RESUMO
Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron-glia signaling pathway whereby Aß 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 Aß 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 Aß 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 Aß 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 Aß 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 ß-amyloid pathology and neuroinflammation in AD mouse models. Our study provides support for targeting C3aR as a potential therapy for Alzheimer's disease.
Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/patologia , Astrócitos/metabolismo , Ativação do Complemento/genética , Microglia/metabolismo , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Células Cultivadas , Complemento C3/genética , Complemento C3/metabolismo , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Presenilina-1/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/genéticaRESUMO
A critical role of the amyloid precursor protein (APP) in Alzheimer's disease (AD) pathogenesis has been well established. However, the physiological function of APP remains elusive and much debated. We reported previously that the APP family of proteins is essential in mediating the developing neuromuscular synapse. In the current study, we created a conditional allele of APP and deleted APP in presynaptic motor neuron or postsynaptic muscle. Crossing these alleles onto the APP-like protein 2-null background reveals that, unexpectedly, inactivating APP in either compartment results in neuromuscular synapse defects similar to the germline deletion and that postsynaptic APP is obligatory for presynaptic targeting of the high-affinity choline transporter and synaptic transmission. Using a HEK293 and primary hippocampus mixed-culture assay, we report that expression of APP in HEK293 cells potently promotes synaptogenesis in contacting axons. This activity is dependent on neuronal APP and requires both the extracellular and intracellular domains; the latter forms a complex with Mint1 and Cask and is replaceable by the corresponding SynCAM (synaptic cell adhesion molecule) sequences. These in vitro and in vivo studies identify APP as a novel synaptic adhesion molecule. We postulate that transsynaptic APP interaction modulates its synaptic function and that perturbed APP synaptic adhesion activity may contribute to synaptic dysfunction and AD pathogenesis.
Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Sistema Nervoso Central/fisiologia , Sistema Nervoso Periférico/metabolismo , Terminações Pré-Sinápticas/metabolismo , Sinapses/metabolismo , Precursor de Proteína beta-Amiloide/fisiologia , Animais , Comunicação Celular/fisiologia , Linhagem Celular , Células Cultivadas , Sistema Nervoso Central/embriologia , Sistema Nervoso Central/metabolismo , Técnicas de Cocultura , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neurogênese/fisiologia , Sistema Nervoso Periférico/embriologia , Gravidez , Terminações Pré-Sinápticas/fisiologia , Sinapses/fisiologia , Potenciais Sinápticos/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Neuronal cell death after DNA damage requires p53 and Bax, but the mechanism by which p53 activation leads to Bax translocation and cell death in neurons is not known. We report here that Peg3/Pw1 is up-regulated after DNA damage in cortical neurons in a p53-dependent manner. Overexpression of Peg3/Pw1 leads to decreased neuronal viability. The deleterious effect of Peg3/Pw1 on neuronal survival is abrogated by deletion of either p53 or Bax, indicating an essential role for both in Peg3/Pw1-mediated neuronal death. Moreover, overexpression of a Peg3/Pw1 dominant negative protein inhibits Bax translocation and neuronal cell death after DNA damage. These findings implicate Peg3/Pw1 as a mediator between p53 and Bax in a neuronal cell death pathway activated by DNA damage.