Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARγ-mediated mechanisms in Alzheimer's disease models.
Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARγ-mediated mechanisms in Alzheimer's disease models.
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DOI：
10.1371/journal.pone.0015816
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发表时间：
2011-01-05
期刊：
影响因子：
3.7
通讯作者：
Bazan NG
中科院分区：
文献类型：
--
作者：
Zhao Y;Calon F;Julien C;Winkler JW;Petasis NA;Lukiw WJ;Bazan NG
神经保护素D1(NPD1)是一种立体选择性介体，来源于omega-3必需脂肪酸二十二碳六烯酸(DHA)，具有很强的消炎和神经保护生物活性。NPD1减少老化的人脑细胞释放Aβ42肽，并在阿尔茨海默病(AD)大脑中严重耗尽。在这里，我们用3xTg-AD小鼠模型和原代培养的人神经胶质细胞进一步研究了NPD1‘S的神经发生作用机制，无论是用Aβ42寡聚肽攻击，还是转染β淀粉样前体蛋白(βAPP)SW(瑞典双突变APP695sw，K595N-M596L)。我们还发现，NPD1下调Aβ42触发的促炎症酶环氧合酶-2(COX-2)和B-94(一种肿瘤坏死因子-α诱导的促炎因子)的表达，并下调HNG细胞的凋亡。此外，NPD1通过下调β分泌酶1(BACE1)，激活β分泌酶ADAM10，上调SAPPα，从而抑制Aβ42肽的脱落，从而将αAPP全酶从淀粉样变性途径转变为非淀粉样变性途径。使用PPARγ激动剂罗格列酮和不可逆PPARγ拮抗剂GW9662，以及过表达PPARγ，表明NPD1介导的BACE1和Aβ42肽释放的下调是依赖PPARγ的。总之，NPD1的生物活性有效地下调炎症信号、淀粉样变性APP的切割和细胞凋亡，强调了这种脂质介体在神经变性的早期阶段拯救人脑细胞的潜力。
Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. NPD1 reduces Aβ42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with Aβ42 oligomeric peptide, or transfected with beta amyloid precursor protein (βAPP)sw (Swedish double mutation APP695sw, K595N-M596L). We also show that NPD1 downregulates Aβ42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-α-inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Aβ42 peptide shedding by down-regulating β-secretase-1 (BACE1) while activating the α-secretase ADAM10 and up-regulating sAPPα, thus shifting the cleavage of βAPP holoenzyme from an amyloidogenic into the non-amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist rosiglitazone, the irreversible PPARγ antagonist GW9662, and overexpressing PPARγ suggests that the NPD1-mediated down-regulation of BACE1 and Aβ42 peptide release is PPARγ-dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations.
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影响因子：
3.7
作者：
Astarita G;Jung KM;Berchtold NC;Nguyen VQ;Gillen DL;Head E;Cotman CW;Piomelli D
通讯作者：
Piomelli D
影响因子：
4.1
作者：
d'Abramo, C;Massone, S;Ricciarelli, R
通讯作者：
Ricciarelli, R
影响因子：
7.4
作者：
Jang, JH;Surh, YJ
通讯作者：
Surh, YJ
影响因子：
2.2
作者：
Galasko D;Montine TJ
通讯作者：
Montine TJ
影响因子：
4.8
作者：
Gonzalez-Periz, Ana;Planaguma, Anna;Claria, Joan
通讯作者：
Claria, Joan