Telephone: +82 53 950 5966; Fax: +82 53 950 5955
Tissue-Specific Stem Cells
Article first published online: 10 DEC 2009
Copyright © 2010 AlphaMed Press
Volume 28, Issue 2, pages 329–343, February 2010
How to Cite
Lee, J. K., Jin, H. K., Endo, S., Schuchman, E. H., Carter, J. E. and Bae, J.-s. (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. doi: 10.1002/stem.277
Author contributions: H.K.J., J.S.B.: conception and design; H.K.J., J.K.L.: provision of study material and collection of data; H.K.J., J.K.L., S.E., J.S.B.: data analysis and interpretation; H.K.J., J.S.B.: financial support; J.K.L., E.H.S., J.E.C., J.S.B. manuscript writing; H.K.J., E.H.S and J.S.B.: final approval.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLSEXPRESS January 28, 2010.
- Issue published online: 16 FEB 2010
- Article first published online: 10 DEC 2009
- Accepted manuscript online: 10 DEC 2009 12:00AM EST
- Manuscript Accepted: 30 NOV 2009
- Manuscript Received: 17 JUL 2009
- 1Alzheimer's disease: Genes, proteins, and therapy. Physiol Rev 2001; 81: 741–766..
- 2Clearing tau pathology with abeta immunotherapy – reversible and irreversible stages revealed. Neuron 2004; 43: 293–294., .
- 3Beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 1995; 14: 879–888., , et al.
- 4Pathways towards and away from Alzheimer's disease. Nature 2004; 430: 631–639..
- 5Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington's disease. Mol Cell Neurosci 2008; 37: 454–470., , et al.
- 6The behavioral effect of human mesenchymal stem cell transplantation in cold brain injured rats. Acta Neurochir Suppl 2006; 99: 125–132., , et al.
- 7Neurodegeneration augments the ability of bone marrow-derived mesenchymal stem cells to fuse with Purkinje neurons in Niemann-Pick type C mice. Hum Gene Ther 2005; 16: 1006–1011., , et al.
- 8Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition and accelerate the activation of microglia in an acutely induced Alzheimer's disease mouse model. Neurosci Lett 2009; 450: 136–141., , .
- 9The role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APP(SW) mice. Neurobiol Aging 2001; 22: 49–61., , et al.
- 10Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzehimer mice. Neurobiol Dis 2005; 18: 134–142., , et al.
- 11Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease. Neuron 2006; 49: 489–502., , et al.
- 12CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta amyloid fibrils. Am J Pathol 2002; 160: 101–112., , et al.
- 13CD36 mediates the innate host response to beta amyloid. J Exp Med 2003; 197: 1657–1666., , et al.
- 14Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 1995; 374: 647–650., , et al.
- 15Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 2002; 40: 260–269., , et al.
- 16Uptake, degradation, and release of fibrillar and soluble forms of Alzheimer's amyloid beta peptide by microglial cells. J Biol Chem 1999; 274: 32301–32308., , et al.
- 17Stem/progenitor cells from bone marrow decrease neuronal death in global ischemia by modulation of inflammatory/immune response. Proc Natl Acad Sci U S A 2008; 105: 14638–14643., , et al.
- 18Cognitive correlates of Abeta deposition in male and female mice bearing amyloid precursor protein and presenilin-1 mutant transgene. Brain Res 2004; 1017: 130–136., , et al.
- 19Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000; 283: 1571–1577., , et al.
- 20Specific spatial learning deficits become severe with age in beta-amyloid precursor protein transgenic mice that harbor diffuse beta-amyloid deposits but do not form plaques. Proc Natl Acad Sci U S A 2001; 98: 14675–14680., , et al.
- 21Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003; 40: 1087–1093., , et al.
- 22Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 2006; 281: 24566–24574., , et al.
- 23RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 1996; 382: 685–691., , et al.
- 24Microglia, scavenger receptor, and the pathogenesis of Alzheimer's disease. Neurobiol Aging 1998; 19: S81–S84., , et al.
- 25Microglial dysfunction and defective beta-amyloid clearance pathway in aging Alzheimer's disease mice. J Neurosci 2008; 28: 8354–8360., , .
- 26Inflammatory processes in Alzheimer's disease. J Neuroimmunol 2007; 184: 69–91., .
- 27Early correlation of microglial activation with enhanced tumor necrosis factor-alpha and monocyte chemoattractant protein-1 expression specifically within the entorhinal cortex of triple transgenic Alzheimer's disease mice. J Neuroinflammation 2005; 2: 23., , et al.
- 28Alternative activation of macrophage. Nat Rev Immunol 2003; 3: 23–35..
- 29Biochemical and functional characterization of three activated macrophage population. J Leukoc Biol 2006; 80: 1298–1307., , et al.
- 30Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 2007; 316: 750–754., , et al.
- 31Aβ deposition and related pathology in an APP x PS1 transgenic mouse model of Alzheimer's disease. Histol Histopathol 2008; 23: 67–76., , et al.
- 32Pathway by which Abeta facilitates tau pathology. Curr Alzheimer Res 2006; 3: 437–448., .
- 33Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer's-like disease. Nat Med 2007; 13: 432–438., , et al.
- 34Metabolic regulation of brain Abeta by neprilysin. Science 2001; 292: 1550–1552., , et al.
- 35Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse of Alzheimer's disease. J Neurosci 2008; 28: 5784–5793., , et al.
- 36Insukin-degrading enzyme regulates the levels of insulin, amyloid beta protein, the β-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA. 2003; 100: 4162–4167., , et al.
- 37Reduced neprilysin in high plaque areas of Alzheimer brain: A possible relationship to deficient degradation of beta-amyloid peptides. Neurosci Lett 2001; 297: 97–100., , et al.
- 38Powerful beneficial effects of macrophage colony-stimulating factor on beta-amyloid deposition and cognitive impairment in Alzheimer's disease. Brain 2009; 132: 1072–1092., , et al.
- 39Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brain. Neurochem Res 2000; 25: 247–255., , et al.
- 40Insulin degrading enzyme activity selectivrly decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging 2007; 28: 824–830., , et al.
- 41Gene expression changes by amyloid beta peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes. J Leukoc Biol 2006; 79: 596–610., , et al.
- 42Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatry 2005; 17: 503–514..
- 43CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 2007; 27: 10714–10721., , et al.
- 44IL-4 inhibits the expression of mouse formyl peptide receptor 2, a receptor for amyloid beta 1-42, in TNF-alpha-activated microglia. J Immunol 2005; 175: 6100–6106., , et al.
- 45A critical role for IL-4 in regulating disease severity in experimental allergic encephalomyelitis as demonstrated in IL-4-deficient C57BL/6 mice and BALB/c mice. J Immunol 1998; 160: 4822–4830., , et al.
- 46Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci 2005; 25: 8240–8249., .
- 47Interleukin 4 potently enhances murine macrophage mannose receptor activity: A marker of alternative immunologic macrophage activation. J Exp Med 1992; 176: 287–292., , et al.
- 48Activation of microglia by aggregated beta-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol Cell Neurosci 2005; 29: 381–393., , et al.
- 49Protective effectives of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia. J Neurochem 2006; 99: 1176–1187., , et al.
- 50Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc Natl Acad Sci U S A 2006; 103: 11784–11789., , et al.
- 51Blocking Abeta42 accumulation delays the onset and progression of tau pathology via the C terminus of heat shock protein70-interacting protein: A mechanistic link between Abeta and tau pathology. J Neurosci 2008; 28: 12163–12175., , et al.
- 52Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A Link Between Abeta And Tau Pathology J Biol Chem 2006; 281: 1599–1604., , et al.
- 53A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature 2000; 408: 975–979., , et al.
- 54Alzheimer's disease-like tau neuropathology leads to memory deficits and loss of functional synapses in a novel mutated tau transgenic mouse without any motor deficits. Am J Pathol 2006; 169: 599–616., , et al.
- 55Place navigation impaired in rats with hippocampal lesion. Nature 1982; 297: 681–683., , et al.
- 56Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury. Bone Marrow Transplant 2007; 40: 609–619., , .
- 57“Stemness” does not explain the repair of many tissues by mesenchymal stem/multipotent stromal cells (MSCs). Clin Pharmacol Ther 2007; 82: 241–243..
- 58Human 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: 18171–18176., , et al.
- 59Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration. Stem Cells 2007; 25: 1307–1316., , et al.