K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression.
K284-6111 prevents the amyloid beta-induced neuroinflammation and impairment of recognition memory through inhibition of NF-κB-mediated CHI3L1 expression.
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DOI：
10.1186/s12974-018-1269-3
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发表时间：
2018-08-11
影响因子：
9.3
通讯作者：
Hong JT
中科院分区：
文献类型：
--
作者：
Choi JY;Yeo IJ;Kim KC;Choi WR;Jung JK;Han SB;Hong JT
阿尔茨海默病是一种退行性脑疾病，是痴呆症的最常见原因，其病理特征是β淀粉样蛋白（a β）原纤维过度积累。在先前的研究中，有报道称AD患者血浆中CHI3L1水平升高。我们研究了几丁质酶3样1 （CHI3L1）抑制剂2-（{3-[2-（1-环己烯-1-基）乙基]-6,7-二甲氧基-4-氧-3,4-二氢-2-喹唑啉基}磺胺）- n-（4-乙基苯基）丁酰胺（K284-6111）对a β1 - 42输注小鼠、小胶质BV-2细胞和星形胶质细胞记忆损伤的抑制作用。我们检测了K284-6111 （3mg /kg口服4周）是否能阻止a β1 - 42诱导的AD小鼠模型的淀粉样蛋白形成和记忆丧失。脑内注射Aβ1-42 14 d后，采用Morris水迷宫试验和被动回避试验评估大鼠认知功能。发现K284-6111处理可减轻a β1 - 42诱导的记忆丧失。研究发现，记忆恢复效应与Aβ1 - 42诱导的炎症蛋白（iNOS、COX-2、GFAP和Iba-1）表达的减少和脑内CHI3L1表达的抑制有关。此外，K284-6111降低了Aβ1 - 42诱导的β分泌酶活性和Aβ的生成。k288 -6111处理（0.5、1、2 μM）可降低脂多糖（LPS）诱导的炎性蛋白（COX-2、iNOS、GFAP、Iba-1）和淀粉样蛋白（APP、BACE1）表达（1 μg/mL）。此外，在体内和体外，K284-6111处理抑制了p50和p65向细胞核的易位，以及i - κ b的磷酸化。提示CHI3L1抑制剂可作为淀粉样变性和神经炎症的干预药物，通过抑制NF-κB来预防记忆功能障碍。本文的在线版本（10.1186/s12974-018-1269-3）包含补充材料，授权用户可使用。
Alzheimer’s disease, which is pathologically characterized by an excessive accumulation of amyloid beta (Aβ) fibrils, is a degenerative brain disease and the most common cause of dementia. In a previous study, it was reported that an increased level of CHI3L1 in plasma was found in AD patients. We investigated the inhibitory effect of 2-({3-[2-(1-cyclohexen-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), an inhibitor of chitinase 3 like 1 (CHI3L1), on memory impairment in Aβ1–42-infused mice, and microglial BV-2 cells and astrocytes. We examined whether K284-6111 (3 mg/kg given orally for 4 weeks) prevents amyloidogenesis and memory loss in Aβ1–42-induced AD mice model. After intracerebroventrical (ICV) infusion of Aβ1–42 for 14 days, the cognitive function was assessed by the Morris water maze test and passive avoidance test. K284-6111 treatment was found to reduce Aβ1–42-induced memory loss. A memory recovery effect was found to be associated with the reduction of Aβ1–42-induced expression of inflammatory proteins (iNOS, COX-2, GFAP, and Iba-1) and the suppression of CHI3L1 expression in the brain. Additionally, K284-6111 reduced Aβ1–42-induced β-secretase activity and Aβ generation. Lipopolysaccharide (LPS)-induced (1 μg/mL) expression of inflammatory (COX-2, iNOS, GFAP, Iba-1) and amyloidogenic proteins (APP, BACE1) were decreased in microglial BV-2 cells and cultured astrocytes by the K284-6111 treatment (0.5, 1, and 2 μM). Moreover, K284-6111 treatment suppressed p50 and p65 translocation into the nucleus, and phosphorylation of IκB in vivo and in vitro. These results suggest that CHI3L1 inhibitor could be an applicable intervention drug in amyloidogenesis and neuroinflammation, thereby preventing memory dysfunction via inhibition of NF-κB. The online version of this article (10.1186/s12974-018-1269-3) contains supplementary material, which is available to authorized users.
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YKL-40：一种用于临床前阿尔茨海默病的新型预后液体生物标志物。
影响因子：
10.6
作者：
Craig-Schapiro, Rebecca;Perrin, Richard J.;Roe, Catherine M.;Xiong, Chengjie;Carter, Deborah;Cairns, Nigel J.;Mintun, Mark A.;Peskind, Elaine R.;Li, Ge;Galasko, Douglas R.;Clark, Christopher M.;Quinn, Joseph F.;D'Angelo, Gina;Malone, James P.;Townsend, R. Reid;Morris, John C.;Fagan, Anne M.;Holtzman, David M.
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Holtzman, David M.
影响因子：
15.1
作者：
Lasagna-Reeves CA;Castillo-Carranza DL;Sengupta U;Clos AL;Jackson GR;Kayed R
通讯作者：
Kayed R
影响因子：
5.8
作者：
Hinsinger, G.;Galeotti, N.;Thouvenot, E.
通讯作者：
Thouvenot, E.
影响因子：
14
作者：
通讯作者：
--
影响因子：
4
作者：
Mitchell, C. M.;Johnson, R. F.;Zakar, T.
通讯作者：
Zakar, T.