Rockenstein Edward, Crews Leslie, Masliah Eliezer
Department of Neurosciences, University of California, San Diego, La Jolla, California 92093-0624, USA.
Adv Drug Deliv Rev. 2007 Sep 30;59(11):1093-102. doi: 10.1016/j.addr.2007.08.013. Epub 2007 Aug 17.
Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressive accumulation of misfolded proteins with the formation of toxic oligomers. Previous studies show that while in Alzheimer's disease (AD) misfolded amyloid-beta protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD), Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders (TNRD), the aggregated proteins accumulate in the plasma membrane and intracellularly. Protein misfolding and accumulation is the result of an altered balance between protein synthesis, aggregation rate and clearance. Based on these studies, considerable advances have been made in the past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of genetic mutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of these diseases. Transgenic and knock out rodents and Drosophila as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington's disease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA. Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapies including use of inhibitors of the APP-processing enzymes beta- and gamma-secretase as well as vaccine therapies.
仅在美国和欧洲，老年人群中的神经退行性疾病就影响着超过500万人。其共同特征是错误折叠的蛋白质逐渐积累并形成有毒的寡聚体。先前的研究表明，在阿尔茨海默病（AD）中，错误折叠的淀粉样β蛋白在细胞内和细胞外空间均有积累，而在路易体病（LBD）、帕金森病（PD）、多系统萎缩（MSA）、额颞叶痴呆（FTD）、朊病毒病、肌萎缩侧索硬化（ALS）和三核苷酸重复障碍（TNRD）中，聚集的蛋白质则在质膜和细胞内积累。蛋白质错误折叠和积累是蛋白质合成、聚集速率和清除之间平衡改变的结果。基于这些研究，在过去几年中，神经退行性疾病新型实验模型的开发取得了相当大的进展。这在一定程度上是由于与这些疾病的家族形式相关的基因突变以及与这些疾病更常见的散发性变体相关的基因多态性的鉴定。转基因和基因敲除啮齿动物、果蝇以及阿尔茨海默病（AD）、帕金森病（PD）、亨廷顿舞蹈病（HD）等的病毒载体驱动模型已经被开发出来，然而，本综述的重点将是AD、FTD、PD/LBD和MSA的啮齿动物模型。利用AD的淀粉样前体蛋白（APP）转基因（tg）模型开发包括使用APP加工酶β-和γ-分泌酶抑制剂以及疫苗疗法在内的治疗方法已经取得了有前景的治疗结果。
