New molecule reverses Alzheimer’s-like memory decline
The drug CMS121 treats neurodegeneration in mice
Date: 日期:August 4, 2020 2020年8月4日Source: 来源:Salk Institute 索尔克研究所Summary: 摘要:A drug candidate previously shown to slow aging in brain cells, successfully reversed memory loss in a mouse model of inherited Alzheimer’s disease. The new research also revealed that the drug, CMS121, works by changing how brain cells metabolize fatty molecules known as lipids. 一种以前被证明可以延缓脑细胞衰老的候选药物，成功地逆转了遗传性阿尔茨海默病小鼠模型的记忆丧失。新的研究还表明，CMS121这种药物是通过改变脑细胞代谢脂肪分子的方式来起作用的Share: 分享: FULL STORY 完整故事
A drug candidate developed by Salk researchers, and previously shown to slow aging in brain cells, successfully reversed memory loss in a mouse model of inherited Alzheimer’s disease. The new research, published online in July 2020 in the journal Redox Biology, also revealed that the drug, CMS121, works by changing how brain cells metabolize fatty molecules known as lipids.
“This was a more rigorous test of how well this compound would work in a therapeutic setting than our previous studies on it,” says Pamela Maher, a senior staff scientist in the lab of Salk Professor David Schubert and the senior author of the new paper. “Based on the success of this study, we’re now beginning to pursue clinical trials.”
“对于这种化合物在治疗环境中的作用，这比我们以前的研究更为严格，”帕梅拉 · 马赫说，她是索尔克实验室的资深科学家，同时也是这篇新论文的资深作者。“基于这项研究的成功，我们现在开始进行临床试验。”
Over the last few decades, Maher has studied how a chemical called fisetin, found in fruits and vegetables, can improve memory and even prevent Alzheimer’s-like disease in mice. More recently, the team synthesized different variants of fisetin and found that one, called CMS121, was especially effective at, improving the animals’ memory, and slowing the degeneration of brain cells.
In the new study, Maher and colleagues tested the effect of CMS121 on mice that develop the equivalent of Alzheimer’s disease. Maher’s team gave a subset of the mice daily doses of CMS121 beginning at 9 months old — the equivalent of middle age in people, and after the mice have already begun to show learning and memory problems. The timing of the lab’s treatment is akin to how a patient who visits the doctor for cognitive problems might be treated, the researchers say.
在这项新的研究中，马赫和他的同事们测试了 CMS121对老鼠的影响，这些老鼠患上了相当于阿尔茨海默氏症的疾病。马赫的研究小组从9个月大开始每天给小鼠注射 CMS121—- 相当于人类的中年时期，在小鼠开始表现出学习和记忆问题之后。研究人员说，实验室治疗的时机类似于一个因认知问题而去看医生的病人可能得到的治疗。
After three months on CMS121, at 12 months old, the mice — both treated and untreated — were given a battery of memory and behavior tests. In both types of tests, mice with Alzheimer’s-like disease that had received the drug performed equally well as healthy control animals, while untreated mice with the disease performed more poorly.
CMS121治疗三个月后，12个月大的老鼠—- 无论是治疗的还是未治疗的—- 都接受了一系列的记忆和行为测试。在这两种类型的实验中，接受过药物治疗的类似老年痴呆症的老鼠和健康对照组的老鼠表现一样好，而未接受药物治疗的老鼠表现更差。
To better understand the impact of CMS121, the team compared the levels of different molecules within the brains of the three groups of mice. They discovered that when it came to levels of lipids — fatty molecules that play key roles in cells throughout the body — mice with the disease had several differences compared to both healthy mice and those treated with CMS121. In particular, the researchers pinpointed differences in something known as lipid peroxidation — the degradation of lipids that produces free radical molecules that can go on to cause cell damage. Mice with Alzheimer’s-like disease had higher levels of lipid peroxidation than either healthy mice or those treated with CMS121.
为了更好地理解 CMS121的影响，研究小组比较了三组老鼠大脑中不同分子的水平。他们发现，当涉及到脂质水平时—- 脂肪分子在全身细胞中扮演关键角色—- 患有这种疾病的老鼠与健康老鼠和那些接受 CMS121治疗的老鼠相比有几个不同。特别是，研究人员精确地指出了一种被称为脂质过氧化的物质的差异—- 脂质的降解产生的自由基分子可以继续引起细胞损伤。患有类似阿尔茨海默病的老鼠的脂质过氧化水平比健康老鼠和 CMS121治疗的老鼠都要高。
“That not only confirmed that lipid peroxidation is altered in Alzheimer’s, but that this drug is actually normalizing those changes,” says Salk postdoctoral fellow Gamze Ates, first author of the new paper.
“这不仅证实了脂质过氧化在老年痴呆症中发生了改变，而且这种药物实际上使这些改变正常化了，”这篇新论文的第一作者，Salk 的博士后研究员 Gamze Ates 说。
The researchers went on to show that CMS121 lowered levels of a lipid-producing molecule called fatty acid synthetase (FASN), which, in turn, lowered levels of lipid peroxidation. When the group analyzed levels of FASN in brain samples from human patients who had died of Alzheimer’s, they found that the patients had higher amounts of the FASN protein than similarly aged controls who were cognitively healthy, which suggests FASN could be a drug target for treating Alzheimer’s disease.
研究人员进一步证明，CMS121降低了一种叫做脂肪酸合成酶(FASN)的产脂分子的水平，而这种分子又反过来降低了脂质过氧化的水平。当研究小组分析死于阿尔茨海默氏症的病人大脑样本中 FASN 的水平时，他们发现这些病人的 FASN 蛋白含量高于同龄认知健康的对照组，这表明 FASN 可能是治疗阿尔茨海默氏症的药物靶点。
While the group is pursuing clinical trials, they hope other researchers will explore additional compounds that may treat Alzheimer’s by targeting FASN and lipid peroxidation.
虽然该小组正在进行临床试验，他们希望其他研究人员将探索额外的化合物，可能治疗阿尔茨海默氏症的目标 FASN 和脂质过氧化。
“There has been a big struggle in the field right now to find targets to go after,” says Maher. “So, identifying a new target in an unbiased way like this is really exciting and opens lots of doors.”