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.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia in the elderly
The peptides showing a significant increase in phosphorylation between AD and CTRL derived brain tissue were compared with phosphorylation profiles of human recombinant protein kinases generated under similar experimental conditions
In this study we show that Interleukin Receptor Associated Kinase 4 (IRAK-4) protein kinase activity is increased in human AD temporal cortex compared with temporal cortex derived from non-neurological control cases
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia in the elderly. Amyloid plaques primarily consist of amyloid β (Aβ), a cleavage product of the amyloid precursor protein (APP). The build-up of Aβ in amyloid plaques in the brain depends on the balance between Aβ production and the removal or degradation of Aβ. Amyloid plaques in AD brain are closely associated with a local innate immune response marked by activated microglia, reactive astrocytes and the production of proteins that regulate inflammation [1]. Astrocytes and microglia are important for the removal of excess Aβ from the brain since they can bind and internalize fibrillar as well as oligomeric forms of Aβ [2,3]. In an activated state these cells induce an inflammatory response that has a neurotoxic effect [1,4].
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