title: Intra-hippocampal transplantation of neural precursor cells with transgenic over-expression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an Alzheimer's disease model.
abstract: Ample evidence implicates neuroinflammatory processes in the etiology and progression of Alzheimer's disease (AD). To assess the specific role of the pro-inflammatory cytokine interleukin-1 (IL-1) in AD we examined the effects of intra-hippocampal transplantation of neural precursor cells (NPCs) with transgenic over-expression of IL-1 receptor antagonist (IL-1raTG) on memory functioning and neurogenesis in a murine model of AD (Tg2576 mice). WT NPCs- or sham-transplanted Tg2576 mice, as well as naive Tg2576 and WT mice served as controls. To assess the net effect of IL-1 blockade (not in the context of NPCs transplantation), we also examined the effects of chronic (4 weeks) intra-cerebroventricular (i.c.v.) administration of IL-1ra. We report that 12-month-old Tg2576 mice exhibited increased mRNA expression of hippocampal IL-1β, along with severe disturbances in hippocampal-dependent contextual and spatial memory as well as in neurogenesis. Transplantation of IL-1raTG NPCs 1 month before the neurobehavioral testing completely rescued these disturbances and significantly increased the number of endogenous hippocampal cells expressing the plasticity-related molecule BDNF. Similar, but less-robust effects were also produced by transplantation of WT NPCs and by i.c.v. IL-1ra administration. NPCs transplantation produced alterations in hippocampal plaque formation and microglial status, which were not clearly correlated with the cognitive effects of this procedure. The results indicate that elevated levels of hippocampal IL-1 are causally related to some AD-associated memory disturbances, and provide the first example for the potential use of genetically manipulated NPCs with anti-inflammatory properties in the treatment of AD.
authors: Ofra
authors: O
authors: Ben-Menachem-Zidon
authors: Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Ofra
authors: O
authors: Ben Menachem-Zidon
authors: Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Yair
authors: Y
authors: Ben-Menahem
authors: Department of Neurology, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
authors: Tamir
authors: T
authors: Ben-Hur
authors: Department of Psychology, The Hebrew University of Jerusalem, Jerusalem, Israel.
authors: Raz
authors: R
authors: Yirmiya
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000601:surgery; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism* / Q000601:surgery; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000637:transplantation*; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000502:physiology
chemical_list: C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein
references: Int J Alzheimers Dis. 2012;2012:314185
references: 22779026
references: Neurobiol Aging. 2004 Nov-Dec;25(10):1293-8
references: 15465625
references: J Neurosci. 2000 Jan 1;20(1):149-55
references: 10627591
references: Stem Cells. 2012 Dec;30(12):2612-8
references: 22997040
references: Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10409-14
references: 9294224
references: J Neuroimmunol. 2004 Oct;155(1-2):119-26
references: 15342202
references: J Neural Transm (Vienna). 2010 Aug;117(8):949-60
references: 20552234
references: J Neurosci. 2013 Mar 13;33(11):5053-64
references: 23486975
references: Apoptosis. 2010 Nov;15(11):1415-21
references: 20339917
references: Nat Rev Drug Discov. 2011 Mar;10(3):209-19
references: 21358740
references: Mol Cell Neurosci. 2003 Nov;24(3):623-31
references: 14664813
references: Neurobiol Aging. 2000 May-Jun;21(3):383-421
references: 10858586
references: J Clin Invest. 2007 Jun;117(6):1595-604
references: 17549256
references: Mol Psychiatry. 2008 Jul;13(7):717-28
references: 17700577
references: J Neurosci. 2009 Mar 18;29(11):3395-403
references: 19295146
references: Cell. 2010 Mar 19;140(6):918-34
references: 20303880
references: J Neurochem. 2008 Mar;104(5):1387-93
references: 18021299
references: J Cell Mol Med. 2008 Jun;12(3):762-80
references: 18363841
references: Nat Neurosci. 2006 Jun;9(6):729-31
references: 16648847
references: Curr Opin Neurol. 2012 Jun;25(3):322-33
references: 22547103
references: Brain Behav Immun. 2011 Feb;25(2):181-213
references: 20970492
references: Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):751-6
references: 18178625
references: Nature. 2013 Jan 31;493(7434):674-8
references: 23254930
references: Brain Behav Immun. 2012 Feb;26(2):292-300
references: 21983279
references: Neurobiol Aging. 2008 Sep;29(9):1380-93
references: 17467122
references: Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):6058-63
references: 20231476
references: J Neurosci. 2003 Mar 1;23(5):1605-11
references: 12629164
references: J Neuroimmune Pharmacol. 2012 Mar;7(1):156-64
references: 22173340
references: Brain Behav Immun. 2011 Jul;25(5):1008-16
references: 21093580
references: Neurobiol Aging. 1996 Sep-Oct;17(5):761-6
references: 8892349
references: Exp Mol Med. 2012 Aug 31;44(8):492-502
references: 22644036
references: Hippocampus. 2003;13(7):826-34
references: 14620878
references: J Neuropathol Exp Neurol. 1997 Sep;56(9):965-73
references: 9291938
references: Neurosci Biobehav Rev. 2009 Mar;33(3):355-66
references: 18996146
references: Anesthesiology. 2010 Jun;112(6):1404-16
references: 20460993
references: F1000 Med Rep. 2011;3:24
references: 22162727
references: Neuropsychopharmacology. 2008 Aug;33(9):2251-62
references: 17987063
references: Neuron. 2011 Jan 27;69(2):203-13
references: 21262461
references: Ann Neurol. 2005 May;57(5):741-5
references: 15852394
references: Neuroscience. 2009 Mar 3;159(1):59-68
references: 19138728
references: Mol Neurobiol. 2009 Oct;40(2):139-56
references: 19629762
references: J Cell Mol Med. 2007 Jul-Aug;11(4):810-25
references: 17760842
references: Ann Surg. 2013 Mar;257(3):439-48
references: 22964728
references: Glia. 2013 Jan;61(1):62-70
references: 22740320
references: Mol Neurodegener. 2011 Dec 22;6:85
references: 22192775
references: Am J Physiol. 1999 Mar;276(3):R644-51
references: 10070123
references: Neuroscience. 2009 Feb 6;158(3):1021-9
references: 18662748
references: Neurosci Biobehav Rev. 2001 Jan;25(1):29-41
references: 11166076
references: J Immunol. 2011 Dec 15;187(12):6539-49
references: 22095718
references: Proc Natl Acad Sci U S A. 1989 Oct;86(19):7611-5
references: 2529544
references: Neuroscience. 2003;121(4):847-53
references: 14580934
references: Science. 1996 Oct 4;274(5284):99-102
references: 8810256
references: Front Neuroendocrinol. 2009 Jan;30(1):30-45
references: 19017533
references: J Neuroinflammation. 2008 Feb 26;5:7
references: 18302763
references: Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13594-9
references: 19633196
references: Nat Rev Drug Discov. 2011 Aug 19;10(9):698-712
references: 21852788
references: Glia. 2013 Feb;61(2):140-9
references: 23001547
references: Am J Pathol. 2013 May;182(5):1780-9
references: 23506847
references: Proc Natl Acad Sci U S A. 1989 Oct;86(19):7606-10
references: 2508093
references: Nat Rev Immunol. 2005 Aug;5(8):629-40
references: 16034365
references: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):741-9
references: 12921904
references: J Neural Transm (Vienna). 2010 Aug;117(8):919-47
references: 20632195