Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer's disease model.
Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer's disease model.
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DOI：
10.4049/jimmunol.1100620
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发表时间：
2011-12-15
期刊：
影响因子：
--
通讯作者：
LaFerla FM
中科院分区：
文献类型：
--
作者：
Kitazawa M;Cheng D;Tsukamoto MR;Koike MA;Wes PD;Vasilevko V;Cribbs DH;LaFerla FM
炎症是阿尔茨海默病 (AD) 的一个关键病理标志，尽管其对疾病进展和神经退行性变的影响仍然是一个积极研究的领域。在与 AD 相关的众多炎症细胞因子中，白细胞介素 1β (IL-1β) 特别具有致病作用。在这里，我们试图研究抑制 IL-1β 信号传导是否可以在 AD 小鼠模型中提供疾病缓解益处，如果可以，是通过什么分子机制实现的。我们报告说，长期给 3xTg-AD 小鼠服用 IL-1 受体 (IL-1R) 阻断抗体可显着改变大脑炎症反应，减轻认知缺陷，显着减弱 tau 病理学，并部分减少某些纤维状和寡聚形式的淀粉样蛋白 -β (Aβ)。炎症反应的改变与 NF-κB 活性的降低相对应。此外，抑制 IL-1 信号传导会降低大脑中几种 tau 激酶的活性，包括 cdk5/p25、GSK-3β 和 p38-MAPK，并降低磷酸 tau 水平。我们还检测到 3xTg-AD 大脑中星形胶质细胞衍生的细胞因子 S100B 以及神经元 Wnt/β-catenin 信号传导程度的减少，并提供了体外证据，表明这些变化可能在一定程度上提供了 IL-1 信号传导和 GSK-3β 激活之间的机制联系。综上所述，我们的结果表明 IL-1 信号级联可能涉及 AD 的关键疾病机制之一。
Inflammation is a key pathological hallmark of Alzheimer's disease (AD), though its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, interleukin-1β (IL-1β) in particular has been implicated in playing a pathogenic role. Here we sought to investigate whether inhibition of IL-1β signaling provides disease-modifying benefits in an AD mouse model, and if so, by what molecular mechanisms. We report that chronic dosing of 3xTg-AD mice with an IL-1 receptor (IL-1R) blocking antibody significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-β (Aβ). Alterations in inflammatory responses correspond to reduced NF-κB activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3β and p38-MAPK, and also reduces phospho-tau levels. We also detected a reduction in the astrocyte-derived cytokine, S100B, and in the extent of neuronal Wnt/β-catenin signaling in 3xTg-AD brains, and provided in vitro evidence that these changes may, in part, provide a mechanistic link between IL-1 signaling and GSK-3β activation. Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.
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影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
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影响因子：
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作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
9.9
作者：
BREITNER, JCS;GAU, BA;ANTHONY, JC
通讯作者：
ANTHONY, JC
影响因子：
2.5
作者：
GOEDERT, M;JAKES, R;VANMECHELEN, E
通讯作者：
VANMECHELEN, E