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

被引：328

作者：

vom Berg, Johannes ^{[2
]}

Prokop, Stefan ^{[1
]}

Miller, Kelly R. ^{[1
]}

Obst, Juliane ^{[1
]}

Kaelin, Roland E. ^{[1
]}

Lopategui-Cabezas, Ileana ^{[1
]}

Wegner, Anja ^{[1
]}

Mair, Florian ^{[2
]}

Schipke, Carola G. ^{[1
,3
]}

Peters, Oliver ^{[3
]}

Winter, York ^{[4
]}

Becher, Burkhard ^{[2
]}

Heppner, Frank L. ^{[1
]}

机构：

[1] Charite, Dept Neuropathol, D-13353 Berlin, Germany

[2] Univ Zurich, Inst Expt Immunol, CH-8091 Zurich, Switzerland

[3] Charite, Dept Psychiat, D-13353 Berlin, Germany

[4] Humboldt Univ, Cognit Neurobiol & Berlin Mouse Clin Neurol & Psy, D-10099 Berlin, Germany

来源：

NATURE MEDICINE | 2012年 / 18卷 / 12期

基金：

美国国家卫生研究院; 瑞士国家科学基金会;

关键词：

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; T-CELLS; CEREBROSPINAL-FLUID; MULTIPLE-SCLEROSIS; PLAQUE PSORIASIS; CROHNS-DISEASE; IL-12; RECEPTOR; DOUBLE-BLIND; MOUSE MODEL; IFN-GAMMA;

D O I：

10.1038/nm.2965

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 Ab 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.

引用

页码：1812 / +

页数：10

共 52 条

[1] Probing the Biology of Alzheimer's Disease in Mice [J].