Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage.
Acyl-coenzyme A:cholesterol acyltransferase 1 blockage enhances autophagy in the neurons of triple transgenic Alzheimer's disease mouse and reduces human P301L-tau content at the presymptomatic stage.
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DOI：
10.1016/j.neurobiolaging.2015.04.002
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发表时间：
2015-07
影响因子：
4.2
通讯作者：
Chang TY
中科院分区：
文献类型：
--
作者：
Shibuya Y;Niu Z;Bryleva EY;Harris BT;Murphy SR;Kheirollah A;Bowen ZD;Chang CCY;Chang TY
阿尔茨海默病(AD)患者表现为淀粉样变性和肌萎缩侧索硬化。在阿尔茨海默病小鼠模型中，使用小分子酶抑制剂的药物抑制，或酰基辅酶A：胆固醇酰基转移酶1(ACAT1)的遗传失活，可以减轻淀粉样变性和恢复认知功能障碍。在小胶质细胞中，ACAT1阻断增加自噬小体的形成，并刺激淀粉样蛋白β肽1-42的降解。在这里，我们假设，在神经元中，阻断ACAT1增强了自噬，并增加了自噬介导的P301L-tau蛋白的降解。我们在异位表达人tau的小鼠神经母细胞瘤细胞和表达突变形式的APP、PS1和人tau的三重转基因AD(3xTg-AD)小鼠的原代神经元中测试了这种可能性。结果表明，阻断ACAT1可增加自噬小体的形成，降低P301L-tau蛋白含量，但不影响内源性tau蛋白含量。在体内，缺乏Acat1会降低年轻3xTg-AD小鼠大脑中P301L-tau蛋白的含量，但在老年小鼠中不会，老年小鼠脑中P301L-tau蛋白发生广泛的过度磷酸化和聚集。这些结果表明，除了改善年轻和老年AD小鼠的淀粉样变性外，ACAT1阻断可能通过减少早期的肌萎缩侧索硬化症而使AD受益。
Patients with Alzheimer’s disease (AD) display amyloidopathy and tauopathy. In mouse models of AD, pharmacological inhibition using small molecule enzyme inhibitors, or genetic inactivation of Acyl-CoA: cholesterol acyltransferase 1 (ACAT1) diminished amyloidopathy and restored cognitive deficits. In microglia, ACAT1 blockage increases autophagosome formation and stimulates amyloid β peptide1–42 degradation. Here we hypothesize that in neurons ACAT1 blockage augments autophagy and increases autophagy-mediated degradation of P301L-tau protein. We tested this possibility in murine neuroblastoma cells ectopically expressing human tau, and in primary neurons isolated from triple transgenic AD (3XTg-AD) mice that express mutant forms of APP, PS1, and human tau. The results show that ACAT1 blockage increases autophagosome formation and decreases P301L-tau protein content without affecting endogenous mouse tau protein content. In vivo, lacking Acat1 decreases P301L-tau protein content in the brains of young 3XTg-AD mice but not in those of old mice, where extensive hyperphosphorylations and aggregation of P301L-tau take place. These results suggest that, in addition to ameliorating amyloidopathy in both young and old AD mice, ACAT1 blockage may benefit AD by reducing tauopathy at early stage.
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神经元中的自噬诱导和自噬体清除：与阿尔茨海默氏病自噬病理学的关系。
影响因子：
5.3
作者：
Boland, Barry;Kumar, Asok;Lee, Sooyeon;Platt, Frances M.;Wegiel, Jerzy;Yu, W. Haung;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
16.2
作者：
Hoover, Brian R.;Reed, Miranda N.;Su, Jianjun;Penrod, Rachel D.;Kotilinek, Linda A.;Grant, Marianne K.;Pitstick, Rose;Carlson, George A.;Lanier, Lorene M.;Yuan, Li-Lian;Ashe, Karen H.;Liao, Dezhi
通讯作者：
Liao, Dezhi
影响因子：
11.4
作者：
Area-Gomez, Estela;Castillo, Maria Del Carmen Lara;Tambini, Marc D.;Guardia-Laguarta, Cristina;de Groof, Ad J. C.;Madra, Moneek;Ikenouchi, Junichi;Umeda, Masato;Bird, Thomas D.;Sturley, Stephen L.;Schon, Eric A.
通讯作者：
Schon, Eric A.
影响因子：
3.6
作者：
Hayashi, Teruo;Fujimoto, Michiko
通讯作者：
Fujimoto, Michiko
影响因子：
4.8
作者：
Chan, Robin B.;Oliveira, Tiago G.;Di Paolo, Gilbert
通讯作者：
Di Paolo, Gilbert