Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity.
Model Senescent Microglia Induce Disease Related Changes in α-Synuclein Expression and Activity.
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DOI：
10.3390/biom8030067
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发表时间：
2018-08-01
期刊：
影响因子：
5.5
通讯作者：
Brown DR
中科院分区：
文献类型：
--
作者：
Angelova DM;Brown DR
衰老是大多数神经退行性疾病最突出的风险因素。然而，将衰老相关的变化纳入神经退行性变模型很少发生。随着我们年龄的增长，大脑中发生的一个重要变化是居住的小胶质细胞群体的表型转变为对大脑中有害变化做出反应的能力较低。这些小胶质细胞被称为营养不良性小胶质细胞。为了更好地模拟神经退行性疾病，我们开发了一种方法，在体外将小胶质细胞转化为衰老表型。在高铁浓度下生长的小鼠小胶质细胞显示出营养不良性小胶质细胞的许多特征，包括铁储存增加、蛋白质（如铁蛋白和钾通道Kv1.3）表达增加、活性氧产生增加和细胞因子释放增加。我们已经将这种新模型应用于α-突触核蛋白的研究，α-突触核蛋白是一种与许多神经退行性疾病密切相关的蛋白质。我们已经证明，来自我们的模型营养不良小胶质细胞的条件培养基通过肿瘤坏死因子α（TNFα）并通过活化B细胞（NF-κB）的核因子κ轻链增强子介导增加α-突触核蛋白的转录和表达。条件培养基还减少α-突触核蛋白四聚体的形成，相关的铁还原酶活性，并增加α-突触核蛋白的聚集体。结果表明，我们已经开发了一种有趣的新的老年小胶质细胞模型，营养不良的小胶质细胞释放的因子，包括TNFα可能对α-突触核蛋白相关疾病的发病机制有显着影响。
Aging is the most prominent risk factor for most neurodegenerative diseases. However, incorporating aging-related changes into models of neurodegeneration rarely occurs. One of the significant changes that occurs in the brain as we age is the shift in phenotype of the resident microglia population to one less able to respond to deleterious changes in the brain. These microglia are termed dystrophic microglia. In order to better model neurodegenerative diseases, we have developed a method to convert microglia into a senescent phenotype in vitro. Mouse microglia grown in high iron concentrations showed many characteristics of dystrophic microglia including, increased iron storage, increased expression of proteins, such as ferritin and the potassium channel, Kv1.3, increased reactive oxygen species production and cytokine release. We have applied this new model to the study of α-synuclein, a protein that is closely associated with a number of neurodegenerative diseases. We have shown that conditioned medium from our model dystrophic microglia increases α-synuclein transcription and expression via tumor necrosis factor alpha (TNFα) and mediated through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The conditioned medium also decreases the formation of α-synuclein tetramers, associated ferrireductase activity, and increases aggregates of α-synuclein. The results suggest that we have developed an interesting new model of aged microglia and that factors, including TNFα released from dystrophic microglia could have a significant influence on the pathogenesis of α-synuclein related diseases.
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影响因子：
7.1
作者：
Bachstetter AD;Van Eldik LJ;Schmitt FA;Neltner JH;Ighodaro ET;Webster SJ;Patel E;Abner EL;Kryscio RJ;Nelson PT
通讯作者：
Nelson PT
DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
3.7
作者：
Charolidi N;Schilling T;Eder C
通讯作者：
Eder C
影响因子：
7.1
作者：
Holtman IR;Raj DD;Miller JA;Schaafsma W;Yin Z;Brouwer N;Wes PD;Möller T;Orre M;Kamphuis W;Hol EM;Boddeke EW;Eggen BJ
通讯作者：
Eggen BJ
影响因子：
9.3
作者：
Flowers A;Bell-Temin H;Jalloh A;Stevens SM Jr;Bickford PC
通讯作者：
Bickford PC