Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice.
Small molecule inhibitor of tau self-association in a mouse model of tauopathy: A preventive study in P301L tau JNPL3 mice.
复制标题
tau蛋白病小鼠模型中tau蛋白自身结合的小分子抑制剂：P301L tau JNPL3小鼠的预防性研究。
DOI：
10.1371/journal.pone.0286523
复制
发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
tau生物学的进展和淀粉样蛋白导向的免疫治疗的困难提高了对tau作为神经退行性疾病的小分子药物发现的靶点的兴趣。在这里，我们评估了OLX-07010，一种tau自缔合的小分子抑制剂，用于预防tau聚集。该研究的主要终点是与媒介物对照小鼠相比，经处理的JNPL 3小鼠中不溶性tau聚集体的统计学显著减少。次要终点是不溶性tau聚集体的剂量依赖性减少、磷酸化tau的减少和可溶性tau的减少。该研究在JNPL 3小鼠中进行，JNPL 3小鼠代表具有P301 L tau突变的4-重复tau蛋白病的遗传形式（例如，进行性核上性麻痹和额颞叶痴呆）。P301 L突变使tau易于聚集;因此，JNPL 3小鼠比没有突变的人tau小鼠模型呈现出更具挑战性的靶标。用媒介物、30 mg/kg化合物剂量或40 mg/kg化合物剂量处理3至7月龄的JNPL 3小鼠。生物化学方法被用来评估自身相关的tau蛋白，不溶性tau蛋白聚集体，总tau蛋白，磷酸化的tau蛋白在后脑，皮质和海马。媒介物组在后脑中具有比基线组更高水平的不溶性tau;用40 mg/kg化合物剂量处理防止了这种增加。在皮质中，不溶性tau的水平在基线组和溶媒组中相似，表明这些小鼠的病理表型在研究终点开始出现，并且如最初表征的模型表型的发展延迟。在4个月的治疗期间未观察到药物相关的不良反应。
Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with the P301L tau mutation (e.g., progressive supranuclear palsy and frontotemporal dementia). The P301L mutation makes tau prone to aggregation; therefore, JNPL3 mice present a more challenging target than mouse models of human tau without mutations. JNPL3 mice were treated from 3 to 7 months of age with Vehicle, 30 mg/kg compound dose, or 40 mg/kg compound dose. Biochemical methods were used to evaluate self-associated tau, insoluble tau aggregates, total tau, and phosphorylated tau in the hindbrain, cortex, and hippocampus. The Vehicle group had higher levels of insoluble tau in the hindbrain than the Baseline group; treatment with 40 mg/kg compound dose prevented this increase. In the cortex, the levels of insoluble tau were similar in the Baseline and Vehicle groups, indicating that the pathological phenotype of these mice was beginning to emerge at the study endpoint and that there was a delay in the development of the phenotype of the model as originally characterized. No drug-related adverse effects were observed during the 4-month treatment period.
登录
查看更多内容
影响因子：
4
作者：
Davidowitz, Eliot J.;Krishnamurthy, Pavan K.;Moe, James G.
通讯作者：
Moe, James G.
影响因子：
12.7
作者：
Jiang, Lulu;Ash, Peter E. A.;Wolozin, Benjamin
通讯作者：
Wolozin, Benjamin
影响因子：
4.8
作者：
通讯作者：
--
影响因子：
14
作者：
Gaugler, Joseph;James, Bryan;Hohman, Timothy J.
通讯作者：
Hohman, Timothy J.
影响因子：
3.3
作者：
Buccarello, Lucia;Grignaschi, Giuliano;Borsello, Tiziana
通讯作者：
Borsello, Tiziana