Le Corre Sylvie, Klafki Hans W, Plesnila Nikolaus, Hübinger Gabriele, Obermeier Axel, Sahagún Heidi, Monse Barbara, Seneci Pierfausto, Lewis Jada, Eriksen Jason, Zehr Cynthia, Yue Mei, McGowan Eileen, Dickson Dennis W, Hutton Michael, Roder Hanno M
Sirenade Pharmaceuticals, Am Klopferspitz 19a, 82152 Martinsried, Germany.
Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9673-8. doi: 10.1073/pnas.0602913103. Epub 2006 Jun 12.
An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.
激酶抑制剂K252a的一种口服生物可利用且能穿透血脑屏障的类似物，能够预防tau（P301L）转基因小鼠模型（JNPL3）中的典型运动缺陷，并显著减少可溶性聚集的高度磷酸化tau。然而，在成功治疗的队列中，神经原纤维缠结计数并未减少，这表明tau的主要细胞毒性作用不是由神经原纤维缠结产生的，而是由较低分子量的tau聚集体产生的。我们的研究结果强烈表明，异常的tau过度磷酸化在tau蛋白病的发展中起关键作用，并提出了一种先前未描述的针对涉及tau病理学的神经退行性疾病的治疗策略。
