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.
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This work was supported by the Deutsche Forschungsgemeinschaft (SFB TRR 43 to F.L.H. and NeuroCure Exc 257 to F.L.H. and Y.W.), the Swiss national science foundation (B.B.), the Koetzer foundation (B.B.), a NeuroCure Exc 257 visiting fellowship (B.B.), the US National Institutes of Health (NINDS R01 NS046006 to F.L.H.) and the European Union (FP7 HEALTH, Project LUPAS to F.L.H.). J.v.B. is a member of the Neuroscience Center Zurich, and F.M. is a member of the Molecular Life Sciences Zurich. We thank P. Matylewski, C. Hempt, C. Klatt and C. Gehlhaar for excellent technical help, F. Hiemeyer for performing the ANOVA statistics, K. Saeger for scanning and processing of histological mouse slides and M. Jucker, University of Tübingen, for generously providing APPPS1 mice.
F.L.H and B.B. hold a patent application by the University of Zurich and the Charité–Universitätsmedizin Berlin entitled “Modulators of IL-12 and/or IL-23 for the Prevention or Treatment of Alzheimer's Disease” (PCT/EP2012/050066).
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vom Berg, J., Prokop, S., Miller, K. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer's disease–like pathology and cognitive decline. Nat Med 18, 1812–1819 (2012). https://doi.org/10.1038/nm.2965
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