Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease

Jan 14, 2016The Journal of neuroscience : the official journal of the Society for Neuroscience

Communication between support and immune brain cells through complement activation influences amyloid buildup in mouse models of Alzheimer's disease

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Abstract

Astrocytic complement factor C3 is implicated in worsening Aβ pathology and neuroinflammation in Alzheimer's disease mouse models.

Neuroinflammation may play a significant role in the development of Alzheimer's disease.
Astroglial activation of nuclear factor kappa B (NF-κB) by Aβ leads to increased release of complement C3.
Acute activation of C3 or C3a promotes microglial phagocytosis, while chronic exposure reduces it.
C3a receptor (C3aR) antagonism can block the negative effects of chronic C3 exposure on microglial function.
In APP transgenic mice, hyperactivation of astroglial NF-κB and elevated C3 levels exacerbate Aβ-related pathology.
Inhibition of C3aR can reduce amyloid plaque load and microgliosis, suggesting a potential therapeutic approach.

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UNLABELLED: 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.

SIGNIFICANCE STATEMENT: 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.

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Astrocyte-Microglia Cross Talk through Complement Activation Modulates Amyloid Pathology in Mouse Models of Alzheimer's Disease

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