title: Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer's disease model.
abstract: Inflammation is a key pathological hallmark of Alzheimer's disease (AD), although its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, IL-1β in particular has been implicated in playing a pathogenic role. In this study, we sought to investigate whether inhibition of IL-1β signaling provides disease-modifying benefits in an AD mouse model and, if so, by what molecular mechanisms. We report that chronic dosing of 3xTg-AD mice with an IL-1R blocking Ab significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-β. Alterations in inflammatory responses correspond to reduced NF-κB activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3β, and p38-MAPK, and also reduces phosphorylated tau levels. We also detected a reduction in the astrocyte-derived cytokine, S100B, and in the extent of neuronal Wnt/β-catenin signaling in 3xTg-AD brains, and provided in vitro evidence that these changes may, in part, provide a mechanistic link between IL-1 signaling and GSK-3β activation. Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, USA. kitazawa@uci.edu
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.forename: David
authors.initials: D
authors.lastname: Cheng
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Tsukamoto
authors.forename: Maya A
authors.initials: MA
authors.lastname: Koike
authors.forename: Paul D
authors.initials: PD
authors.lastname: Wes
authors.forename: Vitaly
authors.initials: V
authors.lastname: Vasilevko
authors.forename: David H
authors.initials: DH
authors.lastname: Cribbs
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000502:physiology*; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: C495267:CTNNB1 protein, mouse; D053583:Interleukin-1beta; D016328:NF-kappa B; D009414:Nerve Growth Factors; D017472:Receptors, Interleukin-1; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579159:S100b protein, mouse; D051176:beta Catenin; D016875:tau Proteins
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