Targeting Rho Kinases for Alzheimer's disease Therapeutics

项目摘要 目前阿尔茨海默病(AD)的治疗主要集中在淀粉样蛋白(Aβ，Aβ)多肽，但生物标记物 研究表明，在临床症状出现之前，Aβ效应可能是最大的。在Aβ下游， 突触丢失和微管相关蛋白tau在细胞内的积聚与 认知功能下降，但很少有治疗策略针对这些机制。目前，二十九个激酶 抑制剂被用来治疗人类疾病，其中有两种是泛Rho相关的蛋白激酶 (ROCK)1和2抑制剂。在2000年代中期，这些岩石被确定为假定的平移目标 遏制Aβ的生产。然而，由于三个关键障碍，这条令人兴奋的道路上的进展停滞不前：1) 除了与A代β相关的机制外，ROCK和AD发病机制之间缺乏联系，2) 缺乏遗传模型来测试ROCK1或ROCK2在阿尔茨海默病小鼠中的作用，以及3)缺乏激酶抑制剂 提供高度的岩石选择性和大脑穿透力。我们的目标是通过新的数据链接来克服这些障碍 岩石在AD进程中的构造塑性变化及采用新的ROCK1和ROCK2条件 基因敲除小鼠以及新型泛素和异构体选择性岩石抑制剂，表现出高生物利用度和 无明显副作用的脑部穿透力。在目标1中，我们将讨论ROCK1和ROCK2的贡献 致β诱导的树突状结构变性。在目标2中，我们将测试慢性摇滚抑制的效果 小鼠AD模型，在目标3中，我们将阐明ROCK1和ROCK2介导AD的机制 Tau蛋白动态平衡和自噬诱导。

Project Summary Current Alzheimer's disease (AD) therapies predominantly focus on amyloid-β (Aβ) peptides, but biomarker studies indicate that Aβ effects may be maximal before onset of clinical symptoms. Downstream of Aβ, synapse loss and intracellular accumulation of the microtubule-associated protein tau correlate strongly with cognitive decline, yet few therapeutic strategies target these mechanisms. Presently, twenty-nine kinase inhibitors are used to treat human diseases, and out of these, two are pan- Rho-associated protein kinases (ROCK) 1 and 2 inhibitors. In the mid-2000s, the ROCKs were identified as putative translational targets to curb Aβ production. However, progress on this exciting avenue languished due to three critical barriers: 1) the lack of connection between ROCKs and AD pathogenesis beyond mechanisms tied to Aβ generation, 2) the lack of genetic models to test the role of ROCK1 or ROCK2 in AD mice, and 3) the lack of kinase inhibitors offering high ROCK-selectivity and brain penetrance. We aim to overcome these barriers with new data linking ROCKs to structural plasticity changes in AD progression and employing new ROCK1 and ROCK2 conditional knockout mice as well as novel pan- and isoform-selective ROCK inhibitors that exhibit high bioavailability and brain penetrance with no gross side-effects. In Aim 1, we will address the contribution of ROCK1 and ROCK2 to Aβ-induced dendritic structure degeneration. In Aim 2, we will test the effects of chronic ROCK inhibition in mouse models of AD, and in Aim 3, we will elucidate the mechanisms by which ROCK1 and ROCK2 mediate tau protein homeostasis and autophagy induction.