Cimino Patrick J, Sokal Izabela, Leverenz James, Fukui Yoshinori, Montine Thomas J
Division of Neuropathology, Department of Pathology, the Neurobiology and Behavior Program, University of Washington, Box 359645, Harborview Medical Center, Seattle, WA 98104, USA.
Am J Pathol. 2009 Oct;175(4):1622-30. doi: 10.2353/ajpath.2009.090443. Epub 2009 Sep 3.
Neuroinflammation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease (AD). Strong epidemiological and experimental evidence supports the use of nonsteroidal anti-inflammatory drugs to reduce AD risk. However, poor outcome in clinical trials and toxicity in a prevention trial have shifted focus away from these cyclooxygenase (COX) inhibitors to seek additional therapeutic targets in the prostaglandin pathway. Previously, the prostaglandin E2 receptor, EP2, was shown to regulate neuroinflammation and reduce Abeta plaque burden in transgenic mice. Unfortunately, widespread EP2 distribution and a direct effect on COX2 induction make EP2 a less desirable target. In this study, we link dedicator of cytokinesis 2 (DOCK2) to the prostaglandin pathway in the brain. Additionally, we show that DOCK2 regulates microglial innate immunity independent of COX2 induction and that DOCK2+ microglia are associated with human AD pathology. Together, these results suggest DOCK2 as a COX2 expression-independent therapeutic target for neurodegenerative diseases such as AD.
神经炎症是包括阿尔茨海默病（AD）在内的几种神经退行性疾病的一个标志。强有力的流行病学和实验证据支持使用非甾体抗炎药来降低AD风险。然而，临床试验结果不佳以及一项预防试验中的毒性问题，已将关注点从这些环氧化酶（COX）抑制剂转移，转而在前列腺素途径中寻找其他治疗靶点。此前，前列腺素E2受体EP2已被证明可调节神经炎症并减轻转基因小鼠的β淀粉样蛋白斑块负担。遗憾的是，EP2广泛分布且对COX2诱导有直接影响，这使得EP2成为一个不太理想的靶点。在本研究中，我们将胞质分裂 dedicator 2（DOCK2）与大脑中的前列腺素途径联系起来。此外，我们表明DOCK2独立于COX2诱导来调节小胶质细胞的固有免疫，并且DOCK2阳性小胶质细胞与人类AD病理学相关。总之，这些结果表明DOCK2作为一种独立于COX2表达的治疗靶点，可用于治疗诸如AD等神经退行性疾病。
