title: Sustained interleukin-1β overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model.
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-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.
authors.affiliation: Department of Neurobiology and Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
authors.forename: Simantini
authors.initials: S
authors.lastname: Ghosh
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wu
authors.forename: Solomon S
authors.initials: SS
authors.lastname: Shaftel
authors.forename: Stephanos
authors.initials: S
authors.lastname: Kyrkanides
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
authors.forename: John A
authors.initials: JA
authors.lastname: Olschowka
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D016089:Immunodeficiency Virus, Feline / Q000235:genetics; D053583:Interleukin-1beta / Q000172:deficiency / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D014312:Trisaccharides / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D053583:Interleukin-1beta; D008840:Microfilament Proteins; D009124:Muscle Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C064068:Thomsen-Friedenreich antigen, cryptic; D014312:Trisaccharides; D014404:Tubulin; D016875:tau Proteins; C051615:transgelin; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases