Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, 231 South 34th St., Philadelphia, PA 19104-6323, USA.
Curr Top Med Chem. 2011;11(3):317-30. doi: 10.2174/156802611794072605.
The recognition that malfunction of the microtubule (MT) associated protein tau is likely to play a defining role in the onset and/or progression of a number of neurodegenerative diseases, including Alzheimer's disease, has resulted in the initiation of drug discovery programs that target this protein. Tau is an endogenous MT-stabilizing agent that is highly expressed in the axons of neurons. The MT-stabilizing function of tau is essential for the axonal transport of proteins, neurotransmitters and other cellular constituents. Under pathological conditions, tau misfolding and aggregation results in axonal transport deficits that appear to have deleterious consequences for the affected neurons, leading to synapse dysfunction and, ultimately, neuronal loss. This review focuses on both progress and unresolved issues surrounding the development of novel therapeutics for the treatment of neurodegenerative tauopathies, which are based on (A) MT-stabilizing agents to compensate for the loss of normal tau function, and (B) small molecule inhibitors of tau aggregation.
微管（MT）相关蛋白 tau 的功能障碍很可能在包括阿尔茨海默病在内的许多神经退行性疾病的发生和/或进展中起决定性作用，这一认识促使人们启动了针对这种蛋白质的药物发现计划。Tau 是一种内源性的 MT 稳定剂，在神经元的轴突中高度表达。Tau 的 MT 稳定功能对于蛋白质、神经递质和其他细胞成分的轴突运输至关重要。在病理条件下，tau 的错误折叠和聚集导致轴突运输缺陷，这似乎对受影响的神经元产生有害影响，导致突触功能障碍，并最终导致神经元丧失。这篇综述重点介绍了针对神经退行性 tau 病治疗的新型治疗药物的开发进展和尚未解决的问题，这些药物基于（A）MT 稳定剂来补偿正常 tau 功能的丧失，和（B）tau 聚集的小分子抑制剂。
