Lemere Cynthia A, Spooner Edward T, Leverone Jodi F, Mori Chica, Iglesias Melitza, Bloom Jeanne K, Seabrook Timothy J
Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Neurochem Res. 2003 Jul;28(7):1017-27. doi: 10.1023/a:1023203122036.
Alzheimer's disease is the most prevalent form of dementia worldwide. Therapies are desperately needed to prevent and cure the disease. Mouse models of amyloid-beta deposition [APP and PSAPP transgenic (tg) mice] have been useful in determining the role of amyloid-beta (A beta) in both the pathogenesis and cognitive changes in AD. In addition, they have allowed scientists to investigate potential AD therapies in living animals. Active and passive A beta immunizations have been employed successfully in APP and PSAPP tg mice to lower cerebral A beta levels and improve cognition. Optimization of immunization protocols and characterization of immune responses in wildtype mice have been reported. Based on the promising results of A beta immunization studies in mice, a clinical trial was initiated for A beta vaccination in humans with AD. Although no adverse effects were reported in the Phase I safety trials, about 5% of AD patients in the phase II clinical trial developed meningoencephalitis, ending the trial prematurely in March 2002. Studies in AD mouse models and wildtype mice may help elucidate the mechanism for these unwanted side effects and will be useful for testing newer, safer vaccines for future use in human clinical trials.
阿尔茨海默病是全球最常见的痴呆形式。迫切需要预防和治疗该疾病的疗法。淀粉样β蛋白沉积的小鼠模型（APP和PSAPP转基因小鼠）在确定淀粉样β蛋白（Aβ）在阿尔茨海默病发病机制和认知变化中的作用方面发挥了作用。此外，它们还使科学家能够在活体动物中研究潜在的阿尔茨海默病疗法。主动和被动Aβ免疫已成功应用于APP和PSAPP转基因小鼠，以降低脑内Aβ水平并改善认知。已报道了野生型小鼠免疫方案的优化和免疫反应的特征。基于小鼠Aβ免疫研究的有希望的结果，启动了一项针对阿尔茨海默病患者的Aβ疫苗临床试验。尽管在I期安全性试验中未报告不良反应，但在II期临床试验中约5%的阿尔茨海默病患者发生了脑膜脑炎，该试验于2002年3月提前结束。对阿尔茨海默病小鼠模型和野生型小鼠的研究可能有助于阐明这些不良副作用的机制，并将有助于测试更新、更安全的疫苗以供未来用于人类临床试验。
