Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.
Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane.
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DOI：
10.1016/j.nbd.2018.02.003
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发表时间：
2018-06
影响因子：
6.1
通讯作者：
Trushina E
中科院分区：
文献类型：
--
作者：
Zhang L;Trushin S;Christensen TA;Tripathi U;Hong C;Geroux RE;Howell KG;Poduslo JF;Trushina E
淀粉样β（Aβ）肽对线粒体轴突运输的抑制与阿尔茨海默病（AD）的早期病理生理学有关。然而，目前尚不清楚运动性的丧失是否不可避免地引起线粒体功能的丧失，以及轴突运输的恢复是否代表有效的治疗靶点。此外，虽然一些研究将Aβ寡聚体确定为运输抑制的罪魁祸首，但其他研究则认为原纤维发挥了有害作用。我们研究了家族性AD中发现的一组具有不同突变的Aβ肽对小鼠原代皮层神经元线粒体运动的影响。具有更高聚集倾向的肽在更大程度上抑制线粒体运输，其中原纤维诱导最强的抑制。Aβ肽与质膜的结合足以诱导运输抑制，而质膜结合和内化减少的肽对线粒体运动的影响较小。我们还发现具有冰岛突变A673T的Aβ肽影响线粒体的轴突运输，但在神经元中具有非常低的质膜结合率和内化率，这可以解释其相对较低的毒性。由Aβ肽或原纤维引起的线粒体动力学抑制不会立即影响线粒体生物能量和功能。我们的研究结果支持了这样一种机制，即轴突运输的抑制是由可溶性低分子量Aβ物质在质膜上启动的，并被原纤维加剧。由于运输抑制并不与线粒体功能的丧失同时发生，因此轴突运输的恢复在AD进展的早期阶段可能是有益的。然而，仅阻断Aβ聚集或原纤维形成而不确保有效清除可溶性Aβ的策略可能不足以缓解运输表型。
Inhibition of mitochondrial axonal trafficking by amyloid beta (Aβ) peptides has been implicated in early pathophysiology of Alzheimer’s Disease (AD). Yet, it remains unclear whether the loss of motility inevitably induces the loss of mitochondrial function, and whether restoration of axonal trafficking represents a valid therapeutic target. Moreover, while some investigations identify Aβ oligomers as the culprit of trafficking inhibition, others propose that fibrils play the detrimental role. We have examined the effect of a panel of Aβ peptides with different mutations found in familial AD on mitochondrial motility in primary cortical mouse neurons. Peptides with higher propensity to aggregate inhibit mitochondrial trafficking to a greater extent with fibrils inducing the strongest inhibition. Binding of Aβ peptides to the plasma membrane was sufficient to induce trafficking inhibition where peptides with reduced plasma membrane binding and internalization had lesser effect on mitochondrial motility. We also found that Aβ peptide with Icelandic mutation A673T affects axonal trafficking of mitochondria but has very low rates of plasma membrane binding and internalization in neurons, which could explain its relatively low toxicity. Inhibition of mitochondrial dynamics caused by Aβ peptides or fibrils did not instantly affect mitochondrial bioenergetic and function. Our results support a mechanism where inhibition of axonal trafficking is initiated at the plasma membrane by soluble low molecular weight Aβ species and is exacerbated by fibrils. Since trafficking inhibition does not coincide with the loss of mitochondrial function, restoration of axonal transport could be beneficial at early stages of AD progression. However, strategies designed to block Aβ aggregation or fibril formation alone without ensuring the efficient clearance of soluble Aβ may not be sufficient to alleviate the trafficking phenotype.
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影响因子：
3.7
作者：
Cha MY;Han SH;Son SM;Hong HS;Choi YJ;Byun J;Mook-Jung I
通讯作者：
Mook-Jung I
影响因子：
3.5
作者：
Chen H;Chan DC
通讯作者：
Chan DC
影响因子：
4.8
作者：
Caspersen, C;Wang, N;Yan, SD
通讯作者：
Yan, SD
影响因子：
4.8
作者：
Benilova, Iryna;Gallardo, Rodrigo;De Strooper, Bart
通讯作者：
De Strooper, Bart
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.