Department of Neurology, University of Washington Medical Center, Seattle, Washington, USA.
J Neurochem. 2013 Dec;127(5):592-9. doi: 10.1111/jnc.12400. Epub 2013 Sep 30.
Microglia, the resident innate immune cells of the CNS, are the primary defenders against microbes and critical to CNS remodeling. Dysregulation of microglial behavior can lead to unchecked pro-inflammatory activity and subsequent neurodegeneration. The molecular mechanisms leading to chronic inflammation and microglial dysfunction in neurodegenerative diseases are not well-understood. It is known that patients with Presenilin 2 (PS2) mutations develop autosomal dominant Alzheimer disease. We have shown that a lack of normal PS2 function is associated with exaggerated microglia pro-inflammatory responses in vitro. To identify pathways by which PS2 regulates microglia and determine how PS2 dysfunction may lead to altered inflammatory pathways, we pursued an unbiased array approach to assess differential expression of microRNAs between murine PS2 knockout (KO) and wild-type microglia. We identified miR146, a negative regulator of monocyte pro-inflammatory response, as constitutively down-regulated in PS2 KO microglia. Consistent with a state of miR146 suppression, we found that PS2 KO microglia express higher levels of the miR146 target protein interleukin-1 receptor-associated kinase-1, and have increased NFκB transcriptional activity. We hypothesize that PS2 impacts microglial responses through modulation of miR146a. PS2 dysfunction, through aging or mutation, may contribute to neurodegeneration by influencing the pro-inflammatory behavior of microglia. Presenilin 2 (PS2), a membrane associated protease, has been implicated in the pathogenesis of Alzheimer disease. We have previously shown that PS2 plays an important role in curbing the proinflammatory response in microglia. Here, we report the novel finding that PS2 participates in maintaining the basal and cytokine induced expression of the innate immunity regulating microRNA, miR146. These data suggest one mechanism by which PS2 works to reign in proinflammatory microglial behavior and that PS2 dysfunction or deficiency could thus result in unchecked proinflammatory activation contributing to neurodegeneration.
小胶质细胞是中枢神经系统中的固有免疫细胞，是抵抗微生物和重塑中枢神经系统的主要防御者。小胶质细胞行为失调可导致不受控制的促炎活性和随后的神经退行性变。导致神经退行性疾病中慢性炎症和小胶质细胞功能障碍的分子机制尚不清楚。已知早老素 2 (PS2) 突变患者会发展出自体显性阿尔茨海默病。我们已经表明，缺乏正常的 PS2 功能与体外小胶质细胞过度的促炎反应有关。为了确定 PS2 调节小胶质细胞的途径，并确定 PS2 功能障碍如何导致改变的炎症途径，我们采用了一种无偏数组方法来评估 PS2 敲除 (KO) 和野生型小胶质细胞之间 microRNA 的差异表达。我们确定了 miR146，一种单核细胞促炎反应的负调节剂，作为 PS2 KO 小胶质细胞中持续下调的 microRNA。与 miR146 抑制状态一致，我们发现 PS2 KO 小胶质细胞表达更高水平的 miR146 靶蛋白白细胞介素 1 受体相关激酶 1，并且具有更高的 NFκB 转录活性。我们假设 PS2 通过调节 miR146a 来影响小胶质细胞的反应。PS2 功能障碍，通过衰老或突变，可能通过影响小胶质细胞的促炎行为导致神经退行性变。早老素 2 (PS2)，一种膜相关蛋白酶，已被牵连到阿尔茨海默病的发病机制中。我们之前已经表明 PS2 在抑制小胶质细胞的促炎反应中起着重要作用。在这里，我们报告了一个新的发现，即 PS2 参与维持先天免疫调节 microRNA miR146 的基础表达和细胞因子诱导表达。这些数据表明 PS2 作用的一种机制是控制促炎小胶质细胞行为，并且 PS2 功能障碍或缺乏可能导致不受控制的促炎激活，从而导致神经退行性变。
