A PDK-1 allosteric agonist improves spatial learning and memory in a βAPP/PS-1 transgenic mouse-high fat diet intervention model of Alzheimer's disease.
A PDK-1 allosteric agonist improves spatial learning and memory in a βAPP/PS-1 transgenic mouse-high fat diet intervention model of Alzheimer's disease.
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PDK-1 变构激动剂可改善阿尔茨海默病 βAPP/PS-1 转基因小鼠高脂肪饮食干预模型中的空间学习和记忆。
DOI：
10.1016/j.bbr.2022.114183
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发表时间：
2023
影响因子：
2.7
通讯作者：
Lee,Han-Kyu
中科院分区：
文献类型：
--
作者：
Querfurth,Henry;Slitt,Angela;DiCamillo,Amy;Surles,Nathan;DeBoef,Brenton;Lee,Han-Kyu
糖尿病（DM）、外周胰岛素抵抗（IR）和肥胖是阿尔茨海默病的明显危险因素。几种抗糖尿病药物和胰岛素已经在患有MCI或AD的啮齿动物和人类中进行了测试，产生了有希望但不确定的结果。然而，对于胰岛素的作用至关重要的PDK-1/Akt轴还没有被类似程度地研究。我们以前的细胞培养和体外研究指出了这种方法。双转基因APPsw/PSENdE 9小鼠是阿尔茨海默病的模型，用于测试口服施用PS48（PDK-1激动剂）对预防Morris水迷宫（MWM）中学习和记忆的预期下降的影响。以标准（SD）或高脂肪（HFD）饮食饲养小鼠，从10个月大开始给药，并在14个月大时进行测试。与媒介物饮食和WT动物相比，在SD或HFD上，PS 48对学习TG动物中隐藏平台的空间位置具有积极作用。在成功获得后的几项空间记忆测量（探针试验）中，该药物也证明对任何一种饮食的动物都有显着益处。在几个探针测量中，与SD相比，HFD组TG动物的PS48处理效应量更明显。HFD产生了一些预期的代谢效应，如体重增加和高血糖，以及加速TG动物的认知障碍。发现PS48在TG组中适度降低体重和改善OGTT反应方面具有附加值，尽管结果不是确定的。PS48耐受性良好，无明显临床体征或症状，本身不影响寿命。这些结果建议在人体试验之前进行更大规模的临床前研究。
Diabetes mellitus (DM), peripheral insulin resistance (IR) and obesity are clear risk factors for Alzheimer's disease. Several anti-diabetic drugs and insulin have been tested in rodents and humans with MCI or AD, yielding promising but inconclusive results. The PDK-1/Akt axis, essential to the action of insulin, has not however been pharmacologically interrogated to a similar degree. Our previous cell culture and in vitro studies point to such an approach. Double transgenic APPsw/PSENdE9 mice, a model for Alzheimer's disease, were used to test the oral administration of PS48, a PDK-1 agonist, on preventing the expected decline in learning and memory in the Morris Water Maze (MWM). Mice were raised on either standard (SD) or high fat (HFD) diets, dosed beginning 10 months age and tested at an advanced age of 14 months.PS48 had positive effects on learning the spatial location of a hidden platform in the TG animals, on either SD or HFD, compared to vehicle diet and WT animals. On several measures of spatial memory following successful acquisition (probe trials), the drug also proved significantly beneficial to animals on either diet. The PS48 treatment-effect size was more pronounced in the TG animals on HFD compared to on SD in several of the probe measures. HFD produced some of the intended metabolic effects of weight gain and hyperglycemia, as well as accelerating cognitive impairment in the TG animals. PS48 was found to have added value in modestly reducing body weights and improving OGTT responses in TG groups although results were not definitive. PS48 was well tolerated without obvious clinical signs or symptoms and did not itself affect longevity. These results recommend a larger preclinical study before human trial.