Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases.
Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases.
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利用培养的人类小胶质细胞研究阿尔茨海默病和其他神经退行性疾病的致病机制。
DOI：
10.1002/jnr.20484
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发表时间：
2005
影响因子：
4.2
通讯作者：
Lue,L-F
中科院分区：
文献类型：
--
作者：
Walker,DG;Lue,L-F
炎症介导的人类神经退行性疾病（如阿尔茨海默病（AD）和帕金森病（PD））的机制已经从医学假设的边缘发展成为主流思想。人类脑组织的开创性免疫病理学研究确定了与这些疾病的神经病理学标志相关的小胶质细胞。由于已知活化的巨噬细胞会产生许多潜在的毒性产物，因此产生了一种假设，即活化的小胶质细胞（脑内驻留的巨噬细胞）可能导致这些疾病中关键靶神经元的变性以及潜在的血管功能障碍。对来自不同来源（包括人脑）的小胶质细胞的研究已经证实，活化的小胶质细胞可以介导神经元细胞死亡。基于这些理论，已经在AD患者中进行了许多使用抗抑郁剂的人体临床试验。迄今为止的结果表明，在减缓疾病进展方面缺乏有效性，并开始对炎症在AD中的意义产生怀疑。最近的研究表明，通过用淀粉样β肽（Aβ）免疫淀粉样斑块形成小鼠来激活小胶质细胞，有希望作为一种治疗策略，尽管有一些挫折，但有可能作为AD患者的治疗方法。本文将考虑小胶质细胞的实验数据，以确定是否需要研究其他靶点。使用人小胶质细胞培养物，特别是那些来自老年患病人脑的培养物，提供了一种实验系统，可以密切模拟人类神经退行性疾病中激活的细胞类型。我们的实验室和其他人产生的实验数据进行审查，以确定这种独特的实验模型的贡献，了解疾病的机制，并可能发现新的治疗靶点。© 2005 Wiley利斯公司
Inflammation‐mediated mechanisms for human neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) have evolved from being on the fringe of medical hypotheses to mainstream thinking. Pioneering immunopathology studies with human brain tissues identified microglia associated with neuropathologic hallmarks of these diseases. As activated macrophages were known to produce many potential toxic products, this gave rise to the hypothesis that activated microglia (brain resident macrophages) could be contributing to the degeneration of key target neurons in these diseases, as well as potential vascular dysfunction. Studies with microglia derived from different sources, including human brains, have confirmed that activated microglia can mediate neuronal cell death. Based on these theories, a number of human clinical trials with antiinflammatory agents have been carried out on AD patients. Results to date have indicated a lack of effectiveness at slowing disease progression and have begun to cast doubt on the significance of inflammation in AD. It has been shown recently that activating microglia through immunization of amyloid plaque‐developing mice with amyloid beta peptide (Aβ) has promise as a therapeutic strategy and despite some setbacks, has potential as a treatment for AD patients. This article will consider experimental data with microglia to determine whether the additional targets need to be investigated. The use of human microglia cultures, in particular those derived from elderly diseased human brains, offers an experimental system that can closely model the cell type activated in human neurodegenerative diseases. Experimental data produced by our laboratory and others is reviewed to determine the contribution of this unique experimental model to understanding disease mechanisms and possibly discovering new therapeutic targets. © 2005 Wiley‐Liss, Inc.