Molecular elevation of insulin receptor signaling improves memory recall in aged Fischer 344 rats.
Molecular elevation of insulin receptor signaling improves memory recall in aged Fischer 344 rats.
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DOI：
10.1111/acel.13220
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发表时间：
2020-10
期刊：
影响因子：
7.8
通讯作者：
Thibault O
中科院分区：
文献类型：
--
作者：
Frazier HN;Anderson KL;Ghoweri AO;Lin RL;Hawkinson TR;Popa GJ;Sompol P;Mendenhall MD;Norris CM;Thibault O
在动物模型中，学习后海马胰岛素受体密度增加，衰老和阿尔茨海默病中胰岛素信号传导、受体密度降低和记忆力下降，许多研究都强调了胰岛素在学习和记忆过程中的重要性。研究表明，鼻内注射胰岛素可以增强胰岛素受体信号，改变脑血流量，提高记忆力，这进一步支持了这一点。此外，使用分子技术抑制胰岛素受体功能或表达与学习能力下降有关。在这里，我们寻求一种不同的方法来增加胰岛素受体活性，而不需要给药配体。在体内将一种具有组成活性的改良人胰岛素受体（IRβ）递送到幼龄（2个月）和老年（18个月）雄性Fischer 344大鼠的海马。通过Morris水迷宫和动态步态表现、免疫荧光、免疫组织化学和免疫印迹等结果测量方法，研究了海马胰岛素受体表达增加的影响。在老年动物中，IRβ结构与Morris水迷宫任务的表现增强有关，这表明该受体能够改善记忆回忆。此外，在两个年龄组中，经IRβ处理的动物步长减少，海马胰岛素受体水平升高。这些结果为老年动物海马神经元胰岛素信号传导增加的潜在影响提供了新的见解，并支持在没有配体的情况下，通过分子提高体内胰岛素受体活性来直接研究这一过程的有效性。为了评估胰岛素信号传导增加对运动表现、空间记忆和受体动力学的影响，无需鼻内胰岛素输送，我们在Fischer 344大鼠海马中表达了一个组成型活性胰岛素受体（IRβ）。在老年动物中，IRβ与改善的记忆表现、更高的受体水平和增加的下游信号传导有关。这项工作证明了分子增强受体活性在体内的功效。
As demonstrated by increased hippocampal insulin receptor density following learning in animal models and decreased insulin signaling, receptor density, and memory decline in aging and Alzheimer's diseases, numerous studies have emphasized the importance of insulin in learning and memory processes. This has been further supported by work showing that intranasal delivery of insulin can enhance insulin receptor signaling, alter cerebral blood flow, and improve memory recall. Additionally, inhibition of insulin receptor function or expression using molecular techniques has been associated with reduced learning. Here, we sought a different approach to increase insulin receptor activity without the need for administering the ligand. A constitutively active, modified human insulin receptor (IRβ) was delivered to the hippocampus of young (2 months) and aged (18 months) male Fischer 344 rats in vivo. The impact of increasing hippocampal insulin receptor expression was investigated using several outcome measures, including Morris water maze and ambulatory gait performance, immunofluorescence, immunohistochemistry, and Western immunoblotting. In aged animals, the IRβ construct was associated with enhanced performance on the Morris water maze task, suggesting that this receptor was able to improve memory recall. Additionally, in both age‐groups, a reduced stride length was noted in IRβ‐treated animals along with elevated hippocampal insulin receptor levels. These results provide new insights into the potential impact of increasing neuronal insulin signaling in the hippocampus of aged animals and support the efficacy of molecularly elevating insulin receptor activity in vivo in the absence of the ligand to directly study this process. To assess the impact of increasing insulin signaling on ambulatory performance, spatial memory, and receptor dynamics without the need for intranasal insulin delivery, we expressed a constitutively active insulin receptor (IRβ) in the hippocampus of Fischer 344 rats. In aged animals, IRβ was associated with improved memory performance, higher receptor levels, and increased downstream signaling. This work demonstrates the efficacy of molecularly enhancing receptor activity in vivo.
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DOI：
10.1016/j.bbrc.2016.08.105
发表时间：
2017-02-19
影响因子：
3.1
作者：
Frazier HN;Maimaiti S;Anderson KL;Brewer LD;Gant JC;Porter NM;Thibault O
通讯作者：
Thibault O
DOI：
10.1126/science.1247485
发表时间：
2014-02-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lovett-Barron M;Kaifosh P;Kheirbek MA;Danielson N;Zaremba JD;Reardon TR;Turi GF;Hen R;Zemelman BV;Losonczy A
通讯作者：
Losonczy A
影响因子：
64.5
作者：
García-Cáceres C;Quarta C;Varela L;Gao Y;Gruber T;Legutko B;Jastroch M;Johansson P;Ninkovic J;Yi CX;Le Thuc O;Szigeti-Buck K;Cai W;Meyer CW;Pfluger PT;Fernandez AM;Luquet S;Woods SC;Torres-Alemán I;Kahn CR;Götz M;Horvath TL;Tschöp MH
通讯作者：
Tschöp MH
鼻内递送绕过靶向治疗剂到中枢神经系统并治疗神经退行性疾病的血脑屏障。
影响因子：
2.4
作者：
Hanson LR;Frey WH 2nd
通讯作者：
Frey WH 2nd
影响因子：
6
作者：
Freiherr, Jessica;Hallschmid, Manfred;Frey, William H., II;Bruenner, Yvonne F.;Chapman, Colin D.;Hoelscher, Christian;Craft, Suzanne;De Felice, Fernanda G.;Benedict, Christian
通讯作者：
Benedict, Christian