title: Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease.
abstract: Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron-glia signaling pathway whereby Aβ acts as an upstream activator of astroglial nuclear factor kappa B (NF-κB), leading to the release of complement C3, which acts on the neuronal C3a receptor (C3aR) to influence dendritic morphology and cognitive function. Here we report that astrocytic complement activation also regulates Aβ dynamics in vitro and amyloid pathology in AD mouse models through microglial C3aR. We show that in primary microglial cultures, acute C3 or C3a activation promotes, whereas chronic C3/C3a treatment attenuates, microglial phagocytosis and that the effect of chronic C3 exposure can be blocked by cotreatment with a C3aR antagonist and by genetic deletion of C3aR. We further demonstrate that Aβ pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NF-κB hyperactivation and resulting C3 elevation, whereas treatment with the C3aR antagonist (C3aRA) ameliorates plaque load and microgliosis. Our studies define a complement-dependent intercellular cross talk in which neuronal overproduction of Aβ activates astroglial NF-κB to elicit extracellular release of C3. This promotes a pathogenic cycle by which C3 in turn interacts with neuronal and microglial C3aR to alter cognitive function and impair Aβ phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuroinflammation conditions.
  
  
  CONCLUSIONS
  The complement pathway is activated in Alzheimer's disease. Here we show that the central complement factor C3 secreted from astrocytes interacts with microglial C3a receptor (C3aR) to mediate β-amyloid pathology and neuroinflammation in AD mouse models. Our study provides support for targeting C3aR as a potential therapy for Alzheimer's disease.
authors.affiliation: Huffington Center on Aging.
authors.forename: Hong
authors.initials: H
authors.lastname: Lian
authors.affiliation: Huffington Center on Aging, Integrative Molecular and Biomedical Sciences Program.
authors.forename: Alexandra
authors.identifier: http://orcid.org/0000-0002-0591-7948
authors.initials: A
authors.lastname: Litvinchuk
authors.affiliation: Department of Neuroscience, and.
authors.forename: Angie C-A
authors.initials: AC
authors.lastname: Chiang
authors.affiliation: Huffington Center on Aging.
authors.forename: Nadia
authors.initials: N
authors.lastname: Aithmitti
authors.affiliation: Huffington Center on Aging, Integrative Molecular and Biomedical Sciences Program, Department of Neuroscience, and.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Jankowsky
authors.affiliation: Huffington Center on Aging, Integrative Molecular and Biomedical Sciences Program, Department of Neuroscience, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030 huiz@bcm.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D003167:Complement Activation / Q000235:genetics*; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D003176:Complement C3; D005904:Glial Fibrillary Acidic Protein; D020672:I-kappa B Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer's disease; C3; C3a receptor; amyloid; mice; microglia