THE ROLE OF IL-¿¿1 RECEPTOR-¿¿ASSOCIATED KINASE 4 IN MICROGLIAL ACTIVATION IN ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is characterized by the deposition of ¿¿-¿¿amyloid into plaques and neurofibrillary tangles in the brain that is accompanied by a robust immune response. Microglia, the tissue macrophages of the brain, detect and respond to deposited amyloid. Their response is coordinated by a cell surface receptor ensemble including CD36, CD47, SRA, ¿¿6¿¿1 integrin, TLR2, TLR4, TLR6, and CD14. The role of individual TLRs in the microglial response to A¿¿ has been controversial. Therefore we elected to inactivate the first kinase activated after TLR ligation, interleukin-¿¿¿1 receptor-¿¿associated kinase 4 (IRAK4), to investigate the role of all TLRs in the microglial response to A¿¿. Using mice where inactive IRAK4 had been knocked into the endogenous IRAK4 (IRAK4 KI) we found that IRAK4 is necessary for microglia to activate proinflammatory MAP kinases and generate reactive oxygen in response to fA¿¿₄₂ <i>in vitro</i>. Furthermore, we analyzed the role of IRAK4 <i>in vivo</i> through use of the APPPS1 mouse model of Alzheimer’s disease. APPPS1;IRAK4 KI animals displayed reductions in both soluble and insoluble A¿¿ by ELISA at 8 months of age and dense core A¿¿ as marked by thioS. At 8 months of age, APPPS1;IRAK4 KI animals had significant reductions in both microgliosis, as marked by iba1 staining, and astrogliosis, as marked by GFAP staining. qPCR analysis of microglial enriched isolates from the adult brain revealed dysregulation of the immune response as marked by transcript levels of ifn¿¿, il-¿¿1¿¿, tnf¿¿, il-¿¿10, il-¿¿4, and socs1. Importantly, this work implicated the interferon response factors (IRFs) in controlling the microglial response to A¿¿ that is, in part, regulated by IRAK4 kinase activity. Analysis of whole brain homogenates revealed significant reductions in the proinflammatory IRF5 and increases in the anti-¿¿inflammatory IRF4 in the APPPS1;IRAK4 KI animals. These changes were correlated with maintenance of A¿¿ clearance pathways and improvements in olfactory behavioral tests. Together, our results demonstrate that IRAK4 activation in later stages of disease impairs clearance of A¿¿ and is correlated with engagement of a proinflammatory gene program. Importantly, they reveal that the previously unappreciated IRFs may be critical to regulating the microglial response to A¿¿.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Neurosciences

Grantor dc:publisher

Case Western Reserve University School of Graduate Studies

Year dc:date

2013

Author dc:creator

• Cameron, Brent D.

Contributors dc:contributor

• Landreth, Gary
• Deneris, Evan

• Biology
• Immunology
• Molecular Biology
• Neurobiology
• Neurosciences
• Alzheimer's disease
• inflammation
• microglia
• amyloid
• IRAK4
• IRFs
• IRF4
• IRF5
• M1 activation
• M2 activation
• IRAKs

Statement dc:rights

• unrestricted
• This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

Language dc:language

English

Repository record dc:identifier

http://rave.ohiolink.edu/etdc/view?acc_num=case1350260708

OAI identifier oai:identifier

oai:etd.ohiolink.edu:case1350260708