Presenilin 2 influences miR146 level and activity in microglia.
Presenilin 2 influences miR146 level and activity in microglia.
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DOI：
10.1111/jnc.12400
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发表时间：
2013-12
影响因子：
4.7
通讯作者：
Garden GA
中科院分区：
文献类型：
--
作者：
Jayadev S;Case A;Alajajian B;Eastman AJ;Möller T;Garden GA
小胶质细胞是中枢神经系统固有的免疫细胞，是抵抗微生物的主要防御者，对中枢神经系统重塑至关重要。小胶质细胞行为的失调可导致不受抑制的促炎活性和随后的神经变性。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。已知具有早老素2（PS2）突变的患者发展为常染色体显性阿尔茨海默病。我们已经表明，缺乏正常的PS2功能与夸大的小胶质细胞促炎反应在体外。为了鉴定PS2调节小胶质细胞的途径并确定PS2功能障碍如何导致炎症途径的改变，我们采用无偏阵列方法来评估小鼠PS2敲除（KO）和野生型小胶质细胞之间microRNA的差异表达。我们鉴定了miR 146，一种单核细胞促炎反应的负调节因子，在PS2 KO小胶质细胞中组成性下调。与miR 146抑制状态一致，我们发现PS2 KO小胶质细胞表达更高水平的miR 146靶蛋白白细胞介素-1受体相关激酶-1，并具有增加的NFκB转录活性。我们假设PS2通过调节miR 146 a影响小胶质细胞反应。PS2功能障碍，通过老化或突变，可能有助于通过影响小胶质细胞的促炎行为的神经变性。
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.
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DOI：
10.3233/jad-2010-1414
发表时间：
2010
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Hensley K
通讯作者：
Hensley K
影响因子：
56.9
作者：
Cao, ZD;Henzel, WJ;Gao, XO
通讯作者：
Gao, XO
影响因子：
6.2
作者：
Ponomarev, Eugene D.;Veremeyko, Tatiana;Weiner, Howard L.
通讯作者：
Weiner, Howard L.
影响因子：
3.7
作者：
Jayadev S;Case A;Eastman AJ;Nguyen H;Pollak J;Wiley JC;Möller T;Morrison RS;Garden GA
通讯作者：
Garden GA
影响因子：
7.3
作者：
Hass MR;Sato C;Kopan R;Zhao G
通讯作者：
Zhao G