Elder Gregory A, Gama Sosa Miguel A, De Gasperi Rita
Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, USA.
Mt Sinai J Med. 2010 Jan-Feb;77(1):69-81. doi: 10.1002/msj.20159.
Alzheimer's disease is the most common cause of senile dementia in the United States and Europe. At present, there is no effective treatment. Given the disease's prevalence and poor prognosis, the development of animal models has been a high research priority. Transgenic modeling has been pursued on the basis of the amyloid hypothesis and has taken advantage of mutations in the amyloid precursor protein and the presenilins that cause familial forms of Alzheimer's disease. Modeling has been most aggressively pursued in mice, for which the techniques of genetic modification are well developed. Transgenic mouse models now exist that mimic a range of Alzheimer's disease-related pathologies. Although none of the models fully replicates the human disease, the models have contributed significant insights into the pathophysiology of beta-amyloid toxicity, particularly with respect to the effects of different beta-amyloid species and the possible pathogenic role of beta-amyloid oligomers. They have also been widely used in the preclinical testing of potential therapeutic modalities and have played a pivotal role in the development of immunotherapies for Alzheimer's disease that are currently in clinical trials. These models will, without a doubt, continue to play central roles in preclinical testing and be used as tools for developing insights into the biological basis of Alzheimer's disease.
在美国和欧洲，阿尔茨海默病是导致老年痴呆症最常见的病因。目前，尚无有效的治疗方法。鉴于该疾病的高发病率和不良预后，动物模型的开发一直是研究的重点。转基因模型是基于淀粉样蛋白假说构建的，并利用了淀粉样前体蛋白和早老素中的突变，这些突变会引发家族性阿尔茨海默病。由于小鼠的基因改造技术已经成熟，因此在小鼠身上进行模型构建的研究最为积极。目前已经存在转基因小鼠模型，它们能够模拟一系列与阿尔茨海默病相关的病理特征。虽然没有一个模型能完全复制人类疾病，但这些模型为β-淀粉样蛋白毒性的病理生理学提供了重要见解，特别是关于不同β-淀粉样蛋白种类的影响以及β-淀粉样蛋白寡聚体可能的致病作用。它们还被广泛用于潜在治疗方法的临床前测试，并在目前正在进行临床试验的阿尔茨海默病免疫疗法的开发中发挥了关键作用。毫无疑问，这些模型将继续在临床前测试中发挥核心作用，并作为深入了解阿尔茨海默病生物学基础的工具。
