Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Int J Mol Sci. 2020 Nov 25;21(23):8948. doi: 10.3390/ijms21238948.
Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer's disease (AD) and can be sporadic or inherited when caused by mutations in the gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifying therapies, and few tau-focused experimental drugs have reached clinical trials. One major hindrance for therapeutic development is the knowledge gap in molecular mechanisms of tau-mediated neuronal toxicity and death. For the promise of precision medicine for brain disorders to be fulfilled, it is necessary to integrate known genetic causes of disease, i.e., mutations, with an understanding of the dysregulated molecular pathways that constitute potential therapeutic targets. Here, the growing understanding of known and proposed mechanisms of disease etiology will be reviewed, together with promising experimental tau-directed therapeutics, such as recently developed tau degraders. Current challenges faced by the fields of tau research and drug discovery will also be addressed.
tau 病是以神经元和神经胶质细胞中微管相关蛋白 tau（MAPT）病理性聚集为特征的神经退行性疾病，其形式为神经纤维缠结和双螺旋丝，导致脑细胞死亡。这些疾病包括额颞叶痴呆（FTD）和阿尔茨海默病（AD），当由基因中的突变引起时，它们可以是散发性的或遗传性的。尽管在全球范围内造成了极高的社会经济负担，但仍然没有有效的疾病修饰疗法，并且很少有针对 tau 的实验药物进入临床试验。治疗开发的一个主要障碍是 tau 介导的神经元毒性和死亡的分子机制知识差距。为了实现针对大脑疾病的精准医学的承诺，有必要将已知的疾病遗传原因（即突变）与对构成潜在治疗靶点的失调分子途径的理解相结合。在这里，将综述已知和拟议的疾病病因机制，以及有前途的实验性 tau 靶向治疗方法，例如最近开发的 tau 降解剂。还将讨论 tau 研究和药物发现领域面临的当前挑战。
