Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease.
Ursodeoxycholic Acid Improves Mitochondrial Function and Redistributes Drp1 in Fibroblasts from Patients with Either Sporadic or Familial Alzheimer's Disease.
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Ursodoxycholic酸改善了线粒体功能，并在患有零星或家族性阿尔茨海默氏病的患者的成纤维细胞中重新分布DRP1。
DOI：
10.1016/j.jmb.2018.08.019
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发表时间：
2018-10-19
影响因子：
5.6
通讯作者：
Mortiboys H
中科院分区：
文献类型：
--
作者：
Bell SM;Barnes K;Clemmens H;Al-Rafiah AR;Al-Ofi EA;Leech V;Bandmann O;Shaw PJ;Blackburn DJ;Ferraiuolo L;Mortiboys H
阿尔茨海默病（AD）是全球痴呆症的主要原因。线粒体异常已被确定在AD的许多细胞类型，与赤字之前的发展的经典病理聚集。熊去氧胆酸（UDCA）是一种治疗原发性胆汁性肝硬化的药物，可改善帕金森病患者以及几种AD和帕金森病动物模型的成纤维细胞中的线粒体功能。在本文中，我们调查了线粒体功能和形态的成纤维细胞与散发性和家族性AD患者。我们发现，散发性AD（sAD）和PSEN1成纤维细胞共享相同的线粒体膜电位和线粒体形态的改变损害。然而，线粒体呼吸在sAD成纤维细胞中减少，在PSEN1成纤维细胞中增加。在AD成纤维细胞中观察到的形态学变化包括线粒体数量减少和细胞核周围线粒体簇集增加以及长线粒体数量增加。我们首次在AD患者组织中发现，UDCA治疗可增加线粒体膜电位和呼吸，并减少AD成纤维细胞中长线粒体的数量。此外，我们发现动力蛋白相关蛋白1（Drp1）水平降低，特别是在sAD和家族性患者成纤维细胞中定位于线粒体的量。UDCA处理后Drp1蛋白表达量和定位增加。当Drp1被敲除时，UDCA的恢复作用被消除。本文强调了UDCA作为神经退行性疾病治疗的潜在用途。散在和PSEN1成纤维细胞共享改变的线粒体表型。这种表型包括降低的膜电位和改变的形态。熊去氧胆酸纠正线粒体形态和膜电位。熊去氧胆酸通过作用于Drp1的数量和定位发挥作用。本文强调了UDCA治疗阿尔茨海默病的潜在用途。
Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinson's disease patients as well as several animal models of AD and Parkinson's disease. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show that both sporadic AD (sAD) and PSEN1 fibroblasts share the same impairment of mitochondrial membrane potential and alterations in mitochondrial morphology. Mitochondrial respiration, however, was decreased in sAD fibroblasts and increased in PSEN1 fibroblasts. Morphological changes seen in AD fibroblasts include reduced mitochondrial number and increased mitochondrial clustering around the cell nucleus as well as an increased number of long mitochondria. We show here for the first time in AD patient tissue that treatment with UDCA increases mitochondrial membrane potential and respiration as well as reducing the amount of long mitochondria in AD fibroblasts. In addition, we show reductions in dynamin-related protein 1 (Drp1) level, particularly the amount localized to mitochondria in both sAD and familial patient fibroblasts. Drp1 protein amount and localization were increased after UDCA treatment. The restorative effects of UDCA are abolished when Drp1 is knocked down. This paper highlights the potential use of UDCA as a treatment for neurodegenerative disease. Sporadic and PSEN1 fibroblasts share a changed mitochondrial phenotype. This phenotype consists of reduced membrane potential and altered morphology. Ursodeoxycholic acid corrects mitochondrial morphology and membrane potential. Ursodeoxycholic acid effects act via action on Drp1 quantity and localization. This paper highlights the potential use of UDCA to treat Alzheimer's disease.
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影响因子：
9.8
作者：
Merrill RA;Dagda RK;Dickey AS;Cribbs JT;Green SH;Usachev YM;Strack S
通讯作者：
Strack S
影响因子：
--
作者：
Martín-Maestro P;Gargini R;García E;Perry G;Avila J;García-Escudero V
通讯作者：
García-Escudero V
DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
影响因子：
4.2
作者：
Huang, HM;Fowler, C;Gibson, GE
通讯作者：
Gibson, GE
影响因子：
4.8
作者：
Chen, Hung-Kai;Ji, Zhong-Sheng;Mahley, Robert W.
通讯作者：
Mahley, Robert W.