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

Simantini Ghosh, Michael D. Wu, Solomon S. Shaftel, Stephanos Kyrkanides, Frank M. LaFerla, John A. Olschowka, M. Kerry O'Banion

Research output: Contribution to journalArticlepeer-review

289 Scopus citations

Abstract

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-1βXAT) 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-1βXAT 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.

Original languageEnglish
Pages (from-to)5053-5064
Number of pages12
JournalJournal of Neuroscience
Volume33
Issue number11
DOIs
StatePublished - Mar 13 2013

ASJC Scopus subject areas

  • General Neuroscience

Fingerprint

Dive into the research topics of 'Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an alzheimer's mouse model'. Together they form a unique fingerprint.

Cite this