title: Intravenous infusion of monocytes isolated from 2-week-old mice enhances clearance of Beta-amyloid plaques in an Alzheimer mouse model.
abstract: Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ) senile plaques and tau-associated neurofibrillary tangles. Other disease features include neuroinflammation and cholinergic neurodegeneration, indicating their possible importance in disease propagation. Recent studies have shown that monocytic cells can migrate into the AD brain toward Aβ plaques and reduce plaque burden. The purpose of this study was to evaluate whether the administration of intravenous infusions of 'young' CD11b-positive (+) monocytes into an AD mouse model can enhance Aβ plaque clearance and attenuate cognitive deficits. Peripheral monocytes were isolated from two-week-old wildtype mice using the Pluriselect CD11b+ isolation method and characterized by FACS analysis for surface marker expression and effective phagocytosis of 1 μm fluorescent microspheres, FITC-Dextran or FITC-Aβ1-42. The isolated monocytes were infused via the tail vein into a transgenic AD mouse model, which expresses the Swedish, Dutch/Iowa APP mutations (APPSwDI). The infusions began when animals reached 5 months of age, when little plaque deposition is apparent and were repeated again at 6 and 7 months of age. At 8 months of age, brains were analyzed for Aβ+ plaques, inflammatory processes and microglial (Iba1) activation. Our data show that infusions of two-week-old CD11b+ monocytes into adult APPSwDI mice results in a transient improvement of memory function, a reduction (30%) in Aβ plaque load and significantly in small (<20 μm) and large (>40 μm) plaques. In addition, we observe a reduction in Iba1+ cells, as well as no marked elevations in cytokine levels or other indicators of inflammation. Taken together, our findings indicate that young CD11b+ monocytes may serve as therapeutic candidates for improved Aβ clearance in AD.
authors.affiliation: Laboratory of Psychiatry and Experimental Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Hohsfield
authors.affiliation: Laboratory of Psychiatry and Experimental Alzheimer's Research, Department of Psychiatry and Psychotherapy, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Humpel
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007262:Infusions, Intravenous; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000378:metabolism / Q000637:transplantation*; D010587:Phagocytosis; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology
chemical_list: D016229:Amyloid beta-Peptides; D039481:CD11b Antigen; D016207:Cytokines; D002374:Catalase
references.citation: N Engl J Med. 2010 Jan 28;362(4):329-44
references.pmid: 20107219
references.citation: Mol Cell Neurosci. 2010 Dec;45(4):408-17
references.pmid: 20696249
references.citation: J Leukoc Biol. 2007 Aug;82(2):244-52
references.pmid: 17475785
references.citation: Cell. 2010 Mar 19;140(6):918-34
references.pmid: 20303880
references.citation: Cell Rep. 2013 Nov 14;5(3):646-53
references.pmid: 24210819
references.citation: Nat Rev Neurosci. 2014 May;15(5):300-12
references.pmid: 24713688
references.citation: Nat Med. 2008 Jun;14(6):681-7
references.pmid: 18516051
references.citation: Eur J Neurosci. 2010 Nov;32(9):1516-27
references.pmid: 21044172
references.citation: Nat Neurosci. 2012 Mar;15(3):349-57
references.pmid: 22286176
references.citation: Brain. 2009 Apr;132(Pt 4):1078-92
references.pmid: 19151372
references.citation: Immun Ageing. 2013 Jun 08;10(1):22
references.pmid: 23758797
references.citation: Neurobiol Learn Mem. 2013 Nov;106:154-62
references.pmid: 23973449
references.citation: Aging Cell. 2012 Oct;11(5):867-75
references.pmid: 22708967
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1261-6
references.pmid: 19164591
references.citation: Nat Neurosci. 2005 Jan;8(1):79-84
references.pmid: 15608634
references.citation: J Neuroimmune Pharmacol. 2009 Dec;4(4):462-75
references.pmid: 19669892
references.citation: J Exp Med. 2009 Mar 16;206(3):595-606
references.pmid: 19273628
references.citation: Pharmacol Biochem Behav. 1989 Mar;32(3):777-85
references.pmid: 2740429
references.citation: Nat Rev Immunol. 2013 Dec;13(12):875-87
references.pmid: 24157572
references.citation: J Comp Neurol. 2013 Dec 1;521(17):3863-76
references.pmid: 23682015
references.citation: Nat Med. 2014 Jun;20(6):659-63
references.pmid: 24793238
references.citation: Nat Rev Neurol. 2010 Jul;6(7):405-10
references.pmid: 20531383
references.citation: Curr Neurovasc Res. 2010 Aug;7(3):192-200
references.pmid: 20560880
references.citation: J Leukoc Biol. 2007 Mar;81(3):584-92
references.pmid: 17135573
references.citation: J Neuroinflammation. 2014;11:161
references.pmid: 25217135
references.citation: Neurobiol Aging. 2000 May-Jun;21(3):383-421
references.pmid: 10858586
references.citation: J Biosci. 2012 Mar;37(1):55-62
references.pmid: 22357203
references.citation: J Neural Transm (Vienna). 2010 Aug;117(8):961-70
references.pmid: 20517700
references.citation: Eur J Pharmacol. 2003 Feb 28;463(1-3):55-65
references.pmid: 12600702
references.citation: J Neurosci. 2013 Aug 21;33(34):13820-33
references.pmid: 23966702
references.citation: J Mol Cell Biol. 2013 Oct;5(5):284-93
references.pmid: 23892208
references.citation: Neuron. 2006 Feb 16;49(4):489-502
references.pmid: 16476660
references.citation: Neuron. 2009 Oct 15;64(1):55-60
references.pmid: 19840549
references.citation: Aging Cell. 2014 Aug;13(4):699-708
references.pmid: 24813244
references.citation: PLoS One. 2013;8(4):e60921
references.pmid: 23577177
references.citation: J Neuroimmunol. 2011 Sep 15;238(1-2):1-11
references.pmid: 21820744
references.citation: Immunobiology. 2006;211(6-8):609-18
references.pmid: 16920499
references.citation: BMC Immunol. 2010;11:30
references.pmid: 20565954
references.citation: Neurochem Res. 2009 Dec;34(12):2147-53
references.pmid: 19495971
references.citation: J Pathol. 2013 Jan;229(2):332-46
references.pmid: 23007711
references.citation: J Biol Chem. 2004 May 7;279(19):20296-306
references.pmid: 14985348
references.citation: Nat Med. 2007 Apr;13(4):432-8
references.pmid: 17351623
references.citation: PLoS One. 2014;9(8):e104522
references.pmid: 25105870
references.citation: PLoS One. 2009;4(7):e6197
references.pmid: 19593388
references.citation: J Alzheimers Dis. 2005 Jun;7(3):221-32; discussion 255-62
references.pmid: 16006665
references.citation: Glia. 2010 Jun;58(8):889-900
references.pmid: 20155817
references.citation: Neuron. 2013 Sep 4;79(5):873-86
references.pmid: 24012002
references.citation: Cell Immunol. 2011;267(2):109-23
references.pmid: 21292246
references.citation: Front Cell Neurosci. 2012 Nov 01;6:51
references.pmid: 23125823
references.citation: Nat Neurosci. 2009 Nov;12(11):1361-3
references.pmid: 19838177
references.citation: J Neurosci. 2011 Aug 3;31(31):11159-71
references.pmid: 21813677
references.citation: J Neurosci. 2010 Jul 21;30(29):9651-8
references.pmid: 20660248
references.citation: Cold Spring Harb Perspect Med. 2012 Jan;2(1):a006346
references.pmid: 22315714
references.citation: FASEB J. 2010 Feb;24(2):548-59
references.pmid: 19825975