An isoform-selective p38α mitogen-activated protein kinase inhibitor rescues early entorhinal cortex dysfunctions in a mouse model of Alzheimer's disease.
An isoform-selective p38α mitogen-activated protein kinase inhibitor rescues early entorhinal cortex dysfunctions in a mouse model of Alzheimer's disease.
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DOI：
10.1016/j.neurobiolaging.2018.06.006
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发表时间：
2018-10
影响因子：
4.2
通讯作者：
Origlia N
中科院分区：
文献类型：
--
作者：
Rutigliano G;Stazi M;Arancio O;Watterson DM;Origlia N
神经炎症是阿尔茨海默病（AD）进展的基本机制。应激诱导的p38α丝裂原活化蛋白激酶（MAPK）的活化导致促炎细胞因子的产生增加和神经变性。我们研究了一种亚型选择性p38α MAPK抑制剂MW 01 -18- 150 SRM（MW 150），以2.5 mg/kg/天（i. p.; 14天）对携带淀粉样前体蛋白（mhAPP）的人突变的AD小鼠模型中的早期内嗅皮层（EC）改变的影响。我们使用的电生理分析与长时程增强（LTP）诱导含EC的脑切片和EC相关的联想记忆任务。我们发现MW 150能够在2个月大的mhAPP小鼠中挽救LTP。将MW 150急性递送至脑切片在挽救LTP方面同样有效，具有与广泛使用的多激酶抑制剂SB 203580相当的功效。MW 150处理的mhAPP小鼠表现出区分物体与其位置/背景之间的新关联的能力提高。我们的研究结果表明，选择性抑制应激激活的p38α MAPK与MW 150可以减轻与神经炎症相关的EC功能障碍在AD进展的早期阶段。
Neuroinflammation is a fundamental mechanism in Alzheimer’s disease (AD) progression. The stress-induced activation of the p38α mitogen-activated protein kinase (MAPK) leads to increased production of proinflammatory cytokines and neurodegeneration. We investigated the effects of an isoform selective p38α MAPK inhibitor, MW01-18-150SRM (MW150), administered at 2.5 mg/kg/day (i.p.; 14 days) on early entorhinal cortex (EC) alterations in an AD mouse model carrying human mutations of the amyloid precursor protein (mhAPP). We used electrophysiological analyses with long-term potentiation (LTP) induction in EC-containing brain slices and EC-relevant associative memory tasks. We found that MW150 was capable of rescuing LTP in 2-month old mhAPP mice. Acute delivery of MW150 to brain slices was similarly effective in rescuing LTP, with a comparable efficacy to that of the widely used multi-kinase inhibitor SB203580. MW150-treated mhAPP mice demonstrated improved ability to discriminate novel associations between objects and their position/context. Our findings suggest that the selective inhibition of the stress-activated p38α MAPK with MW150 can attenuate the EC dysfunctions associated with neuroinflammation in an early stage of AD progression.
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DOI：
10.1016/j.trci.2016.05.001
发表时间：
2016-06
期刊：
Alzheimer's & dementia (New York, N. Y.)
影响因子：
--
作者：
Van Eldik LJ;Carrillo MC;Cole PE;Feuerbach D;Greenberg BD;Hendrix JA;Kennedy M;Kozauer N;Margolin RA;Molinuevo JL;Mueller R;Ransohoff RM;Wilcock DM;Bain L;Bales K
通讯作者：
Bales K
影响因子：
5.3
作者：
Origlia, Nicola;Criscuolo, Chiara;Domenici, Luciano
通讯作者：
Domenici, Luciano
影响因子：
2.1
作者：
Ferrer, I.;Gomez-Isla, T.;Avila, J.
通讯作者：
Avila, J.
影响因子：
5
作者：
Roy, Saktimayee M.;Grum-Tokars, Valerie L.;Schavocky, James P.;Saeed, Faisal;Staniszewski, Agnieszka;Teich, Andrew F.;Arancio, Ottavio;Bachstetter, Adam D.;Webster, Scott J.;Van Eldik, Linda J.;Minasov, George;Anderson, Wayne F.;Pelletier, Jeffrey C.;Watterson, D. Martin
通讯作者：
Watterson, D. Martin
影响因子：
9.3
作者：
Benedet, Andrea L.;Labbe, Aurelie;Rosa-Neto, Pedro
通讯作者：
Rosa-Neto, Pedro