title: Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline.
abstract: The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.
authors.affiliation: Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Vom Berg
authors.forename: Stefan
authors.initials: S
authors.lastname: Prokop
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Miller
authors.forename: Juliane
authors.initials: J
authors.lastname: Obst
authors.forename: Roland E
authors.initials: RE
authors.lastname: Kälin
authors.forename: Ileana
authors.initials: I
authors.lastname: Lopategui-Cabezas
authors.forename: Anja
authors.initials: A
authors.lastname: Wegner
authors.forename: Florian
authors.initials: F
authors.lastname: Mair
authors.forename: Carola G
authors.initials: CG
authors.lastname: Schipke
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.forename: York
authors.initials: Y
authors.lastname: Winter
authors.forename: Burkhard
authors.initials: B
authors.lastname: Becher
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D015153:Blotting, Western; D003071:Cognition / Q000187:drug effects*; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053762:Interleukin-12 Subunit p40 / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D017931:DNA Primers; D053762:Interleukin-12 Subunit p40; D018664:Interleukin-12