, Yazdani U, Norris RD, Games D, German DC, Eisch AJ. Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer’s disease. J Comp Neurol. 2006;495:70–83. doi: 10.1002/cne.20840.
    1. Acharya MM, Christie L-A, Lan ML, Donovan PJ, Cotman CW, Fike JR, Limoli CL. Rescue of radiation-induced cognitive impairment through cranial transplantation of human embryonic stem cells. Proc Natl Acad Sci. 2009;106:19150–5. doi: 10.1073/pnas.0909293106.
    1. Fong CY, Gauthaman K, Bongso A. Teratomas from pluripotent stem cells: a clinical hurdle. J Cell Biochem. 2010;111:769–81. doi: 10.1002/jcb.22775.
    1. Moghadam FH, Alaie H, Karbalaie K, Tanhaei S, Esfahani MHN, Baharvand H. Transplantation of primed or unprimed mouse embryonic stem cell-derived neural precursor cells improves cognitive function in Alzheimerian rats. Differentiation. 2009;78:59–68. doi: 10.1016/j.diff.2009.06.005.
    1. Bissonnette CJ, Lyass L, Bhattacharyya BJ, Belmadani A, Miller RJ, Kessler JA. The controlled generation of functional basal forebrain cholinergic neurons from human embryonic stem cells. Stem Cells. 2011;29:802–11. doi: 10.1002/stem.626.
    1. Liu Y, Weick JP, Liu H, Krencik R, Zhang X, Ma L, Zhou G-m, Ayala M, Zhang S-C. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol. 2013;31:440–7. doi: 10.1038/nbt.2565.
    1. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller F-J, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci. 2009;106:13594–9. doi: 10.1073/pnas.0901402106.
    1. Kordower JH, Winn SR, Liu Y-T, Mufson EJ, Sladek JR, Hammang JP, Baetge EE, Emerich DF. The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor. Proc Natl Acad Sci. 1994;91:10898–902. doi: 10.1073/pnas.91.23.10898.
    1. Park D, Yang Y-H, Bae DK, Lee SH, Yang G, Kyung J, Kim D, Choi E-K, Lee SW, Kim GH. Improvement of cognitive function and physical activity of aging mice by human neural stem cells over-expressing choline acetyltransferase. Neurobiol Aging. 2013;34:2639–46. doi: 10.1016/j.neurobiolaging.2013.04.026.
    1. Zhang Q, Wu Hh, Wang Y, Gu Gj, Zhang W, Xia R. Neural stem cell transplantation decreases neuroinflammation in a transgenic mouse model of Alzheimer’s disease. J Neurochem. 2015;136:815–825.
    1. Lee I-S, Jung K, Kim I-S, Lee H, Kim M, Yun S, Hwang K, Shin JE, Park KI. Human neural stem cells alleviate Alzheimer-like pathology in a mouse model. Mol Neurodegener. 2015;10:1. doi: 10.1186/s13024-015-0035-6.
    1. Lilja AM, Malmsten L, Röjdner J, Voytenko L, Verkhratsky A, Ögren SO, Nordberg A, Marutle A. Neural stem cell transplant-induced effect on neurogenesis and cognition in Alzheimer Tg2576 mice is inhibited by concomitant treatment with amyloid-lowering or cholinergic 7 nicotinic receptor drugs. Neural Plast. 2015;2015:370432.
    1. Ager RR, Davis JL, Agazaryan A, Benavente F, Poon WW, LaFerla FM, Blurton-Jones M. Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer’s disease and neuronal loss. Hippocampus. 2015;25:813–26. doi: 10.1002/hipo.22405.
    1. Xuan A, Luo M, Ji W, Long D. Effects of engrafted neural stem cells in Alzheimer’s disease rats. Neurosci Lett. 2009;450:167–71. doi: 10.1016/j.neulet.2008.12.001.
    1. Park D, Yang G, Bae DK, Lee SH, Yang YH, Kyung J, Kim D, Choi EK, Choi KC, Kim SU. Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice. J Neurosci Res. 2013;91:660–70. doi: 10.1002/jnr.23182.
    1. Lee J, Kuroda S, Shichinohe H, Ikeda J, Seki T, Hida K, Tada M, Sawada K, Iwasaki Y. Migration and differentiation of nuclear fluorescence‐labeled bone marrow stromal cells after transplantation into cerebral infarct and spinal cord injury in mice. Neuropathology. 2003;23:169–80. doi: 10.1046/j.1440-1789.2003.00496.x.
    1. Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ. Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci U S A. 2005;102:18171–6. doi: 10.1073/pnas.0508945102.
    1. Teixeira FG, Carvalho MM, Neves-Carvalho A, Panchalingam KM, Behie LA, Pinto L, Sousa N, Salgado AJ. Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem Cell Rev Rep. 2015;11:288–97. doi: 10.1007/s12015-014-9576-2.
    1. Zilka N, Zilkova M, Kazmerova Z, Sarissky M, Cigankova V, Novak M. Mesenchymal stem cells rescue the Alzheimer’s disease cell model from cell death induced by misfolded truncated tau. Neuroscience. 2011;193:330–7. doi: 10.1016/j.neuroscience.2011.06.088.
    1. Lee HJ, Lee JK, Lee H, Carter JE, Chang JW, Oh W, Yang YS, Suh J-G, Lee B-H, Jin HK. Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through modulation of neuroinflammation. Neurobiol Aging. 2012;33:588–602. doi: 10.1016/j.neurobiolaging.2010.03.024.
    1. Yun H, Kim H, Park K, Shin J, Kang A, Il Lee K, Song S, Kim Y, Han S, Chung H. Placenta-derived mesenchymal stem cells improve memory dysfunction in an Aβ1–42-infused mouse model of Alzheimer’s disease. Cell Death Dis. 2013;4 doi: 10.1038/cddis.2013.490.
    1. Yang H, Xie ZH, Wei LF, Yang HN, Yang SN, Zhu ZY, Wang P, Zhao CP, Bi JZ. Human umbilical cord mesenchymal stem cell-derived neuron-like cells rescue memory deficits and reduce amyloid-beta deposition in an AβPP/PS1 transgenic mouse model. Stem Cell Res Ther. 2013;4:1. doi: 10.1186/scrt227.
    1. Kim K-S, Kim HS, Park J-M, Kim HW, M-k P, Lee H-S, Lim DS, Lee TH, Chopp M, Moon J. Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer’s disease model. Neurobiol Aging. 2013;34:2408–20. doi: 10.1016/j.neurobiolaging.2013.03.029.
    1. Naaldijk Y, Jaeger C, Fabian C, Leovsky C, Blüher A, Rudolph L, Hinze A, Stolzing A. Effect of systemic transplantation of bone marrow‐derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Neuropathol Appl Neurobiol. 2016.
    1. Oh SH, Kim HN, Park H-J, Shin JY, Lee PH. Mesenchymal stem cells increase hippocampal neurogenesis and neuronal differentiation by enhancing the Wnt signaling pathway in an Alzheimer’s disease model. Cell Transplant. 2015;24:1097–109.
    1. Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY, Yoon EJ, Choi HJ. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011;20:1297–308. doi: 10.1089/scd.2010.0466.
    1. Pang ZP, Yang N, Vierbuchen T, Ostermeier A, Fuentes DR, Yang TQ, Citri A, Sebastiano V, Marro S, Südhof TC. Induction of human neuronal cells by defined transcription factors. Nature. 2011;476:220–3.
    1. Liu X, Li F, Stubblefield EA, Blanchard B, Richards TL, Larson GA, He Y, Huang Q, Tan A-C, Zhang D. Direct reprogramming of human fibroblasts into dopaminergic neuron-like cells. Cell Res. 2012;22:321–32. doi: 10.1038/cr.2011.181.
    1. Eckert A, Huang L, Gonzalez R, Kim H-S, Hamblin MH, Lee J-P. Bystander effect fuels human induced pluripotent stem cell‐derived neural stem cells to quickly attenuate early stage neurological deficits after stroke. Stem Cells Transl Med. 2015;4:841–51. doi: 10.5966/sctm.2014-0184.
    1. Fujiwara N, Shimizu J, Takai K, Arimitsu N, Saito A, Kono T, Umehara T, Ueda Y, Wakisaka S, Suzuki T. Restoration of spatial memory dysfunction of human APP transgenic mice by transplantation of neuronal precursors derived from human iPS cells. Neurosci Lett. 2013;557:129–34. doi: 10.1016/j.neulet.2013.10.043.
    1. Hallett PJ, Deleidi M, Astradsson A, Smith GA, Cooper O, Osborn TM, Sundberg M, Moore MA, Perez-Torres E, Brownell A-L. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson’s disease. Cell Stem Cell. 2015;16:269–74. doi: 10.1016/j.stem.2015.01.018.
    1. Balez R, Steiner N, Engel M, Muñoz SS, Lum JS, Wu Y, Wang D, Vallotton P, Sachdev P, O’Connor M. Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease. Sci Report. 2016;6:31450. doi: 10.1038/srep31450.
    1. Hossini AM, Megges M, Prigione A, Lichtner B, Toliat MR, Wruck W, Schröter F, Nuernberg P, Kroll H, Makrantonaki E. Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer’s disease donor as a model for investigating AD-associated gene regulatory networks. BMC Genomics. 2015;16:1. doi: 10.1186/1471-2164-16-1.
    1. Muratore CR, Rice HC, Srikanth P, Callahan DG, Shin T, Benjamin LN, Walsh DM, Selkoe DJ, Young-Pearse TL. The familial Alzheimer’s disease APPV717I mutation alters APP processing and Tau expression in iPSC-derived neurons. Hum Mol Genet. 2014;23:3523–36. doi: 10.1093/hmg/ddu064.
    1. Truong A, Si E, Duncan T, Valenzuela M. Modeling neurodegenerative disorders in adult somatic cells: a critical review. Front Biol. 2016;11:232–45. doi: 10.1007/s11515-016-1413-3.
    1. Kim HJ, Seo SW, Chang JW, Lee JI, Kim CH, Chin J, Choi SJ, Kwon H, Yun HJ, Lee JM. Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: a phase 1 clinical trial. Alzheimers Dement. 2015;1:95–102.
    1. Vertelov G, Kharazi L, Muralidhar M, Sanati G, Tankovich T, Kharazi A. High targeted migration of human mesenchymal stem cells grown in hypoxia is associated with enhanced activation of RhoA. Stem Cell Res Ther. 2013;4:1. doi: 10.1186/scrt153.
    1. Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37–44. doi: 10.1186/alzrt269.
    1. Thirabanjasak D, Tantiwongse K, Thorner PS. Angiomyeloproliferative lesions following autologous stem cell therapy. J Am Soc Nephrol. 2010;21:1218–22. doi: 10.1681/ASN.2009111156.
    1. Amariglio N, Hirshberg A, Scheithauer BW, Cohen Y, Loewenthal R, Trakhtenbrot L, Paz N, Koren-Michowitz M, Waldman D, Leider-Trejo L. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009;6 doi: 10.1371/journal.pmed.1000029.
    1. Fazel SS, Angoulvant D, Butany J, Weisel RD, Li R-K. Mesenchymal stem cells engineered to overexpress stem cell factor improve cardiac function but have malignant potential. J Thorac Cardiovasc Surg. 2008;136:1388–9. doi: 10.1016/j.jtcvs.2007.11.068.

Source: PubMed

3
Suscribir