Alzheimer Aβ Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKα3 Neurons by Secretion
Alzheimer Aβ Assemblies Accumulate in Excitatory Neurons upon Proteasome Inhibition and Kill Nearby NAKα3 Neurons by Secretion
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蛋白酶体抑制后，阿尔茨海默病 Aβ 聚集在兴奋性神经元中积累，并通过分泌杀死附近的 NAKα3 神经元
DOI：
10.1016/j.isci.2019.01.018
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发表时间：
2019
期刊：
影响因子：
5.8
通讯作者：
Hoshi Minako
中科院分区：
文献类型：
--
作者：
Komura Hitomi;Kakio Shota;Sasahara Tomoya;Arai Yoshie;Takino Naomi;Sato Michio;Satomura Kaori;Ohnishi Takayuki;Nabeshima Yo-ichi;Muramatsu Shin-ichi;Kii Isao;Hoshi Minako
我们从阿尔茨海默病（AD）患者脑中鉴定出β-淀粉样蛋白（Aβ）30聚体，称为淀粉样球蛋白（amylospheroids），是导致神经退行性变的毒性实体，并表明Na+，K+-ATP酶α3（NAKα3）是淀粉样球蛋白介导的神经退行性变的唯一靶点。然而，目前尚不清楚淀粉样蛋白在神经元中的何处形成以及它们如何到达其靶点以诱导神经变性。在这里，我们提出了一个体外培养系统，旨在按时间顺序遵循淀粉样蛋白前体蛋白轴承早发性AD突变的成熟神经元中淀粉样蛋白球的形成。发现淀粉球主要积聚在兴奋性神经元的trans-Golgi网络中，并且最初在轴突中运输。蛋白酶体抑制通过增加Aβ水平和诱导树突转运显著增加trans-Golgi中的淀粉样球蛋白量。淀粉样球蛋白的分泌导致邻近的表达NAKα3的神经元变性。有趣的是，产生ASPD的神经元后来非自动死亡。我们的研究结果表明ASPD水平和蛋白酶体功能之间的联系，这可能对AD的病理生理学有重要意义。
We identified∼ 30-mer amyloid-β protein (Aβ) assemblies, termed amylospheroids, from brains of patients with Alzheimer disease (AD) as toxic entities responsible for neurodegeneration and showed that Na+, K+-ATPase α3 (NAKα3) is the sole target of amylospheroid-mediated neurodegeneration. However, it remains unclear where in neurons amylospheroids form and how they reach their targets to induce neurodegeneration. Here, we present an in vitro culture system designed to chronologically follow amylospheroid formation in mature neurons expressing amyloid precursor protein bearing early-onset AD mutations. Amylospheroids were found to accumulate mainly in the trans-Golgi network of excitatory neurons and were initially transported in axons. Proteasome inhibition dramatically increased amylospheroid amounts in trans-Golgi by increasing Aβ levels and induced dendritic transport. Amylospheroids were secreted and caused the degeneration of adjacent NAKα3-expressing neurons. Interestingly, the ASPD-producing neurons later died non-apoptotically. Our findings demonstrate a link between ASPD levels and proteasome function, which may have important implications for AD pathophysiology.
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DOI：
10.1073/pnas.0408007101
发表时间：
2004-12-07
影响因子：
11.1
作者：
Tarassishin, L;Yin, YI;Li, YM
通讯作者：
Li, YM
AAV8载体的体内趋向性
DOI：
--
发表时间：
2006
期刊：
影响因子：
--
作者：
Mizukami;H
通讯作者：
H
影响因子：
3.5
作者：
Burns, Mark P.;Zhang, Lihua;Moussa, Charbel E. -H.
通讯作者：
Moussa, Charbel E. -H.
DOI：
10.1083/jcb.120.5.1123
发表时间：
1993-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Humphrey JS;Peters PJ;Yuan LC;Bonifacino JS
通讯作者：
Bonifacino JS
影响因子：
5.3
作者：
Tonoki, Ayako;Kuranaga, Erina;Miura, Masayuki
通讯作者：
Miura, Masayuki