Lefort Roger
The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, and Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA,
Neurotherapeutics. 2015 Jan;12(1):19-28. doi: 10.1007/s13311-014-0328-4.
Alzheimer's disease (AD) is a monumental public health crisis with no effective cure or treatment. To date, therapeutic strategies have focused almost exclusively on upstream signaling events in the disease, namely on β-amyloid and amyloid precursor protein processing, and have, unfortunately, yielded few, if any, promising results. An alternative approach may be to target signaling events downstream of β-amyloid and even tau. However, with so many pathways already linked to the disease, understanding which ones are "drivers" versus "passengers" in the pathogenesis of the disease remains a tremendous challenge. Given the critical roles of Rho-guanosine triphosphatases (GTPases) in regulating the actin cytoskeleton and spine dynamics, and the strong association between spine abnormalities and cognition, it is not surprising that mutations in a number of genes involved in Rho-GTPase signaling have been implicated in several brain disorders, including schizophrenia and autism. And now, there is mounting literature implicating Rho-GTPase signaling in AD pathogenesis as well. Here, I review this evidence, with a particular emphasis on the regulators of Rho-GTPase signaling, namely guanine nucleotide exchange factors and GTPase-activating proteins. Several of these have been linked to various aspects of AD, and each offers a novel potential therapeutic target for AD.
阿尔茨海默病（AD）是一场重大的公共卫生危机，目前尚无有效的治愈方法或治疗手段。迄今为止，治疗策略几乎完全集中在该疾病的上游信号事件上，即β-淀粉样蛋白和淀粉样前体蛋白的加工过程，然而不幸的是，即便有成效，也收效甚微。另一种方法可能是针对β-淀粉样蛋白甚至tau蛋白下游的信号事件。然而，鉴于已有众多途径与该疾病相关联，要弄清楚哪些是疾病发病机制中的“驱动因素”，哪些是“乘客因素”，仍然是一项巨大的挑战。鉴于Rho-鸟苷三磷酸酶（GTP酶）在调节肌动蛋白细胞骨架和突触棘动态方面的关键作用，以及突触棘异常与认知之间的紧密关联，参与Rho-GTP酶信号传导的一些基因发生突变与包括精神分裂症和自闭症在内的多种脑部疾病有关，这也就不足为奇了。如今，越来越多的文献表明Rho-GTP酶信号传导也与AD的发病机制有关。在此，我将综述这方面的证据，尤其着重于Rho-GTP酶信号传导的调节因子，即鸟嘌呤核苷酸交换因子和GTP酶激活蛋白。其中有几种已与AD的各个方面相关联，并且每种都为AD提供了一个新的潜在治疗靶点。
