alexa Increased IRAK-4 Kinase Activity in Alzheimerand#8217;s Disease; IRAK-1/4 Inhibitor I Prevents Pro-inflammatory Cytokine Secretion but not the Uptake of Amyloid Beta by Primary Human Glia | Abstract
ISSN: 2155-9899

Journal of Clinical & Cellular Immunology
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Research Article

Increased IRAK-4 Kinase Activity in Alzheimer’s Disease; IRAK-1/4 Inhibitor I Prevents Pro-inflammatory Cytokine Secretion but not the Uptake of Amyloid Beta by Primary Human Glia

Jeroen J.M. Hoozemans1*, Elise S. van Haastert1, Sandra D. Mulder2, Henrietta M. Nielsen1,2,4, Robert Veerhuis2,3, Rob Ruijtenbeek5,
Annemieke J.M. Rozemuller1, Riet Hilhorst5, and Saskia M. van der Vies1
1Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
2Department of Clinical Chemistry, Neurology and Alzheimer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
3Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
4Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, USA
5PamGene International BV, ‘s Hertogenbosch, The Netherlands
Corresponding Author : Jeroen J.M. Hoozemans
Department of Pathology, VU University Medical Center
P.O. Box 7057, 1007 MB Amsterdam, The Netherlands
Tel: 31-20-4444910
Fax: 31-20-4442964
E-mail: [email protected]
Received May 11, 2014; Accepted July 29, 2014; Published August 05, 2014
Citation: Hoozemans JJM, van Haastert ES, Mulder SD, Nielsen HM, Veerhuis R, et al. (2014) Increased IRAK-4 Kinase Activity in Alzheimer’s Disease; IRAK-1/4 Inhibitor I Prevents Pro-inflammatory Cytokine Secretion but not the Uptake of Amyloid Beta by Primary Human Glia. J Clin Cell Immunol 5:243. doi: 10.4172/2155-9899.1000243
Copyright: © 2014 Hoozemans JJM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Abstract

Alzheimer’s disease (AD) is characterized by the deposition of amyloid-β (Aβ), which is associated with a neuroinflammatory response involving microglia and astrocytes. This neuroinflammatory response has detrimental effects on disease progression but also has a beneficial function on removal of excess Aβ. Microglia and astrocytes are involved in the clearance of Aβ from the brain, but neuroinflammation also promotes neurodegeneration. In order to identify signal transduction pathways critically involved in AD we analysed human brain tissue using protein kinase activity profiling. We identified increased activity of the Interleukin 1 Receptor Associated Kinase 4 (IRAK-4) in AD compared to control brain tissue. IRAK-4 is a component of the signal transduction pathway that functions downstream of the Toll-like receptors and the interleukin-1 receptor. Immunohistochemical analysis of human brain tissue revealed the presence of IRAK-4 in astrocytes and microglia. Quantification of IRAK-4 and the phosphorylated form of IRAK-1, a specific substrate for IRAK-4, revealed increased expression and activity of IRAK-4 in AD. Interestingly, IRAK-1/4 inhibitor I reduces the lipopolysaccharide-induced secretion of monocyte chemotactic protein-1 (MCP-1) by primary human microglia and the interleukin-1β-induced secretion of MCP-1 and interleukin 6 by primary human astrocytes. In contrast, the uptake of Aβ by astrocytes and microglia is not affected by IRAK-1/4 inhibition. Our data show that IRAK-4 protein kinase activity is increased in AD and selective inhibition of IRAK-1/4 inhibits a pro-inflammatory response without affecting the uptake of Aβ by glial cells, indicating that the IRAK signalling pathway is a potential target for modulating neuroinflammation in AD.

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