Complement-dependent Proinflammatory Properties of the Alzheimer's Disease β-Peptide

Bradt, Bonnie M.; Kolb, William P.; Cooper, Neil R.

doi:10.1084/jem.188.3.431

Cited by 240 publications

(213 citation statements)

References 33 publications

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“…Although secretion of C1q and C5 could not be demonstrated, since other cells in the microvascular environment, including macrophages/microglia, can secrete these proteins (Walker, 1998, unpublished data), there is the potential for all complement proteins to be produced in the localized microvascular environment. The strongly increased secretion of C3 by HCSMC following Aβ stimulation is of significance as this is a pivotal protein in both the classical and alternative activation pathways of the complement cascade (Bradt et al, 1998). Markers for complement activation have now been found in many neurodegenerative diseases or where brain injury has occurred (Barnum, 2002;van Beek et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Aβ peptide can activate the classical complement pathway by binding C1q in the absence of specific antibodies (Rogers et al, 1992;Webster et al, 1997), as well as activating the alternative complement pathway in the absence of C1q (Bergamaschini et al, 1999;Bradt et al, 1998). Studies have shown localized expression of different complement mRNAs within the brain (Johnson et al, 1992;Walker and McGeer, 1992), with significant increases of complement mRNA expression in brain regions selectively affected by AD (Yasojima et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Walker

Dalsing-Hernandez

Lue

2008

Microvascular Research

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Deposition of amyloid around blood vessels, known as cerebral amyloid angiopathy (CAA), is a major pathological feature found in the majority of Alzheimer's disease (AD) cases, and activated complement fragments have been detected on CAA deposits in AD brains. In this study, we demonstrate for the first time that human cerebrovascular smooth muscle cells (HCSMC) isolated from cortical vessels derived from postmortem brains can express mRNAs for complement genes C1qB, C1r, C1s, C2, C3, C4, C5, C6, C7, C8 and C9, the components of the classical complement pathway. Secretion of the corresponding complement proteins for these genes was also demonstrated, except for C1q and C5. Of particular significance was the observation that treatment of HCSMC with aggregated amyloid beta (Aβ)1-42 increased expression of complement C3 mRNA and increased release of C3 protein. Aβ treatment of HCSMC also increased expression of C6 mRNA. Interferon-γ induced expression and release of complement C1r, C1s, C2 and C4. As HCSMC are closely associated with Aβ deposits in vessels in the brain, their production of complement proteins could amplify the proinflammatory effects of amyloid in the perivascular environment, further compromising brain vascular integrity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Walker

Dalsing-Hernandez

Lue

2008

Microvascular Research

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“…One common disease exemplifying this idea is Alzheimer's disease, in which the accumulation of extracellular A␤ peptide contributes to the pathogenesis (Hardy and Selkoe, 2002). Aggregated A␤ peptide can activate both the classical and alternative complement cascades in vitro by binding C1q and C3b, respectively (Jiang et al, 1994;Bradt et al, 1998); this is likely to be the trigger of sequential activation of these pathways, resulting in the formation of C5b, the initial component of the membrane attack pathway, thereby leading to the deposition of the MAC evident in Alzheimer's disease brains (McGeer et al, 1989;Itagaki et al, 1994;Webster et al, 1997;Yasojima et al, 1999). Interestingly, the binding of A␤ peptide by C3b likely promotes its phagocytosis and removal, because the transgenic overexpression of an inhibitor of C3b formation increases A␤ peptide accumulation in mice expressing the human amyloid precursor protein (WyssCoray et al, 2002); importantly, the increased A␤ peptide deposition is accompanied by enhanced neurodegeneration in these mice (Wyss-Coray et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration

et al. 2003

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The complement system consists of Ͼ30 proteins that interact in a carefully regulated manner to destroy invading bacteria and prevent the deposition of immune complexes in normal tissue. This complex system can be activated by diverse mechanisms proceeding through distinct pathways, yet all converge on a final common pathway in which five proteins assemble into a multimolecular complex, the membrane attack complex (MAC). The MAC inserts into cell membranes to form a functional pore, resulting in ion flux and ultimately osmotic lysis. Immunohistochemical evidence of the MAC decorating neurons in cortical gray matter has been identified in multiple CNS diseases, yet the deleterious consequences, if any, of MAC deposition in the cortex of mammalian brain in vivo are unknown. Here we demonstrate that the sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioral and electrographic seizures as well as cytotoxicity. The onset of seizures occurred during or shortly after the infusion of C8/C9. Neither seizures nor cytotoxicity resulted from the simultaneous infusion of all five proteins premixed in vitro. The requirement for the sequential infusion of all five proteins together with the temporal relationship of seizure onset to infusions of C8/C9 implies that the MAC was formed in vivo and triggered both seizures and cytotoxicity. Deposition of the complement MAC in cortical gray matter may contribute to epileptic seizures and cell death in diverse diseases of the human brain.

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“…The immune system also appears to participate in AD pathogenesis (7)(8)(9)(10)(11). Moreover, immune-based strategies have been shown to be effective in clearing A␤ from the brains of APP transgenic (Tg) mice (12)(13)(14)(15).…”

mentioning

confidence: 99%

Immune hyporesponsiveness to amyloid β-peptide in amyloid precursor protein transgenic mice: Implications for the pathogenesis and treatment of Alzheimer's disease

Monsonego

Maron

Zota

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

163

112

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Alzheimer's disease is a dementia that involves progressive deposition of amyloid ␤-protein (A␤) in brain regions important for memory and cognition, followed by secondary inflammation that contributes to the neuropathologic process. Immunization with A␤ can reduce cerebral A␤ burden and consequent neuropathologic changes in the brains of mice transgenic for the ␤-amyloid precursor protein (APP). We found that transgenic expression of human APP in B6SJL mice, under the prion promoter, results in immune hyporesponsiveness to human A␤, in terms of both antibody and cellular immune responses. The decreased antibody responses were related not to B cell tolerance but rather to the inability of A␤-specific T cells to provide help for antibody production. The immune hyporesponsiveness could be overcome if T cell help was provided by coupling an A␤ B cell epitope to BSA. Our results suggest that expression of APP in transgenic mice is associated with an A␤-specific impaired adaptive immune response that may contribute to the neuropathology. Moreover, humans with lifelong elevation of brain and peripheral A␤ (e.g., patients with presenilin mutations or Down syndrome) could have reduced immune responses to A␤ vaccination. A lzheimer's disease (AD) is a highly prevalent dementia that is associated with the abnormal accumulation and aggregation of amyloid ␤-peptide (A␤), a process that precedes neuronal injury (reviewed in ref. 1). Accumulating evidence suggests that aggregated forms of A␤ extracellularly, and perhaps also intracellularly, have neurotoxic properties (1-4). Moreover, the autosomal dominant familial forms of AD involve mutations in the genes encoding ␤-amyloid precursor protein (APP), presenilin 1 (PS1), or PS2, and these mutations all cause increased production and accumulation of A␤, a process that begins many years before clinical symptoms (1). A␤ is also overproduced in trisomy 21 (Down syndrome) patients, who overexpress APP from birth, thus making them more susceptible to AD (5, 6). Although there are numerous unresolved issues regarding the molecular and cellular cytotoxic events mediating AD, it is likely that A␤ plays a very early and central role in both the inherited and sporadic forms of the disease.The immune system also appears to participate in AD pathogenesis (7-11). Moreover, immune-based strategies have been shown to be effective in clearing A␤ from the brains of APP transgenic (Tg) mice (12-15). A␤ deposition causes activation of microglia and astrocytes at sites of its accumulation, followed by the induction of an inflammatory response (9,10,16). This inflammatory response may represent in part an attempt by the immune system to clear excess amounts of A␤. The proinflammatory environment in the brain may become chronic probably because of progressive accumulation of A␤ and its aggregation into forms that are less efficiently cleared and͞or more cytotoxic to neurons (7, 10). We hypothesized that chronic exposure of the immune system to A␤ in humans and mouse models might lead to hyporespons...

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Complement-dependent Proinflammatory Properties of the Alzheimer's Disease β-Peptide

Cited by 240 publications

References 33 publications

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Human postmortem brain-derived cerebrovascular smooth muscle cells express all genes of the classical complement pathway: A potential mechanism for vascular damage in cerebral amyloid angiopathy and Alzheimer's disease

Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration

Immune hyporesponsiveness to amyloid β-peptide in amyloid precursor protein transgenic mice: Implications for the pathogenesis and treatment of Alzheimer's disease

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