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Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline

Item Type:Article
Title:Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease-like pathology and cognitive decline
Creators Name:Vom Berg, J. and Prokop, S. and Miller, K.R. and Obst, J. and Kaelin, R.E. and Lopategui-Cabezas, I. and Wegner, A. and Mair, F. and Schipke, C.G. and Peters, O. and Winter, Y. and Becher, B. and Heppner, F.L.
Abstract:The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-{beta} (A{beta}). 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 A{beta} 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.
Keywords:Alzheimer Disease, Amyloid beta-Peptides, Analysis of Variance, Antibodies, Cognition, DNA Primers, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Interleukin-12, Interleukin-12 Subunit p40, Intraperitoneal Injections, Microglia, Real-Time Polymerase Chain Reaction, Signal Transduction, Transgenic Mice, Western Blotting, Animals, Mice
Source:Nature Medicine
Publisher:Nature Publishing Group
Page Range:1812-1819
Date:December 2012
Official Publication:https://doi.org/10.1038/nm.2965
PubMed:View item in PubMed

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