Article
Reducing alzheimer´s disease β-amyloid and cognitive deficits by manipulating il-12/il-23 signaling
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Published: | September 11, 2012 |
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Alzheimer's disease (AD) pathology displays an inflammatory component characterized by the presence of pro-inflammatory cytokines particularly in response to β-amyloid. Using transgenic APPPS1mice serving as a model of AD, we observed the production of the common interleukin (IL)-12 and IL-23 subunit p40 by microglia. Genetic ablation of p40 and two other IL-12/IL-23 subunits, namely p35 and p19, resulted in a drastic decrease in cerebral amyloid plaque load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain either by removing p40 or its respective receptors was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing anti-p40 antibody likewise resulted in a significant reduction of cerebral β-amyloid in APPPS1mice. Furthermore intracerebroventricular delivery of anti-p40 antibodies ameliorated behavioral deficits in old APPPS1mice. Our results suggest that inhibition of IL-12/IL-23 signaling reduces cerebral amyloidosis and cognitive dysfunction and poses a novel potential pharmacological target to combat AD.