Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model

• Published in: The Journal of neuroscience 2013-03, Vol.33 (11), p.5053-5064
• Main Authors: Ghosh, Simantini, Wu, Michael D, Shaftel, Solomon S, Kyrkanides, Stephanos, LaFerla, Frank M, Olschowka, John A, O'Banion, M Kerry
• Format: Article
• Language: English
• Subjects: Age Factors; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid Precursor Protein Secretases - metabolism; Analysis of Variance; Animals; Brain - metabolism; Brain - pathology; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation - genetics; Glial Fibrillary Acidic Protein - metabolism; Glycogen Synthase Kinase 3 - metabolism; Humans; Immunodeficiency Virus, Feline - genetics; Interleukin-1beta - deficiency; Interleukin-1beta - metabolism; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Microfilament Proteins; Muscle Proteins; Mutation - genetics; Presenilin-1 - genetics; tau Proteins - genetics; tau Proteins - metabolism; Trisaccharides - metabolism; Tubulin - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4361-12.2013

Neuroinflammation is an important component of Alzheimer's disease (AD) pathogenesis and has been implicated in neurodegeneration. Interleukin-1 (IL-1), a potent inflammatory cytokine in the CNS, is chronically upregulated in human AD and believed to serve as part of a vicious inflammatory cycle that drives AD pathology. To further understand the role of IL-1β in AD pathogenesis, we used an inducible model of sustained IL-1β overexpression (IL-1β(XAT)) developed in our laboratory. The triple transgenic mouse model of AD, which develops plaques and tangles later in its life cycle, was bred with IL-1β(XAT) mice, and effects of IL-1β overexpression on AD pathology were assessed in F1 progeny. After 1 and 3 months of transgene expression, we found robust increases in tau phosphorylation despite an ∼70-80% reduction in amyloid load and fourfold to sixfold increase in plaque-associated microglia, as well as evidence of greater microglial activation at the site of inflammation. We also found evidence of increased p38 mitogen-activated protein kinase and glycogen synthase kinase-3β activity, which are believed to contribute to tau phosphorylation. Thus, neuroinflammation regulates amyloid and tau pathology in opposing ways, suggesting that it provides a link between amyloid accumulation and changes in tau and raising concerns about the use of immunomodulatory therapies in AD.