Complement Component C1q Modulates the Phagocytosis of Aβ by Microglia

Webster, Scott D.; Yang, Austin J.; Margol, Larry; Garzon-Rodriguez, William; Glabe, Charles G.; Tenner, Andrea J.

doi:10.1006/exnr.1999.7260

Cited by 123 publications

(91 citation statements)

References 76 publications

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“…The association of the complement component C1q with A␤ was reported to inhibit microglial phagocytosis (Webster et al, 2000) or enhance uptake if immune complexes were present (Webster et al, 2001). Wyss-Coray et al (2002) have recently shed significant new light on this issue by demonstrating that there is a complement-dependent process that is responsible for removing A␤ deposits from the brain.…”

Section: Discussionmentioning

confidence: 99%

“…The present study has established that CD36 is also essential for stimulation of fA␤ phagocytosis by microglia. The microglial scavenger receptor A (SRA) has been shown previously to bind and participate in the internalization of fA␤ (Paresce et al, 1996;Webster et al, 2000). However, it does not appear to play an essential role in these events.…”

Section: Discussionmentioning

confidence: 99%

“…It remains unclear why the plaque-associated microglia in vivo are unable to effectively phagocytose the amyloid deposits despite their physical association with the plaques (Stalder et al, 2001). It is possible that other plaque constituents block the interaction of the microglia with the plaque, as has been suggested for C1q (Webster et al, 2000). We favor a model in which autocrine proinflammatory cytokine stimulation of the microglia acts to suppress activation of the phagocytic machinery and suggest that anti-inflammatory therapies may act to facilitate removal of fA␤ and ameliorate amyloid pathology in the AD brain.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Koenigsknecht

Landreth²

2004

J. Neurosci.

402

347

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Microglia are the principle immune effector and phagocytic cells in the CNS. These cells are associated with fibrillar ␤-amyloid (fA␤)-containing plaques found in the brains of Alzheimer's disease (AD) patients. The plaque-associated microglia undergo a phenotypic conversion into an activated phenotype and are responsible for the development of a focal inflammatory response that exacerbates and accelerates the disease process. Paradoxically, despite the presence of abundant activated microglia in the brain of AD patients, these cells fail to mount a phagocytic response to A␤ deposits but can efficiently phagocytose A␤ fibrils and plaques in vitro.We report that exposure of microglia to fA␤ in vitro induces phagocytosis through mechanisms distinct from those used by the classical phagocytic receptors, the Ig receptors (FcR␥I and Fc␥RIII) or complement receptors. Microglia interact with fA␤ through a recently characterized A␤ cell surface receptor complex comprising the B-class scavenger receptor CD36, ␣ 6 ␤ 1 integrin, and CD47 (integrin-associated protein). Antagonists specific for each component of the receptor complex blocks fA␤-stimulated phagocytosis. These data demonstrated that engagement of this ensemble of receptors is required for induction of phagocytosis. The phagocytic response stimulated by this receptor complex is driven principally by a ␤ 1 integrin-linked process that is morphologically and mechanistically distinct from the classical type I and type II phagocytic mechanisms. These data provide evidence for phagocytic uptake of fA␤ through a receptor-mediated, nonclassical phagocytic mechanism.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Koenigsknecht

Landreth²

2004

J. Neurosci.

402

347

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“…Two controversial roles of C1q have been reported: C1q enhances phagocytosis of Ab 41) and inhibits it. 42) 3.2.3. Chromogranin A Chromogranin A, a multifunctional protein, is localized in dystrophic neurites and in senile plaques.…”

Section: Complement Componentsmentioning

confidence: 99%

Regulating Factors for Microglial Activation.

Nakamura

2002

Biological & Pharmaceutical Bulletin

219

114

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“…Furthermore, several C1q-receptors have been identified that upon binding to isolated C1q result in responses, such as reactive oxygen species production by neutrophils (Guan et al, 1994;Goodman et al, 1995;Ruiz et al, 1999), enhancement of phagocytosis by monocytes, macrophages (Bobak et al, 1987) and microglial cells (Webster et al, 2000), and improvement of immunoglobulin production by B-lymphocytes Young et al, 1991).…”

Section: Introductionmentioning

confidence: 99%

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

Duvall

Tomlinson

Boackle

2008

Molecular Immunology

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We sought to specifically regulate the binding of human C1q, and thus the activation of the first complement component, via the construction of a single chain antibody variable binding region fragment (scFv) targeting the C1q globular heads. Here we describe details of the construction, expression and evaluation of this scFv, which was derived from a high affinity hybridoma (Qu) specific for the C1q globular heads. The scFv was comprised of the Qu variable-heavy chain domain (VH) linked to the Qu variable-light chain domain (VL) and was termed scFv-QuVHVL. When mixed with either purified C1q or with human serum as a source of C1, scFv-QuVHVL bound to C1q and competitively restricted the interaction of C1q or C1 with immobilized IgG or with IgG1 antibody-coated cells, and prevented the activation of native C1 in human serum as determined by analyses of C1-mediated C4 deposition and fluid phase C4 conversion. However scFv-QuVHVL could be manipulated to become a C1 activator when it was irreversibly immobilized onto microtiter ELISA plates, prior to contact with human serum complement. This functional dichotomy can be a useful tool in selectively elucidating, differentiating, inducing or inhibiting specific roles of human C1q and the classical complement pathway in complement-mediated physiological processes. We project that once fully humanized, fluid phase scFv-QuVHVL could become a useful therapeutic in limiting inadvertent host tissue damage elicited by the classical complement pathway.

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Complement Component C1q Modulates the Phagocytosis of Aβ by Microglia

Cited by 123 publications

References 76 publications

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Regulating Factors for Microglial Activation.

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

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Complement Component C1q Modulates the Phagocytosis of Aβ by Microglia

Cited by 123 publications

References 76 publications

Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism

Microglial Phagocytosis of Fibrillar β-Amyloid through a β1Integrin-Dependent Mechanism

Regulating Factors for Microglial Activation.

Highly specific inhibition of C1q globular-head binding to human IgG: A novel approach to control and regulate the classical complement pathway using an engineered single chain antibody variable fragment

Contact Info

Product

Resources

About

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism

Microglial Phagocytosis of Fibrillar β-Amyloid through a β₁Integrin-Dependent Mechanism