title: Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques.
abstract: In Alzheimer's disease (AD), β-amyloid (Aβ) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown. Here we show that microglia constitute a barrier with profound impact on plaque composition and toxicity. Using high-resolution confocal and in vivo two-photon imaging in AD mouse models, we demonstrate that this barrier prevents outward plaque expansion and leads to compact plaque microregions with low Aβ42 affinity. Areas uncovered by microglia are less compact but have high Aβ42 affinity, leading to the formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In ageing, microglia coverage is reduced leading to enlarged protofibrillar Aβ42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-Aβ immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar Aβ hotspots may constitute novel therapeutic and clinical imaging targets for AD.
authors: Department of Neurology, Yale University, New Haven, Connecticut 06511, USA.
authors: Carlo
authors: C
authors: Condello
authors: 1] Department of Neurology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Neurobiology, Yale University, New Haven, Connecticut 06510, USA.
authors: Peng
authors: P
authors: Yuan
authors: Department of Neurology, Yale University, New Haven, Connecticut 06511, USA.
authors: Aaron
authors: A
authors: Schain
authors: 1] Department of Neurology, Yale University, New Haven, Connecticut 06511, USA [2] Department of Neurobiology, Yale University, New Haven, Connecticut 06510, USA.
authors: Jaime
authors: J
authors: Grutzendler
mesh_terms: D000375:Aging; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000187:drug effects / Q000473:pathology; D000073883:CX3C Chemokine Receptor 1; D004396:Coloring Agents / Q000378:metabolism; D004058:Diffusion; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007114:Immunization; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D012995:Solubility; D013194:Staining and Labeling
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D000073883:CX3C Chemokine Receptor 1; D004396:Coloring Agents; C471885:Cx3cr1 protein, mouse; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D019707:Receptors, Chemokine; C075222:amyloid beta-protein (1-42)
references: Cell. 2009 Dec 11;139(6):1157-69
references: 20005808
references: Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9758-63
references: 23703910
references: J Neurosci. 2005 Feb 2;25(5):1071-80
references: 15689542
references: Neuron. 2008 Jan 24;57(2):178-201
references: 18215617
references: J Neurosci. 2008 Aug 13;28(33):8354-60
references: 18701698
references: PLoS One. 2010;5(7):e11820
references: 20676404
references: Acc Chem Res. 2006 Sep;39(9):663-70
references: 16981683
references: N Engl J Med. 2013 Jan 10;368(2):107-16
references: 23150908
references: J Clin Invest. 2006 Jan;116(1):193-201
references: 16341263
references: N Engl J Med. 2013 Jan 10;368(2):117-27
references: 23150934
references: Ann N Y Acad Sci. 1992 Dec 31;674:65-88
references: 1288372
references: J Am Chem Soc. 2013 Nov 6;135(44):16397-409
references: 24116384
references: Nature. 2006 Oct 19;443(7113):768-73
references: 17051202
references: EMBO J. 2010 Oct 6;29(19):3408-20
references: 20818335
references: Nat Neurosci. 2005 Jun;8(6):752-8
references: 15895084
references: J Neuroimmunol. 1989 Oct;24(3):173-82
references: 2808689
references: Nat Neurosci. 2013 Jul;16(7):848-50
references: 23708142
references: J Neurosci. 2011 Mar 16;31(11):4124-36
references: 21411653
references: Sci Rep. 2011;1:19
references: 22355538
references: J Biol Chem. 2005 Feb 18;280(7):5892-901
references: 15590663
references: Ann Neurol. 2013 Jan;73(1):104-19
references: 23225543
references: Nat Neurosci. 2004 Nov;7(11):1181-3
references: 15475950
references: J Nucl Med. 2009 May;50(5):818-22
references: 19372469
references: Acta Neuropathol. 1990;81(2):116-24
references: 2082651
references: J Neuroinflammation. 2011;8:92
references: 21827663
references: Mol Neurodegener. 2007 Sep 26;2:18
references: 17897471
references: J Neurosci. 2010 Oct 27;30(43):14411-9
references: 20980598
references: Acta Neuropathol. 2012 Jan;123(1):53-70
references: 22020633
references: Neurobiol Aging. 2014 Feb;35(2):444.e1-4
references: 24041969
references: Neurobiol Aging. 2004 May-Jun;25(5):663-74
references: 15172746
references: J Biol Chem. 2012 Feb 17;287(8):5650-60
references: 22157754
references: J Alzheimers Dis. 2011;23(1):37-48
references: 20930313
references: J Neuroinflammation. 2004 Dec 08;1(1):24
references: 15588287
references: J Neurosci. 2010 Dec 15;30(50):17091-101
references: 21159979
references: Trends Neurosci. 2006 Sep;29(9):506-10
references: 16859761
references: Neuron. 2009 Aug 13;63(3):287-303
references: 19679070
references: J Biol Chem. 2009 Oct 30;284(44):30148-58
references: 19748895
references: J Neuropathol Exp Neurol. 2005 Feb;64(2):113-22
references: 15751225
references: J Biol Chem. 2003 Jun 27;278(26):23648-55
references: 12716908
references: Chem Commun (Camb). 2014 Oct 9;50(78):11550-3
references: 25134928
references: Neurobiol Aging. 2001 May-Jun;22(3):427-34
references: 11378249
references: J Alzheimers Dis. 2010;19(1):355-61
references: 20061650
references: Mol Neurodegener. 2010 Dec 13;5:57
references: 21144050
references: Neuron. 2013 May 22;78(4):631-43
references: 23623698
references: J Biol Chem. 2004 Nov 5;279(45):46363-6
references: 15385542
references: J Neurosci. 2009 Apr 1;29(13):4252-62
references: 19339619
references: Nat Med. 2007 Apr;13(4):432-8
references: 17351623
references: J Biol Chem. 2011 Mar 11;286(10):8585-96
references: 21156804
references: J Alzheimers Dis. 2011;24 Suppl 2:33-42
references: 21335654
references: Neuron. 2013 Nov 20;80(4):844-66
references: 24267647
references: Neuron. 2013 May 22;78(4):575-7
references: 23719156
references: J Neurosci. 2011 Jan 26;31(4):1355-65
references: 21273420
references: Neurobiol Dis. 2011 Jun;42(3):221-30
references: 21220023
references: Neuron. 2010 Oct 21;68(2):270-81
references: 20955934
references: J Mol Biol. 2004 Apr 23;338(2):203-6
references: 15066425
references: Nat Neurosci. 2009 Nov;12(11):1361-3
references: 19838177
references: Glia. 1993 Feb;7(2):183-91
references: 8432559
references: Nat Neurosci. 2007 Nov;10(11):1387-94
references: 17965659
references: J Neurosci. 2008 Jun 18;28(25):6333-41
references: 18562603
references: Nucl Med Biol. 2010 May;37(4):497-508
references: 20447562
references: J Neurosci. 2011 Apr 20;31(16):6208-20
references: 21508244
references: Cold Spring Harb Perspect Med. 2012 Jun;2(6):a006262
references: 22675658
references: Nat Rev Neurol. 2010 Feb;6(2):108-19
references: 20140000