AAIC 2014：贝沙罗汀治疗AD的功效取决于AD疾病所处阶段

虽然一种癌症治疗药物贝沙罗汀（bexarotene）显示出对阿尔茨海默氏病小鼠有治疗功效，但其在小鼠AD新模型中得到了令人困惑的结果（药物贝沙罗汀bexarotene对于晚期阿尔茨海默氏症小鼠，能减少神经毒性蛋白--β-淀粉样蛋白的水平，但在AD疾病的早期阶段，却是增加β-淀粉样蛋白水平），新的小鼠AD模型比任何其他动物模型更加紧密地模仿了人类阿尔茨海默氏症疾病的遗传学和病理学机制。

伊利诺伊大学研究人员Mary Jo LaDu的这一发现是在7月16日，在哥本哈根举行的阿尔茨海默氏症协会国际会议上提出的，Mary Jo LaDu在2012年开发出一种转基因小鼠，即现在被认为是最好的模拟人类疾病的动物模型。该实验小鼠携带赋予人类患AD风险高出15倍的基因，该基因使其成为该疾病的最重要的已知遗传危险因素。

阿尔茨海默氏病是痴呆最常见的形式，影响超过500万美国人。这种疾病是渐进的，并最终导致死亡。AD的特点之一就是大脑中β-淀粉样团块组成密集的斑块。但最近的研究表明，负责神经细胞死亡，导致认知能力下降的不是实心斑块，而是可溶性形式的小β-淀粉样，。

载脂蛋白E（ApoE）通过结合到β-淀粉样蛋白，分解β-淀粉样蛋白，以此来清除大脑淀粉样蛋白。LaDu说：载脂蛋白E中的APOE4是老年痴呆症的最大的遗传危险因素。以前的工作表明，相比APOE3，载脂蛋白E4基因产生的载脂蛋白不能很好地结合淀粉样蛋白，因此不会从脑中清除毒素（淀粉样蛋白）。

虽然有关贝沙罗汀对小鼠AD影响的研究结果有好有坏，但还没有一项研究是在携带人类APOE基因、渐进性AD样病理小鼠中进行。伊利诺伊大学Mary Jo LaDu开展了首个这样的研究。

LaDu以及他们的同事在AD早期，中期或晚期，给予携带载脂蛋白E4或APOE3小鼠贝沙罗汀，为期七天。然后，研究人员测定小鼠大脑可溶性β-淀粉样蛋白的水平。

在携带人载脂蛋白E4小鼠的AD疾病后期中，研究人员发现可溶性β-淀粉样蛋白减少40％，载脂蛋白结合β-淀粉样增加。但在携带载脂蛋白E4或APOE3小鼠的AD的早期阶段，可溶性β-淀粉样蛋白的量实际上增加。研究人员在载脂蛋白E4小鼠AD早期开始时给予贝沙罗汀为期一个月，他们分析药物是否可以防止病情恶化，结果发现药物没有发挥有利的影响。

研究认为在携带载脂蛋白E4基因小鼠的AD疾病的后期阶段给予贝沙罗汀，进行短期治疗可能是有益的。但还需要进一步研究确定治疗持续时间和治疗开始时间，更重要的是确认APOE3携带者是否也会受益于药物。

贝沙罗汀的肝脏毒性极强，除非小心地控制剂量和密切监视患者，否则对于预防疾病，即在阿尔茨海默氏病的症状出现之前，较长时间周期给予药物贝沙罗汀几乎是不可能的，这是因为药物已知的肝毒性。

详细英文报导：

Drug's effect on Alzheimer's may depend on severity of disease

A cancer drug that has shown promise against Alzheimer's disease in mice and has begun early clinical trials has yielded perplexing results in a novel mouse model of AD that mimics the genetics and pathology of the human disease more closely than any other animal model.

The drug, bexarotene, was found to reduce levels of the neurotoxic protein amyloid-beta in experimental mice with late-stage Alzheimer's but to increase levels during early stages of disease.

The finding, by researchers at the University of Illinois at Chicago College of Medicine, was reported July 16 at the Alzheimer's Association International Conference in Copenhagen by Mary Jo LaDu, who in 2012 developed a transgenic mouse that is now regarded as the best animal model of the human disease. That experimental mouse carries a human gene that confers on people a 15-fold elevated risk of developing AD, making it the most important known genetic risk factor for the disease.

Alzheimer's disease is the most common form of dementia, affecting more than five million Americans. The disease is progressive and eventually fatal. One of the hallmarks of AD is the appearance of dense plaques in the brain composed of clumps of amyloid-beta. But recent research indicates that smaller, soluble forms of amyloid-beta—rather than the solid plaques—are responsible for the death of nerve cells that leads to cognitive decline.

Humans carry a gene for a protein in cells called apolipoprotein E, which helps clear amyloid-beta from the brain by binding to it and breaking it down. LaDu's mice carry the most unfortunate variant in humans, called APOE4, or APOE3, which is neutral for AD risk.

"APOE4 is the greatest genetic risk factor for Alzheimer's disease," said LaDu, who is professor of anatomy and cell biology at UIC. "Our previous work showed that compared to APOE3, the apolipoprotein produced by the APOE4 gene does not bind well to amyloid-beta and so does not clear the neurotoxin from the brain."

Results of previous studies in mice of bexarotene's effect on AD have been mixed, and none of those studies were done in mice that carry a human APOE gene and also develop progressive, AD-like pathology. The UIC research presented in Copenhagen is the first to do so.

LaDu, working with Leon Tai, research assistant professor in anatomy and cell biology, and their coworkers gave bexarotene to mice carrying APOE4 or APOE3 for seven days during the early, intermediate, or late stages of AD. The researchers then measured the levels of soluble amyloid-beta in the brains of the mice.

In mice carrying human APOE4 with later-stage AD, the researchers saw a 40 percent reduction in soluble amyloid-beta and an increase in the binding of apolipoprotein to amyloid-beta. But in APOE4 or APOE3 mice with earlier-stage AD, the amount of soluble amyloid-beta actually increased. When the researchers gave APOE4 mice bexarotene for one month starting when they had early-stage AD to see if the drug could prevent disease progression, there was no beneficial effect.

Tai thinks that for people who carry the APOE4 gene, short-term treatment with bexarotene in the later stages of disease may be beneficial. But further research is needed, he said, to determine length and timing of treatment—and, importantly, whether the drug will benefit APOE3 carriers.

"Bexarotene also is extremely toxic to the liver," Tai said. "For prevention, where a drug is given before the symptoms of Alzheimer's disease appear, and likely over longer periods of time, bexarotene is not likely a viable therapeutic because of this known toxicity unless dosing is carefully controlled and patients are closely monitored."