APP metabolism regulates tau proteostasis in human cerebral cortex neurons.
APP metabolism regulates tau proteostasis in human cerebral cortex neurons.
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DOI：
10.1016/j.celrep.2015.03.068
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发表时间：
2015-05-05
期刊：
影响因子：
8.8
通讯作者：
Livesey FJ
中科院分区：
文献类型：
--
作者：
Moore S;Evans LD;Andersson T;Portelius E;Smith J;Dias TB;Saurat N;McGlade A;Kirwan P;Blennow K;Hardy J;Zetterberg H;Livesey FJ
APP蛋白的Aβ肽片段的积累和微管相关蛋白tau的神经元缠结是阿尔茨海默病（AD）的细胞标志。为了研究APP代谢与tau蛋白水平和磷酸化之间的关系，我们研究了具有遗传形式的AD的人干细胞来源的前脑神经元，所有这些神经元都增加了致病性Aβ肽的释放。我们发现，在突变APP或增加其剂量的遗传形式的AD中，细胞内tau蛋白显著增加，这表明APP代谢与tau蛋白稳态的变化相关联。通过β-分泌酶和γ-分泌酶抑制以及γ-分泌酶调节来操纵APP代谢，导致tau蛋白水平的特异性增加和减少。这些数据表明，APP代谢调节tau蛋白质稳态，并表明APP加工和tau蛋白之间的关系并不仅仅通过细胞外Aβ信号传导到神经元介导。来自不同遗传形式的阿尔茨海默病的神经元在APP加工方面存在差异APP突变增加总tau蛋白和磷酸化tau蛋白; PSEN 1突变不APP加工的药理学操作改变tau蛋白水平APP对tau蛋白稳定的调节不仅仅是通过细胞外Aβ摩尔等人。使用由家族性阿尔茨海默病干细胞制成的神经元来揭示与疾病有关的三种蛋白质如何在控制疾病进展的途径中联系起来。他们表明，靶向这一途径的药物改变了参与神经变性的蛋白质，微管相关蛋白tau的水平，开辟了一条潜在的治疗途径。
Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons. Neurons from different genetic forms of Alzheimer’s disease differ in APP processing APP mutations increase total and phosphorylated tau; PSEN1 mutations do not Pharmacological manipulation of APP processing changes tau protein levels APP regulation of tau proteostasis is not solely mediated through extracellular Aβ Moore et al. use neurons made from familial Alzheimer’s disease stem cells to reveal how three proteins involved in the disease are linked in a pathway that controls disease progression. They show that drugs that target this pathway change levels of a protein involved in neurodegeneration, microtubule-associated protein tau, opening up a potential therapeutic pathway.
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
DOI：
10.1016/s0006-291x(84)80190-4
发表时间：
1984-01-01
影响因子：
3.1
作者：
GLENNER, GG;WONG, CW
通讯作者：
WONG, CW
DOI：
10.1523/jneurosci.2775-12.2012
发表时间：
2012-11-14
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Lauritzen I;Pardossi-Piquard R;Bauer C;Brigham E;Abraham JD;Ranaldi S;Fraser P;St-George-Hyslop P;Le Thuc O;Espin V;Chami L;Dunys J;Checler F
通讯作者：
Checler F