Amyloid β<sub>42</sub>Activates a G-Protein-Coupled Chemoattractant Receptor, FPR-Like-1

Le, Yingying; Gong, Wanghua; Tiffany, H. Lee; Tumanov, Alexei V.; Nedospasov, Sergei A.; Shen, Weiping; Dunlop, Nancy M.; Gao, Ji-Liang; Murphy, Philip M.; Oppenheim, Joost J.; Wang, Ji Ming

doi:10.1523/jneurosci.21-02-j0003.2001

Cited by 253 publications

(240 citation statements)

References 39 publications

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“…2). Other findings suggest that Aβ can promote Ca 2+ influx by forming channels in membranes or by activating cell surface receptors coupled to calcium influx 26,28 .…”

Section: Uncontrollable Calciummentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,712

2,045

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Slowly, but surely, Alzheimer's disease (AD) patients lose their memory, their cognitive abilities and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. While drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise is increasing optimism that effective preventative and therapeutic strategies are in the offing.Alzheimer's disease (AD) is a neurodegenerative disorder that currently affects nearly 2% of the population in industrialized countries; the risk of AD dramatically increases in individuals beyond the age of 70 and it is predicted that the incidence of AD will triple within the next 50 years (www.alz.org). There can be other causes of memory loss and definitive diagnosis of AD therefore requires postmortem examination of the brain, which must contain sufficient numbers of "plaques" and "tangles" to qualify as AD 1, 2 . Plaques are extracellular deposits of fibrils and amorphous aggregates of amyloid β-peptide (Aβ); diffuse deposits of Aβ are also present in high amounts. Neurofibrillary tangles are intracellular fibrillar aggregates of the microtubule-associated protein tau which exhibit hyperphosphorylation and oxidative modifications. Plaques and tangles are present mainly in brain regions involved in learning and memory and emotional behaviors such as the entorhinal cortex, hippocampus, basal forebrain and amygdala. Brain regions with plaques typically exhibit reduced numbers of synapses, and neurites associated with the plaques are often damaged, suggesting that Aβ damages synapses and neurites. Neurons that employ glutamate or acetylcholine as neurotransmitters appear to be particularly affected, but neurons that produce serotonin and norepinephrine are also damaged. This review focuses on the molecular and cellular abnormalities that occur in the brain in AD, how they result in synaptic dysfunction and cell death, and how they can be counteracted. Central to the disease is altered proteolytic processing of the amyloid precursor protein (APP) resulting in the production and aggregation of neurotoxic forms of Aβ. Neurons that degenerate in AD exhibit increased oxidative damage, impaired energy metabolism and perturbed cellular calcium homeostasis; Aβ appears to be an important instigator of these abnormalities. Genetic and environmental factors can determine one's risk for and an understanding of these risk factors and how they modify the amyloid cascade is leading to the development of interventions for the prevention and treatment of AD that range from changes in diet and lifestyle, to vaccines and drugs.

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“…2). Other findings suggest that Aβ can promote Ca 2+ influx by forming channels in membranes or by activating cell surface receptors coupled to calcium influx 26,28 .…”

Section: Uncontrollable Calciummentioning

confidence: 99%

Pathways towards and away from Alzheimer's disease

Mattson

2004

Nature

2,712

2,045

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“…2C). In contrast, RBL-2H3 and RBL-2H3/ETFR cell response to fibronectin (Fn) [16] was not prevented by pERERY-NH 2 (Fig. 2C).…”

Section: Perery-nh 2 Antagonizes Fpr Signallingmentioning

confidence: 91%

“…Human Embryonic Kidney HEK-293, Rat Basophilic Leukemia RBL-2H3, and RBL-2H3/ETFR [16] cells were grown in DMEM supplemented with 10% FBS, 100 IU/ml penicillin and 50 lg/ml streptomycin.…”

Section: Cell Culturesmentioning

confidence: 99%

“…A likely possibility is that pER-ERY-NH 2 recognizes FPR which is constitutively expressed by HEK-293 cells [14]. To study the role of FPR, we took advantage of RBL-2H3 cells which are devoid of FPR and RBL-2H3/ETFR which stably express FPR [16]. In a migration assay toward N-formyl-Met-Leu-Phe (fMLF), we found that pERERY-NH 2 inhibits RBL-2H3/ETFR cell migration in a dose-dependent manner (Fig.…”

Section: Perery-nh 2 Antagonizes Fpr Signallingmentioning

confidence: 99%

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An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor

et al. 2008

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Urokinase receptor (uPAR) plays a key role in physiological and pathological processes sustained by an altered cell migration. We have developed peptides carrying amino acid substitutions along the Ser 88 -Arg-Ser-Arg-Tyr 92 (SRSRY) uPAR chemotactic sequence. The peptide pyro glutamic acid (pGlu)-Arg-Glu-Arg-Tyr-NH2 (pERERY-NH 2 ) shares the same binding site with SRSRY and competes with N-formyl-Met-LeuPhe (fMLF) for binding to the G-protein-coupled N-formylpeptide receptor (FPR). pERERY-NH 2 is a dose-dependent inhibitor of both SRSRY-and fMLF-directed cell migration, and prevents agonist-induced FPR internalization and fMLFdependent ERK1/2 phosphorylation. pERERY-NH 2 is a new and potent uPAR inhibitor which may suggest the generation of new pharmacological treatments for pathological conditions involving increased cell migration.

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“…Binding of FPRL1 by the agonists results in a cascade of G protein -mediated signaling events leading to chemotaxis, phagocytic cell adhesion, enhanced phagocytosis, release of oxygen intermediate, bacterial killing, mitogen-activated protein kinase activation, and gene transcription (7). As more FPRL1 binding partners were recently identified, additional roles of FPRL1 have been proposed, involving FPRL1 in the host defense against pathogenic infection, in the clearance of damaged cells, as well as in various diseases such as amyloidosis, Alzheimer's disease, prion disease, and AIDS (2,8,9). However, the molecular mechanisms of the involvement of FPRL1 in physiologic processes remain to be clarified.…”

Section: Introductionmentioning

confidence: 99%

Formyl peptide receptor-like 1–mediated endogenousTRAILgene expression with tumoricidal activity

Lin¹,

Wei²,

Zhang³

et al. 2007

Molecular Cancer Therapeutics

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Formyl peptide receptor-like 1 (FPRL1), which is a G protein -coupled receptor of chemoattractant subfamily, plays an important role in the regulation of host defense against pathogenic infection and the chemotactic and activating effects of AB 42 on mononuclear phagocytes as well as in the elimination of damaged or pathogen-infected cells. In the present study, we showed that stimulation of FPRL1 agonist ligands (W peptide from a synthetic peptide library, N36 peptide from HIV-1 gp41, and F peptide from HIV-1 envelope protein gp120) elevated endogenous tumor necrosis factor -related apoptosis-inducing ligand (TRAIL) expression in human THP-1 monocytes, primary neutrophils, and mouse leukocytes. Activation of nuclear factor KB was required by the FPRL1-mediated TRAIL expression in the human THP-1 cells and primary neutrophils. The increased TRAIL expression in the mice significantly suppressed the growth of transplanted mouse liver tumor cells by inducing apoptotic cell death. Together, these data provide novel evidence for the physiologic role of FPRL1 and TRAIL in tumor immune surveillance and innate immunity, and implicate a novel strategy for cancer therapy by triggering the endogenous TRAIL expression via stimulation of G protein -coupled receptor FPRL1. [Mol Cancer Ther 2007;6(10):2618 -25]

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Amyloid β₄₂Activates a G-Protein-Coupled Chemoattractant Receptor, FPR-Like-1

Cited by 253 publications

References 39 publications

Pathways towards and away from Alzheimer's disease

Pathways towards and away from Alzheimer's disease

An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor

Formyl peptide receptor-like 1–mediated endogenousTRAILgene expression with tumoricidal activity

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Amyloid β42Activates a G-Protein-Coupled Chemoattractant Receptor, FPR-Like-1

Cited by 253 publications

References 39 publications

Pathways towards and away from Alzheimer's disease

Pathways towards and away from Alzheimer's disease

An urokinase receptor antagonist that inhibits cell migration by blocking the formyl peptide receptor

Formyl peptide receptor-like 1–mediated endogenousTRAILgene expression with tumoricidal activity

Contact Info

Product

Resources

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Amyloid β₄₂Activates a G-Protein-Coupled Chemoattractant Receptor, FPR-Like-1