Complement activation as a biomarker for Alzheimer's disease

Aiyaz, Mohammed; Lupton, Michelle K.; Proitsi, Petroula; Powell, John; Lovestone, Simon

doi:10.1016/j.imbio.2011.07.023

Cited by 59 publications

(51 citation statements)

References 156 publications

(120 reference statements)

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“…TREM2 is a glycosylated innate immune receptor expressed on the plasma membrane by a subset of myeloid cells including immature dendritic cells, tissue macrophages, and myeloid-derived microglia and is an integral part of the evolutionarily ancient innate immune and complement signaling system [2,3]. Signaling through TREM2 or its adaptor protein TYROBP (also called DAP12) is known to play neuroprotective roles through the clearance of noxious cellular debris from within the CNS, the resolution of damage-associated inflammation, and the phagocytosis of pathogens, which is accompanied by the release of reactive oxygen species [2–6].…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms by which innate immune responses contribute to neuroinflammation and neurodegeneration remain incompletely understood. Microglial cells are a major resident myeloid-derived, TREM2-producing cell type in central nervous system (CNS) and are thought to fulfill important functions in immune surveillance, cell–cell interactions, tissue debris clearance, and the resolution of latent inflammatory reactions [3–7]. Absence of TREM2 expression on microglia not only impairs their capacity to phagocytose cellular debris but also increases their production of proinflammatory cytokines [4,6].…”

Section: Introductionmentioning

confidence: 99%

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Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a

Zhao¹,

Bhattacharjee²,

Jones³

et al. 2013

NeuroReport

108

126

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Genetic deficits and loss of function for the triggering receptor expressed in myeloid cells 2 (TREM2; encoded at chr6p21.1), a transmembrane spanning stimulatory receptor of the immunoglobulin/lectin-like gene superfamily, have been associated with deficiencies in phagocytosis and the innate immune system in Alzheimer’s disease. In this study, we provide evidence that TREM2 is downregulated in samples of sporadic Alzheimer hippocampal CA1 compared with age-matched controls. A nuclear factor-κB (NF-κB)-sensitive miRNA-34a (encoded at chr1p36.22), upregulated in Alzheimer’s disease, was found to target the 299 nucleotide human TREM2 mRNA 3′-untranslated region (3′-UTR) and downregulate the expression of a TREM2-3′-UTR reporter vector. A stabilized anti-miRNA-34a (AM-34a) quenched this pathogenic response. The results suggest that an epigenetic mechanism involving an NF-κB-mediated, miRNA-34a-regulated downregulation of TREM2 expression may shape innate immune and phagocytic responses that contribute to inflammatory neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a

Zhao¹,

Bhattacharjee²,

Jones³

et al. 2013

NeuroReport

108

126

View full text Add to dashboard Cite

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“…However, the downregulation of CD59 is also involved in the pathogenesis of many human diseases to different extents. Complement activation, such as by ␤-amyloid, plays an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer disease (24), and the degree of neuron damage has been positively correlated with the intensity of deposition of complement-activating products in plaques or tangles, especially SC5b-9; this phenomenon is most likely due to the undetectable expression of mCRPs, including CD59 (25,26). Therefore, it is reasonable to hypothesize that a CD59 deficiency may contribute to the pathogenesis of Alzheimer disease (27).…”

Section: Discussionmentioning

confidence: 99%

NF-κB and Enhancer-binding CREB Protein Scaffolded by CREB-binding Protein (CBP)/p300 Proteins Regulate CD59 Protein Expression to Protect Cells from Complement Attack

Teng

Wang

et al. 2014

Journal of Biological Chemistry

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Background: CD59 is the sole membrane complement regulatory protein in restricting membrane attack complex assembly. Results: CD59 gene produces eight transcripts that share three transcriptional initiation sites but the same open reading frame. Conclusion: NF-B and CREB (as an enhancer-binding protein) bridged by CBP/p300 are responsible for the inducible expression of CD59. Significance: CD59 regulation mechanism suggests potential drug targets for controlling various complement-related human diseases.

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“…CR1 is a multifunctional protein, which is widely expressed on the extracellular membrane of, B lymphocytes, monocytes, macrophages, erythrocytes, eosinophils, some CD4-positive T cells, dendritic cells, Langerhan cells in the skin glomerular podocytes and microglia as well (Crehan et al 2013;Klickstein et al 1988Klickstein et al , 1997Korotzer et al 1995;Liu and Niu 2009). CR1 has two isoforms: CR1-F and CR1-S, where the F means the ''fast'' isoform with a smaller molecular weight while the S refers to ''slow'' isoform (Aiyaz et al 2012). In addition, the expression of CR1-S isoform is lower than CR1-F in the brain of AD patients, compared with controls (Hazrati et al 2012).…”

Section: Complement Receptormentioning

confidence: 99%

“…1). Several interesting hypotheses have been proposed, for example, the deficiency in C3b-mediated clearance of neurotoxic Ab deposits from the brain and the potential beneficial effect through minimizing inflammation-mediated impairment of healthy neurons (Aiyaz et al 2012;Thambisetty et al 2013). …”

Section: Complement Receptormentioning

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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Complement activation as a biomarker for Alzheimer's disease

Cited by 59 publications

References 156 publications

Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a

Regulation of TREM2 expression by an NF-кB-sensitive miRNA-34a

NF-κB and Enhancer-binding CREB Protein Scaffolded by CREB-binding Protein (CBP)/p300 Proteins Regulate CD59 Protein Expression to Protect Cells from Complement Attack

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

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