High Levels of Circulating Aβ42 Are Sequestered by Plasma Proteins in Alzheimer's Disease

Kuo, Yu Min; Emmerling, Mark R.; Lampert, Heather C.; Hempelman, Stephen R.; Kokjohn, Tyler A.; Woods, Amina S.; Cotter, Robert J.; Roher, Alex E.

doi:10.1006/bbrc.1999.0552

Cited by 175 publications

(140 citation statements)

References 28 publications

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“…The results presented in this study show that A␤ peptides (A␤ and A␤ ) at physiological concentrations, as found in the plasma of AD individuals (8), initiate cellular signaling in THP-1 monocytes and peripheral blood monocytes (PBM) to increase the gene expression of specific cytokines (TNF-␣ and IL-1␤) and chemokines (monocyte chemoattractant protein-1 ((MCP-1), IL-8, and macrophage inflammatory protein-1␤ (MIP-1␤)). The cellular signaling involves activation of tyrosine kinase and extracellular signal-regulated kinase (ERK-1 and ERK-2), but not of p38 mitogen-activated protein kinase (MAPK).…”

supporting

confidence: 53%

“…Studies showed that interaction of fibrillar A␤ at micromolar concentrations (10 -40 M) with either microglial cells or THP-1 monocytes, pretreated with LPS, elicited similar responses and resulted in increased secretion of TNF-␣, IL-6, IL-8, and MIP-1␤ (28). However, the amounts of circulating amyloid peptides in plasma of AD subjects have been observed to be in the submicromolar range (8), thus suggesting that studies should be undertaken at these physiological concentrations.…”

Section: Discussionmentioning

confidence: 99%

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Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

Giri

Selvaraj

Kalra

2003

The Journal of Immunology

107

138

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In Alzheimer’s disease (AD) one finds increased deposition of Aβ and also an increased presence of monocytes/macrophages in the vessel wall and activated microglial cells in the brain. AD patients show increased levels of proinflammatory cytokines by activated microglia. Here we used a human monocytic THP-1 cell line as a model for microglia to delineate the cellular signaling mechanism involved in amyloid peptides (Aβ1–40 and Aβ1–42)-induced expression of inflammatory cytokines and chemokines. We observed that Aβ peptides at physiological concentrations (125 nM) increased mRNA expression of cytokines (TNF-α, and IL-1β) and chemokines (monocyte chemoattractant protein-1 (MCP-1), IL-8, and macrophage inflammatory protein-1β (MIP-1β)). The cellular signaling involved activation of c-Raf, extracellular signal-regulated kinase-1 (ERK-1)/ERK-2, and c-Jun N-terminal kinase, but not p38 mitogen-activated protein kinase. This is further supported by the data showing that Aβ causes phosphorylation of ERK-1/ERK-2, which, in turn, activates Elk-1. Furthermore, Aβ mediated a time-dependent increase in DNA binding activity of early growth response-1 (Egr-1) and AP-1, but not of NF-κB and CREB. Moreover, Aβ-induced Egr-1 DNA binding activity was reduced >60% in THP-1 cells transfected with small interfering RNA duplexes for Egr-1 mRNA. We show that Aβ-induced expression of TNF-α, IL-1β, MCP-1, IL-8, and MIP-1β was abrogated in Egr-1 small inhibitory RNA-transfected cells. Our results indicate that Aβ-induced expression of cytokines (TNF-α and IL-1β) and chemokines (MCP-1, IL-8, and MIP-1β) in THP-1 monocytes involves activation of ERK-1/ERK-2 and downstream activation of Egr-1. The inhibition of Egr-1 by Egr-1 small inhibitory RNA may represent a potential therapeutic target to ameliorate the inflammation and progression of AD.

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supporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

Giri

Selvaraj

Kalra

2003

The Journal of Immunology

107

138

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“…125,130 This ability to interact with a variety of molecules presents a difficulty when attempting to measure Ab levels in biological fluids as the antigenic epitopes may be masked by these bound molecules. 131,132 The interaction of Ab with these binding proteins has been shown to modulate the formation of Ab fibrils 127,128,130 and the binding of Ab complexes to the LRP-1 receptor. Therefore, plasma Ab-binding proteins may have a dual function by reducing the formation of toxic oligomers and fibrils and by enhancing the clearance and degradation of Ab peptides through LRP-1-mediated endocytosis.…”

Section: Ab-binding Proteins In Blood Plasmamentioning

confidence: 99%

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

et al. 2008

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Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

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“…The higher concentration of soluble A␤ accumulates over time in the brain extracellular space, polymerizes into insoluble fibrils, and eventually forms amyloid plaques (Craft et al, 2002;Cirrito et al, 2003). Studies in AD patients indicated increased levels of peripherally circulating A␤ (Kuo et al, 1999;Matsubara et al, 1999). DeMattos et al (2002) suggested that A␤ in plasma and CSF exist in equilibrium, which is controlled by a novel, yet unknown mechanism that shifts toward the brain during plaque development.…”

mentioning

confidence: 99%

Pharmacokinetic Analysis of the Blood-Brain Barrier Transport of¹²⁵I-Amyloid β Protein 40 in Wild-Type and Alzheimer's Disease Transgenic Mice (APP,PS1) and Its Implications for Amyloid Plaque Formation

Kandimalla¹,

Curran²,

Holasek³

et al. 2005

J Pharmacol Exp Ther

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Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid ␤ (A␤) proteins such as A␤40. The relationship between A␤40 pharmacokinetics and its accumulation within and clearance from the brain in both wild-type (WT) and AD transgenic mice (APP,PS1) was studied to understand the mechanism of amyloid plaque formation and the potential use of A␤40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the 125 I-A␤40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The 125 I-A␤40 was significantly metabolized in the liver kidney Ͼ spleen. Coadministration of exogenous A␤40 inhibited the plasma clearance and the uptake of 125 I-A␤40 at the bloodbrain barrier (BBB) in WT animals but did not affect its elimination from the brain. The 125 I-A␤40 was shown to be metabolized within and effluxed from the brain parenchyma. The rate of efflux from APP,PS1 brain slices was substantially lower compared with WT brain slices. Since the A␤40 receptor at the BBB can be easily saturated, the blood-to-brain transport of A␤40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of A␤40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP,PS1 mice. Furthermore, inadequate targeting of A␤40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of A␤40 transporter at the BBB and its metabolism and efflux from the brain.

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High Levels of Circulating Aβ42 Are Sequestered by Plasma Proteins in Alzheimer's Disease

Cited by 175 publications

References 28 publications

Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Pharmacokinetic Analysis of the Blood-Brain Barrier Transport of¹²⁵I-Amyloid β Protein 40 in Wild-Type and Alzheimer's Disease Transgenic Mice (APP,PS1) and Its Implications for Amyloid Plaque Formation

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High Levels of Circulating Aβ42 Are Sequestered by Plasma Proteins in Alzheimer's Disease

Cited by 175 publications

References 28 publications

Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

Amyloid Peptide-Induced Cytokine and Chemokine Expression in THP-1 Monocytes Is Blocked by Small Inhibitory RNA Duplexes for Early Growth Response-1 Messenger RNA

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Pharmacokinetic Analysis of the Blood-Brain Barrier Transport of125I-Amyloid β Protein 40 in Wild-Type and Alzheimer's Disease Transgenic Mice (APP,PS1) and Its Implications for Amyloid Plaque Formation

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Pharmacokinetic Analysis of the Blood-Brain Barrier Transport of¹²⁵I-Amyloid β Protein 40 in Wild-Type and Alzheimer's Disease Transgenic Mice (APP,PS1) and Its Implications for Amyloid Plaque Formation