Complement activation by neurofibrillary tangles in Alzheimer's disease

Shen, Yong; Lue, Lih Fen; Yang, Li; Roher, Alex E.; Kuo, Yu Min; Strohmeyer, Ron; Goux, Warren J.; Lee, Virginia; Johnson, Gail V.W.; Webster, Scott D.; Cooper, Neil R.; Bradt, Bonnie M.; Rogers, Joseph

doi:10.1016/s0304-3940(01)01842-0

Cited by 158 publications

(125 citation statements)

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“…Complement activation has been considered to be positively involved in the progress of these diseases. In amyloid plaques and neurofibrill tangles, C1q and other components are deposited (14,15), leading to complement activation. mRNAs of complement components are largely increased at the diseased regions (16,25).…”

Section: Discussionmentioning

confidence: 99%

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Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Ohmi¹,

Tajima

Ohkawa³

et al. 2009

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

124

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Gangliosides are considered to be essential in the maintenance and repair of nervous tissues; however, the mechanisms for neurodegeneration caused by ganglioside defects are unknown. We examined gene expression profiles in double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase genes and showed that the majority of complement genes and their receptors were up-regulated in cerebellum in DKO mice. Inflammatory reactions were demonstrated in those tissues by measuring up-regulated inflammatory cytokines, indicating the presence of complement activation and inflammation as reported in Alzheimer's disease. Immunoblotting of fractionated membrane extracts by sucrose density gradient revealed that complement-regulatory molecules such as decay-accelerating factor and CD59 were dispersed from glycolipid-enriched microdomain/rafts in DKO cerebellum. Immunohistostaining of these molecules showed disordered membrane localization. These results suggested that dysfunction of complement-regulatory molecules may be due to abnormal glycolipid-enriched microdomain/rafts that triggered complement activation, subsequent inflammation, and neurodegeneration in DKO mice. Generation of the triple KO mice lacking complement activity in addition to the two glycosyltransferases suggested that complement activation is involved in the inflammatory reactions and neurodegeneration caused by the ganglioside deficiency.cerebellum ͉ degeneration ͉ inflammation ͉ knockout ͉ lipid raft

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Section: Discussionmentioning

confidence: 99%

“…All components of the classical complement pathway have been identified in neurons (13), and this pathway has been reported to be activated in AD by fibrillar ␤ amyloid peptide (14) or neurofibrillary tangles (15). The detection and activation of the alternative pathway in AD has also been reported (16).…”

mentioning

confidence: 99%

Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Ohmi¹,

Tajima

Ohkawa³

et al. 2009

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

124

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“…The abnormality of the complement system has been reported in brain injury and neurodegenerative disease (D'Ambrosio et al 2001;Gasque 2004), including AD. In the brain of AD patient, it has been observed that the expression of C1q, C3b, C4d and C5b-9 is elevated, and the MAC colocalizes with senile plaques and tangle-positive neurons (Blalock et al 2004;Fonseca et al 2004;Katsel et al 2009;Shen et al 2001). In addition, in the microvasculature, microglia are reported to surround the fibrillar Ab deposits (Fan et al 2007).…”

Section: Neuronmentioning

confidence: 99%

“…In vitro studies demonstrated that Ab aggregates activated the complement system by binding C1q or C3b (Jiang et al 1994;Rogers et al 1992). Neurofibrillary tangles or aggregated tau were also observed to activate the classical pathway (Shen et al 2001). In conclusion, both of Ab and tau in AD can activate the complement system.…”

Section: Neuronmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

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“…Activation of the complement system in AD and in brains affected by other neurodegenerative diseases has been extensively characterized (Gasque et al, 2002;McGeer and McGeer, 2002;van Beek et al, 2003). Aβ plaques and other hallmark features of AD, including vascular amyloid deposits, are tagged with different complement fragments, indicating that the complement system is activated in the AD brain (McGeer et al, 1989;Rogers et al, 1992;Shen et al, 2001;Veerhuis et al, 1996). The presence of activated complement protein fragments C1q, C3c, C4d and C5b-9 on cerebrovascular-associated amyloid in AD brains has been observed (Verbeek et al, 1998), though the source of these proteins was not determined.…”

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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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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Complement activation by neurofibrillary tangles in Alzheimer's disease

Cited by 158 publications

References 11 publications

Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

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

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