Hoozemans J J M, Rozemuller J M, van Haastert E S, Veerhuis R, Eikelenboom P
Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
Curr Pharm Des. 2008;14(14):1419-27. doi: 10.2174/138161208784480171.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征在于β淀粉样蛋白（Aβ）沉积和神经原纤维缠结的形成。此外，AD患者大脑中的炎症蛋白也会增加。流行病学研究表明，非甾体抗炎药（NSAIDs）可降低患AD的风险，这促使人们对炎症在AD中的作用进行研究。大多数NSAIDs最明确的作用是抑制环氧化酶（COX）。在AD大脑和不同的AD疾病模型中，对组成性表达的COX-1和炎症诱导的COX-2的表达进行了深入研究。尽管有这些研究，但NSAIDs或选择性COX-2抑制剂的临床试验对AD的临床进展几乎没有影响。COX-1和COX-2的表达水平在AD病理的不同阶段会发生变化。在早期，当存在低纤维状Aβ沉积且在皮质区域仅观察到极少数神经原纤维缠结时，神经元中的COX-2会增加。神经元COX-2表达的增加与细胞周期蛋白的表达平行且共定位。COX-1主要在与纤维状Aβ沉积相关的小胶质细胞中表达。这表明在AD大脑中，COX-1和COX-2分别参与炎症和再生途径。在本综述中，我们将讨论COX-1和COX-2在AD病理不同阶段的作用。了解环氧化酶在AD病理中的生理和病理作用可能有助于设计治疗或预防AD的疗法。
