Inflammatory mechanisms in Alzheimer's disease:: Inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists
Inflammatory mechanisms in Alzheimer's disease:: Inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists
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DOI：
10.1523/jneurosci.20-02-00558.2000
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发表时间：
2000-01-15
影响因子：
5.3
通讯作者：
Landreth, GE
中科院分区：
文献类型：
--
作者：
Combs, CK;Johnson, DE;Landreth, GE
阿尔茨海默病（AD）的特征在于β-淀粉样蛋白原纤维在脑内的细胞外沉积以及随后与淀粉样蛋白斑块相关的小胶质细胞的缔合和表型活化。活化的小胶质细胞产生复杂的局部促炎反应，分泌多种炎症产物。非甾体抗炎药（NSAID）可有效降低AD的发病率和风险，并显著延缓疾病进展。最近认识到的NSAID的靶点是配体激活的核受体过氧化物酶体增殖物激活受体γ（PPAR γ）。PPAR γ是一种DNA结合转录因子，其转录调节作用在激动剂结合后被激活。我们报告说，NSAIDs，噻唑烷二酮类药物和天然配体前列腺素J2作为PPAR γ的激动剂，抑制β-淀粉样蛋白刺激的小胶质细胞和单核细胞分泌促炎产物，负责神经毒性和星形胶质细胞活化。激活的过氧化物酶体增殖物激活物受体γ也阻止单核细胞分化成活化的巨噬细胞。PPAR-gamma激动剂显示抑制β-淀粉样蛋白刺激的细胞因子基因白细胞介素-6和肿瘤坏死因子α的表达。此外，过氧化物酶体增殖物激活受体γ激动剂抑制环氧合酶-2的表达。这些数据提供了直接的证据，PPARgamma在调节小胶质细胞和单核细胞对β-淀粉样蛋白的炎症反应中起着关键作用。我们认为，非甾体类抗炎药治疗AD的疗效可能是其对过氧化物酶体增殖物激活受体γ的作用的结果，而不是其典型的目标环加氧酶。重要的是，这些药物在抑制广泛的炎症反应方面的功效表明，PPAR γ激动剂可能为AD提供一种新的治疗方法。
Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid fibrils within the brain and the subsequent association and phenotypic activation of microglial cells associated with the amyloid plaque. The activated microglia mount a complex local proinflammatory response with the secretion of a diverse range of inflammatory products. Nonsteroidal anti-inflammatory drugs (NSAIDs) are efficacious in reducing the incidence and risk of AD and significantly delaying disease progression. A recently appreciated target of NSAIDs is the ligand-activated nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma). PPAR gamma is a DNA-binding transcription factor whose transcriptional regulatory actions are activated after agonist binding. We report that NSAIDs, drugs of the thiazolidinedione class, and the natural ligand prostaglandin J2 act as agonists for PPAR gamma and inhibit the beta-amyloid-stimulated secretion of proinflammatory products by microglia and monocytes responsible for neurotoxicity and astrocyte activation. The activation of PPAR gamma also arrested the differentiation of monocytes into activated macrophages. PPAR gamma agonists were shown to inhibit the beta-amyloid-stimulated expression of the cytokine genes interleukin-6 and tumor necrosis factor alpha. Furthermore, PPAR gamma agonists inhibited the expression of cyclooxygenase-2. These data provide direct evidence that PPAR gamma plays a critical role in regulating the inflammatory responses of microglia and monocytes to beta-amyloid. We argue that the efficacy of NSAIDs in the treatment of AD may be a consequence of their actions on PPAR gamma rather than on their canonical targets the cyclooxygenases. Importantly, the efficacy of these agents in inhibiting a broad range of inflammatory responses suggests PPAR gamma agonists may provide a novel therapeutic approach to AD.