Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D.
Aβ-mediated spine changes in the hippocampus are microtubule-dependent and can be reversed by a subnanomolar concentration of the microtubule-stabilizing agent epothilone D.
复制标题
海马中Aβ介导的脊柱变化是微管依赖性的，可以通过微管稳定剂EpothiloneD的亚洋摩尔浓度逆转。
DOI：
10.1016/j.neuropharm.2016.01.002
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发表时间：
2016-06
影响因子：
4.7
通讯作者：
Brandt R
中科院分区：
文献类型：
--
作者：
Penazzi L;Tackenberg C;Ghori A;Golovyashkina N;Niewidok B;Selle K;Ballatore C;Smith AB 3rd;Bakota L;Brandt R
树突棘代表兴奋性突触的主要突触后输入。脊椎的丧失及其形态学变化与阿尔茨海默病（AD）中的认知障碍相关，并被认为在病理学早期发生。因此，在AD的临床前阶段进行治疗干预以改变脊柱变化可能是必要的。为了跟踪发育并潜在地干扰脊柱随时间的变化，我们从来自APP转基因小鼠和对照小鼠的海马的器官型培养物建立了长期离体模型。培养物表现出主要海马神经元的棘丢失，这与体内发生的变化非常相似，棘形态从蘑菇形逐渐变化为蘑菇状。我们证明，在用γ-分泌酶抑制剂DAPT阻断淀粉样蛋白-β（Aβ）产生后，脊柱变化在几天内完全逆转。我们发现微管破坏药物诺考达唑导致类似于Aβ表达培养物的脊柱丢失，并抑制APP转基因小鼠切片中DAPT介导的脊柱恢复。最后，我们报告了亚纳摩尔浓度的埃坡霉素D（EpoD），它稍微稳定了模型神经元中的微管，完全逆转了Aβ诱导的棘丢失并增加了薄棘密度。综上所述，数据表明Aβ通过微管不稳定引起脊柱变化，脊柱恢复需要微管聚合。此外，我们的研究结果表明，低的亚毒性浓度的EpoD足以减少AD临床前阶段的脊柱丢失。
Dendritic spines represent the major postsynaptic input of excitatory synapses. Loss of spines and changes in their morphology correlate with cognitive impairment in Alzheimer’s disease (AD) and are thought to occur early during pathology. Therapeutic intervention at a preclinical stage of AD to modify spine changes might thus be warranted. To follow the development and to potentially interfere with spine changes over time, we established a long term ex vivo model from organotypic cultures of the hippocampus from APP transgenic and control mice. The cultures exhibit spine loss in principal hippocampal neurons, which closely resembles the changes occurring in vivo, and spine morphology progressively changes from mushroom-shaped to stubby. We demonstrate that spine changes are completely reversed within few days after blocking amyloid-β (Aβ) production with the gamma-secretase inhibitor DAPT. We show that the microtubule disrupting drug nocodazole leads to spine loss similar to Aβ expressing cultures and suppresses DAPT-mediated spine recovery in slices from APP transgenic mice. Finally, we report that epothilone D (EpoD) at a subnanomolar concentration, which slightly stabilizes microtubules in model neurons, completely reverses Aβ-induced spine loss and increases thin spine density. Taken together the data indicate that Aβ causes spine changes by microtubule destabilization and that spine recovery requires microtubule polymerization. Moreover, our results suggest that a low, subtoxic concentration of EpoD is sufficient to reduce spine loss during the preclinical stage of AD.