CRISPR/Cas9-mediated CysLT1R deletion reverses synaptic failure, amyloidosis and cognitive impairment in APP/PS1 mice.
CRISPR/Cas9-mediated CysLT1R deletion reverses synaptic failure, amyloidosis and cognitive impairment in APP/PS1 mice.
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CRISPR/Cas9介导的CysLT1R缺失可逆转APP/PS1小鼠的突触衰竭、淀粉样变性和认知障碍
DOI：
10.18632/aging.202501
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发表时间：
2021-02-11
期刊：
影响因子：
--
通讯作者：
Hong H
中科院分区：
文献类型：
--
作者：
Chen F;Fang S;Du Y;Ghosh A;Reed MN;Long Y;Suppiramaniam V;Tang S;Hong H
β淀粉样蛋白（amyloid-β，Aβ）是阿尔茨海默病（Alzheimer's disease，AD）的主要病理标志，被认为是导致认知功能障碍的重要因素。广泛的研究发现Aβ可诱导一系列的病理生理反应，最终导致AD患者的记忆丧失。我们以前的研究结果表明，半胱氨酰白三烯受体1（CysLT 1 R）拮抗剂改善外源性Aβ诱导的记忆障碍。但CysLT 1 R在AD中的作用及其机制仍不清楚。在这项研究中，我们研究了CysLT 1 R在AD患者和APP/PS1小鼠中的水平。我们还通过成簇调节间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9（Cas9）介导的APP/PS1小鼠中的CysLT 1 R缺失产生APP/PS1-CysLT 1 R-/-小鼠，并研究了CysLT 1 R敲除对淀粉样蛋白生成、突触结构和可塑性、认知、神经炎症和犬尿氨酸途径的影响。在慢病毒介导的CysLT 1 R基因敲低APP/PS1小鼠后，也研究了这些属性。我们发现CysLT 1 R基因敲除或敲低可以保护APP/PS1小鼠的突触结构和可塑性，并改善其认知能力。这些作用与淀粉样蛋白加工的同时减少、神经炎症减少和犬尿氨酸途径抑制相关。我们的研究表明，CysLT 1 R缺陷可以介导对AD发病机制的几种有益作用，这种蛋白质的遗传/药理学消融可能是AD的潜在治疗选择。
As a major pathological hallmark of Alzheimer’s disease (AD), amyloid-β (Aβ) is regarded as a causative factor for cognitive impairment. Extensive studies have found Aβ induces a series of pathophysiological responses, finally leading to memory loss in AD. Our previous results demonstrated that cysteinyl leukotrienes receptor 1 (CysLT1R) antagonists improved exogenous Aβ-induced memory impairment. But the role of CysLT1R in AD and its underlying mechanisms still remain elusive. In this study, we investigated CysLT1R levels in AD patients and APP/PS1 mice. We also generated APP/PS1-CysLT1R-/- mice by clustered regulatory interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated CysLT1R deletion in APP/PS1 mice and studied the effect of CysLT1R knockout on amyloidogenesis, synapse structure and plasticity, cognition, neuroinflammation, and kynurenine pathway. These attributes were also studied after lentivirus-mediated knockdown of CysLT1R gene in APP/PS1 mice. We found that CysLT1R knockout or knockdown could conserve synaptic structure and plasticity, and improve cognition in APP/PS1 mice. These effects were associated with concurrent decreases in amyloid processing, reduced neuroinflammation and suppression of the kynurenine pathway. Our study demonstrates that CysLT1R deficiency can mediate several beneficial effects against AD pathogenesis, and genetic/pharmacological ablation of this protein could be a potential therapeutic option for AD.
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影响因子：
9.3
作者：
Choi JY;Yeo IJ;Kim KC;Choi WR;Jung JK;Han SB;Hong JT
通讯作者：
Hong JT
影响因子：
4.8
作者：
Ries M;Sastre M
通讯作者：
Sastre M
影响因子：
16.6
作者：
Marschallinger J;Schäffner I;Klein B;Gelfert R;Rivera FJ;Illes S;Grassner L;Janssen M;Rotheneichner P;Schmuckermair C;Coras R;Boccazzi M;Chishty M;Lagler FB;Renic M;Bauer HC;Singewald N;Blümcke I;Bogdahn U;Couillard-Despres S;Lie DC;Abbracchio MP;Aigner L
通讯作者：
Aigner L
影响因子：
3.7
作者：
Braidy, Nady;Grant, Ross;Guillemin, Gilles J.
通讯作者：
Guillemin, Gilles J.
辛伐他汀可改善链脲佐菌素诱发的糖尿病小鼠的记忆损伤和神经毒性
影响因子：
3.3
作者：
Fang, Shun-Chang;Xie, Hang;Tang, Su-Su
通讯作者：
Tang, Su-Su