title: IKKβ deficiency in myeloid cells ameliorates Alzheimer's disease-related symptoms and pathology.
abstract: Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposits and microglia-dominated inflammatory activation. Innate immune signaling controls microglial inflammatory activities and Aβ clearance. However, studies examining innate immunity in Aβ pathology and neuronal degeneration have produced conflicting results. In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKKβ, specifically in the myeloid cells of TgCRND8 APP-transgenic mice. Deficiency of IKKβ in myeloid cells, especially microglia, simultaneously reduced inflammatory activation and Aβ load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKKβ deficiency enhanced microglial recruitment to Aβ deposits and facilitated Aβ internalization, perhaps by inhibiting TGF-β-SMAD2/3 signaling, but did not affect Aβ production and efflux. Therefore, inhibition of IKKβ signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing Aβ clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression.
authors.affiliation: Department of Neurology, German Institute for Dementia Prevention (DIDP), and a.liu@mx.uni-saarland.de.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, German Institute for Dementia Prevention (DIDP), and.
authors.forename: Xu
authors.identifier: http://orcid.org/0000-0002-4689-5554
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, German Institute for Dementia Prevention (DIDP), and.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Hao
authors.affiliation: Department of Neurology, German Institute for Dementia Prevention (DIDP), and.
authors.forename: Yann
authors.initials: Y
authors.lastname: Decker
authors.affiliation: Department of Neurology, German Institute for Dementia Prevention (DIDP), and.
authors.forename: Robert
authors.initials: R
authors.lastname: Schomburg
authors.affiliation: Department of Medical Chemistry, Albert Szent Gyorgyi Medical University, 6720 Szeged, Hungary, and.
authors.forename: Livia
authors.initials: L
authors.lastname: Fülöp
authors.affiliation: Institute for Genetics, Center for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Institute for Clinical and Experimental Surgery, University of the Saarland, 66421 Homburg/Saar, Germany.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.affiliation: Department of Neurology, German Institute for Dementia Prevention (DIDP), and.
authors.forename: Klaus
authors.initials: K
authors.lastname: Fassbender
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017353:Gene Deletion; D006801:Humans; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000378:metabolism*; D021381:Protein Transport
chemical_list: D016229:Amyloid beta-Peptides; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse
keywords: Alzheimer's disease; NF-κB; endocytosis; inflammation; microglia; neurodegeneration