Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer's disease.
Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer's disease.
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DOI：
10.1016/j.bbi.2017.05.012
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Fukuchi KI
中科院分区：
文献类型：
--
作者：
Yang J;Kou J;Lalonde R;Fukuchi KI
神经炎症是阿尔茨海默病（AD）的普遍特征，其特征在于活化的小胶质细胞、增加的促炎细胞因子和/或浸润的免疫细胞。辅助性T细胞17（Th 17）存在于AD脑实质中，并且在聚集的淀粉样β蛋白（Aβ）沉积物周围鉴定出白细胞介素-17A（IL-17 A）。然而，IL-17 A在AD发病机制中的作用仍然难以捉摸。我们通过重组腺相关病毒血清型5（rAAV 5）介导的颅内基因递送在AD小鼠模型中过表达IL-17 A。注射载体（PBS）或携带lacZ基因的rAAV 5的AD模型小鼠作为对照。IL-17 A没有加重IL-17 A过表达小鼠的神经炎症。我们发现，IL-17 A过表达显著改善葡萄糖代谢，降低海马和脑脊液中可溶性Aβ水平，显著减少脑淀粉样血管病，并适度但显著改善焦虑和学习障碍。此外，ATP结合盒亚家族A成员1（ABCA 1），可以将Aβ从大脑转运到血液循环中，在IL-17 A过表达小鼠中显著增加。在体外用IL-17 A处理脑内皮bEnd.3细胞通过ERK激活诱导ABCA 1蛋白表达的剂量依赖性增加。我们的研究表明，IL-17 A可能通过上调血脑屏障内皮细胞中的ABCA 1来降低脑中的Aβ水平。
Neuroinflammation is a pervasive feature of Alzheimer’s disease (AD) and characterized by activated microglia, increased proinflammatory cytokines and/or infiltrating immune cells. T helper 17 (Th17) cells are found in AD brain parenchyma and interleukin-17A (IL-17A) is identified around deposits of aggregated amyloid β protein (Aβ). However, the role of IL-17A in AD pathogenesis remains elusive. We overexpressed IL-17A in an AD mouse model via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated intracranial gene delivery. AD model mice subjected to injection of a vehicle (PBS) or rAAV5 carrying the lacZ gene served as controls. IL-17A did not exacerbate neuroinflammation in IL-17A-overexpressing mice. We found that IL-17A overexpression markedly improved glucose metabolism, decreased soluble Aβ levels in the hippocampus and cerebrospinal fluid, drastically reduced cerebral amyloid angiopathy, and modestly but significantly improved anxiety and learning deficits. Moreover, the ATP-binding cassette subfamily A member 1 (ABCA1), which can transport Aβ from the brain into the blood circulation, significantly increased in IL-17A-overexpressing mice. In vitro treatment of brain endothelial bEnd.3 cells with IL-17A induced a dose-dependent increase in protein expression of ABCA1 through ERK activation. Our study suggests that IL-17A may decrease Aβ levels in the brain by upregulating ABCA1 in blood-brain barrier endothelial cells.
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影响因子：
--
作者：
Craft, Suzanne;Baker, Laura D.;Montine, Thomas J.;Minoshima, Satoshi;Watson, G. Stennis;Claxton, Amy;Arbuckle, Matthew;Callaghan, Maureen;Tsai, Elaine;Plymate, Stephen R.;Green, Pattie S.;Leverenz, James;Cross, Donna;Gerton, Brooke
通讯作者：
Gerton, Brooke
DOI：
10.3233/jad-140027
发表时间：
2014
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Ghiso J;Fossati S;Rostagno A
通讯作者：
Rostagno A
影响因子：
3.8
作者：
Akhter, Hasina;Ballinger, Carol;Liu, Rui-Ming
通讯作者：
Liu, Rui-Ming
7, 8-二羟基黄酮激活 TrkB 可增加突触 AMPA 亚基并改善阿尔茨海默病小鼠模型的空间记忆缺陷
影响因子：
4.7
作者：
Gao, Lei;Tian, Mi;Zeng, Yan
通讯作者：
Zeng, Yan
影响因子：
6.9
作者：
Cupino, Tanya L.;Zabel, Matthew K.
通讯作者：
Zabel, Matthew K.