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

• Published in: Nature medicine Vol. 18; no. 12; pp. 1812 - 1819
• Main Authors: vom Berg, Johannes, Prokop, Stefan, Miller, Kelly R, Obst, Juliane, Kälin, Roland E, Lopategui-Cabezas, Ileana, Wegner, Anja, Mair, Florian, Schipke, Carola G, Peters, Oliver, Winter, York, Becher, Burkhard, Heppner, Frank L
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2012; Nature Publishing Group
• Subjects: 631/250/127/1213; 631/250/516; 692/699/375/365/1283; 692/700/139/422; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Analysis of Variance; Animals; Antibodies - administration & dosage; Antibodies - pharmacology; Biomedicine; Blotting, Western; Cancer Research; Care and treatment; Cognition & reasoning; Cognition - drug effects; Cognitive ability; Complications and side effects; Disease; DNA Primers - genetics; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Genetic aspects; Health aspects; Infectious Diseases; Injections, Intraperitoneal; Interleukin-12 - genetics; Interleukin-12 - immunology; Interleukin-12 - metabolism; Interleukin-12 Subunit p40 - cerebrospinal fluid; Interleukin-12 Subunit p40 - genetics; Interleukin-12 Subunit p40 - immunology; Interleukin-12 Subunit p40 - metabolism; Interleukins; Memory, Disorders of; Metabolic Diseases; Mice; Mice, Transgenic; Microglia - metabolism; Molecular Medicine; Neurosciences; Pathology; Real-Time Polymerase Chain Reaction; Risk factors; Signal Transduction - drug effects; Signaling; Statistics; Cuba; Switzerland; Germany
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2965

Proinflammatory cytokine expression increases as a result of amyloid deposition in Alzheimer's disease. Frank L. Heppner and colleagues show that genetic and pharmacological inhibition of IL-12 and IL-23 signaling reduces plaque load and improves cognitive deficits in mouse models of Alzheimer's disease. As the concentration of p40 is also increased in the cerebrospinal fluid of individuals with Alzheimer's disease, this suggests that this pathway may be targeted therapeutically in patients. 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.