Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease
Autor: | Angie C.A. Chiang, Nadia Aithmitti, Joanna L. Jankowsky, Alexandra Litvinchuk, Hui Zheng, Hong Lian |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Male Mice Transgenic Complement factor I Microgliosis 03 medical and health sciences Amyloid beta-Protein Precursor Mice 0302 clinical medicine Phagocytosis Alzheimer Disease Glial Fibrillary Acidic Protein medicine Amyloid precursor protein Presenilin-1 Animals Humans Complement Activation Neuroinflammation Cells Cultured Microglia biology General Neuroscience Complement C3 Articles medicine.disease Complement system Up-Regulation Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Astrocytes biology.protein Female I-kappa B Proteins C3a receptor Alzheimer's disease Neuroscience 030217 neurology & neurosurgery Signal Transduction |
Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 36(2) |
ISSN: | 1529-2401 |
Popis: | 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 dynamicsin vitroand 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 ofC3aR. 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.SIGNIFICANCE STATEMENTThe 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. |
Databáze: | OpenAIRE |
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