Effects of Lipotoxicity in Brain Microvascular Endothelial Cells During Sirt3 Deficiency-Potential Role in Comorbid Alzheimer's Disease.
Effects of Lipotoxicity in Brain Microvascular Endothelial Cells During Sirt3 Deficiency-Potential Role in Comorbid Alzheimer's Disease.
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SIRT3缺乏对脑微血管内皮细胞脂毒性的影响--在阿尔茨海默病中的潜在作用。
DOI：
10.3389/fnagi.2021.716616
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发表时间：
2021
影响因子：
4.8
通讯作者：
Pugazhenthi S
中科院分区：
文献类型：
--
作者：
Tyagi A;Mirita C;Shah I;Reddy PH;Pugazhenthi S
沉默信息调节因子3（SIRT 3）是一种NAD+依赖性脱乙酰酶，可增强关键线粒体蛋白的功能。我们先前已经证明，Sirt 3基因的缺失导致脑中代谢酶的下调、线粒体功能障碍和神经炎症，这是阿尔茨海默病（AD）的主要原因。我们最近还报道了阿尔茨海默氏症转基因小鼠中Sirt 3基因缺失导致神经炎症加剧、淀粉样斑块沉积和小胶质细胞活化。AD常与其他由合并症引起的脑病变共存，这些合并症可通过神经血管单位发挥其有害作用。该单位由脑微血管内皮细胞（BMEC）、星形胶质细胞的尾足和周细胞组成。BMEC与其他血管内皮细胞的独特之处在于它们通过紧密连接蛋白粘合在一起。BMEC与循环因子持续接触，因为它们排列在管腔侧。因此，我们假设由合并症引起的血管内皮损伤在神经炎症中起重要作用。在此，我们研究了脂毒性在BMEC中的作用，以及Sirt 3缺陷如何使用体内和体外模型促进脂毒性对它们的有害作用。我们观察到在西方饮食喂养的APP/PS1小鼠的脑样品中SIRT 3和紧密连接蛋白的水平降低。类似的观察结果也出现在阿尔茨海默氏症的尸检样本中。将BEND 3细胞（小鼠脑源性内皮细胞3）暴露于高葡萄糖和棕榈酸的组合导致SIRT 3、密蛋白-5和ZO-1的水平显著（P <0.01-P < 0.001）降低。在这些处理的细胞中还观察到炎症介质的诱导，包括考克斯-2、CXCL 1、RANTES和GADD 45 β。有趣的是，Sirt 3沉默的BEND 3细胞的诱导作用更强，表明Sirt 3缺乏加剧了炎症反应。软脂酸诱导炎症介质的能力更强。当Sirt 3沉默的BEND 3和Sirt 3沉默的BV 2细胞的共培养物暴露于棕榈酸时，观察到显著的细胞毒性和小胶质细胞形态的变化。这些共培养物的跨内皮电阻测量表明屏障完整性降低。这项研究的结果表明，合并症的高脂血症可以通过诱导炎症介质和减少AD脑血管内皮细胞中的紧密连接蛋白，导致小胶质细胞活化，从而损害血脑屏障的完整性。
Silence information regulator 3 (SIRT3) is an NAD+ dependent deacetylase enzyme that enhances the function of key mitochondrial proteins. We have earlier demonstrated that deletion of Sirt3 gene leads to downregulation of metabolic enzymes, mitochondrial dysfunction and neuroinflammation in the brain, the major causes of Alzheimer’s disease (AD). We also reported recently that Sirt3 gene deletion in Alzheimer’s transgenic mice leads to exacerbation of neuroinflammation, amyloid plaque deposition and microglial activation. AD often coexists with other brain lesions caused by comorbidities which can exert their deleterious effects through the neurovascular unit. This unit consists of brain microvascular endothelial cells (BMECs), end feet of astrocytes, and pericytes. BMECs are uniquely different from other vascular endothelial cells because they are glued together by tight-junction proteins. BMECs are in constant contact with circulating factors as they line the luminal side. Therefore, we hypothesized that vascular endothelial injury caused by comorbidities plays a significant role in neuroinflammation. Herein, we investigated the effects of lipotoxicity in BMECs and how Sirt3 deficiency facilitate the deleterious effects of lipotoxicity on them using in vivo and in vitro models. We observed decreases in the levels of SIRT3 and tight junction proteins in the brain samples of western diet-fed APP/PS1 mice. Similar observations were obtained with Alzheimer’s post-mortem samples. Exposure of BEND3 cells, mouse brain-derived Endothelial cells3, to a combination of high glucose and palmitic acid resulted in significant (P < 0.01-P < 0.001) decreases in the levels of SIRT3, claudin-5 and ZO-1. Induction of inflammatory mediators, including Cox-2, CXCL1, RANTES, and GADD45β was also observed in these treated cells. Interestingly, the induction was more with Sirt3-silenced BEND3 cells, suggesting that Sirt3 deficiency exacerbates inflammatory response. Palmitic acid was more potent in inducing the inflammatory mediators. Significant cytotoxicity and changes in microglial morphology were observed when cocultures of Sirt3-silenced BEND3 and Sirt3-silenced BV2 cells were exposed to palmitic acid. Transendothelial electrical resistance measurement with these cocultures suggested decreased barrier integrity. The findings of this study suggest that hyperlipidemia in comorbidities can compromise blood brain barrier integrity by inducing inflammatory mediators and decreasing tight junction proteins in the vascular endothelial cells of the AD brain, leading to activation of microglia.
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影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
9.3
作者：
Krasnow, Stephanie M.;Knoll, J. Gabriel;Marks, Daniel L.
通讯作者：
Marks, Daniel L.
影响因子：
4.2
作者：
Mehrabadi, Abbas Rezaeian;Korolainen, Minna A.;Kauppinen, Tiina M.
通讯作者：
Kauppinen, Tiina M.
影响因子：
7.2
作者：
Daneman, Richard;Prat, Alexandre
通讯作者：
Prat, Alexandre