Complement C1q and C3 mRNA expression in the frontal cortex of Alzheimer's patients

Fischer, Barbara; Schmoll, Harald; Riederer, Peter; Bauer, Joachim; Platt, D.; Popa‐Wagner, Aurel

doi:10.1007/bf00202265

Cited by 65 publications

(42 citation statements)

References 51 publications

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“…However, both neurons and glia have been reported to express complement proteins, leaving unclear which cell types mediate specific aspects of the complement response (Fischer et al, 1995;Shen et al, 1997;Walker et al, 1998;Lue et al, 2001). Using in situ hybridization and immunofluorescence staining, we show here that under physiological conditions, C3 is primarily expressed in astrocytes where its expression is further upregulated in APP/PS1 (Tg) and APP/TTA mice.…”

Section: Discussionmentioning

confidence: 60%

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

Lian¹,

Litvinchuk²,

Chiang³

et al. 2016

J. Neurosci.

459

373

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Increasing evidence supports a role of neuroinflammation in the pathogenesis of Alzheimer's disease (AD). Previously, we identified a neuron-glia signaling pathway whereby A␤ acts as an upstream activator of astroglial nuclear factor kappa B (NF-B), 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 A␤ 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 A␤ pathology and neuroinflammation in amyloid precursor protein (APP) transgenic mice are worsened by astroglial NF-B 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 A␤ activates astroglial NF-B 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 A␤ phagocytosis. This feedforward loop can be effectively blocked by C3aR inhibition, supporting the therapeutic potential of C3aR antagonists under chronic neuroinflammation conditions.

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Section: Discussionmentioning

confidence: 60%

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

Lian¹,

Litvinchuk²,

Chiang³

et al. 2016

J. Neurosci.

459

373

View full text Add to dashboard Cite

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“…6,8,9,20,21 Cells in the central nervous system (CNS) are capable of synthesizing a complete set of complement components and upregulating this production in response to injury. [22][23][24][25] Additionally, it has been demonstrated that complement activation has deleterious proinflammatory effects in other CNS processes, such as Alzheimer disease. 26 -30 Finally, neurons in vitro are highly susceptible to complement-mediated lysis, leading to the hypothesis that complement can cause neuronal death through membrane attack complex (MAC) deposition.…”

Section: Discussionmentioning

confidence: 99%

Complement Component C3 Mediates Inflammatory Injury Following Focal Cerebral Ischemia

Mocco

Mack

Ducruet

et al. 2006

Circulation Research

204

226

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Abstract-The complement cascade has been implicated in ischemia/reperfusion injury, and recent studies have shown that complement inhibition is a promising treatment option for acute stroke. The development of clinically useful therapies has been hindered, however, by insufficient understanding of which complement subcomponents contribute to post-ischemic injury. To address this issue, we subjected mice deficient in selected complement proteins (C1q, C3, C5) to transient focal cerebral ischemia. Of the strains investigated, only C3 Ϫ/Ϫ mice were protected, as demonstrated by 34% reductions in both infarct volume (PϽ0.01) and neurological deficit score (PϽ0.05). C3-deficient mice also manifested decreased granulocyte infiltration (PϽ0.02) and reduced oxidative stress (PϽ0.05). Finally, administration of a C3a-receptor antagonist resulted in commensurate neurological improvement and stroke volume reduction (PϽ0.05). Together, these results establish C3 activation as the key constituent in complement-related inflammatory tissue injury following stroke and suggest a C3a anaphylatoxin-mediated mechanism. (Circ Res. 2006;99:209-217.)

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“…In fact, there is evidence that in the course of cerebrovascular disease and Alzheimer's disease, serum proteins like Ig, fibrinogen, and complement factors are deposited in the brain parenchyma (41). Although there is accumulating evidence for enhanced cerebral biosynthesis of C1q in Alzheimer's disease brain, based on Northern blot, RT-PCR, and Western blot results, the issue of neuronal vs nonneuronal biosynthesis of C1q in normal human brains and in Alzheimer's disease brains is still controversial (2,5,7,8,41,42). Likewise, in experimental studies of different types of inflammatory and neurodegenerative brain lesions, the neuronal vs nonneuronal biosynthesis of C1q is a matter of controversy (21, 22, 24 -27).…”

Section: Discussionmentioning

confidence: 99%

Complement C1q Is Dramatically Up-Regulated in Brain Microglia in Response to Transient Global Cerebral Ischemia

Schäfer

Schwaeble

Post

et al. 2000

The Journal of Immunology

150

108

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Recent evidence suggests that the pathophysiology of neurodegenerative and inflammatory neurological diseases has a neuroimmunological component involving complement, an innate humoral immune defense system. The present study demonstrates the effects of experimentally induced global ischemia on the biosynthesis of C1q, the recognition subcomponent of the classical complement activation pathway, in the CNS. Using semiquantitative in situ hybridization, immunohistochemistry, and confocal laser scanning microscopy, a dramatic and widespread increase of C1q biosynthesis in rat brain microglia (but not in astrocytes or neurons) within 24 h after the ischemic insult was observed. A marked increase of C1q functional activity in cerebrospinal fluid taken 1, 24, and 72 h after the ischemic insult was determined by C1q-dependent hemolytic assay. In the light of the well-established role of complement and complement activation products in the initiation and maintenance of inflammation, the ischemia-induced increase of cerebral C1q biosynthesis and of C1q functional activity in the cerebrospinal fluid implies that the proinflammatory activities of locally produced complement are likely to contribute to the pathophysiology of cerebral ischemia. Pharmacological modulation of complement activation in the brain may be a therapeutic target in the treatment of stroke.

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Complement C1q and C3 mRNA expression in the frontal cortex of Alzheimer's patients

Cited by 65 publications

References 51 publications

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

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

Complement Component C3 Mediates Inflammatory Injury Following Focal Cerebral Ischemia

Complement C1q Is Dramatically Up-Regulated in Brain Microglia in Response to Transient Global Cerebral Ischemia

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