Fabbretti Elsa, Antognolli Giulia, Tongiorgi Enrico
Department of Life Sciences, University of Trieste, Trieste, Italy.
Front Mol Neurosci. 2021 Jun 3;14:661728. doi: 10.3389/fnmol.2021.661728. eCollection 2021.
Neurite atrophy with loss of neuronal polarity is a pathological hallmark of Alzheimer's disease (AD) and other neurological disorders. While there is substantial agreement that disruption of intracellular vesicle trafficking is associated with axonal pathology in AD, comparatively less is known regarding its role in dendritic atrophy. This is a significant gap of knowledge because, unlike axons, dendrites are endowed with the complete endomembrane system comprising endoplasmic reticulum (ER), ER-Golgi intermediate compartment (ERGIC), Golgi apparatus, post-Golgi vesicles, and a recycling-degradative route. In this study, using live-imaging of pGOLT-expressing vesicles, indicative of Golgi outposts and satellites, we investigate how amyloid-β (Aβ) oligomers affect the trafficking of Golgi-like organelles in the different dendritic compartments of cultured rat hippocampal neurons. We found that short-term (4 h) treatment with Aβ led to a decrease in anterograde trafficking of Golgi vesicles in dendrites of both resting and stimulated (with 50 mM KCl) neurons. We also characterized the ability of mirtazapine, a noradrenergic and specific serotonergic tetracyclic antidepressant (NaSSA), to rescue Golgi dynamics in dendrites. Mirtazapine treatment (10 μM) increased the number and both anterograde and retrograde motility, reducing the percentage of static Golgi vesicles. Finally, mirtazapine reverted the neurite atrophy induced by 24 h treatment with Aβ oligomers, suggesting that this drug is able to counteract the effects of Aβ by improving the dendritic trafficking of Golgi-related vesicles.
神经突萎缩伴神经元极性丧失是阿尔茨海默病（AD）和其他神经疾病的病理标志。虽然人们普遍认为细胞内囊泡运输的破坏与AD中的轴突病理有关，但关于其在树突萎缩中的作用相对了解较少。这是一个重大的知识空白，因为与轴突不同，树突拥有完整的内膜系统，包括内质网（ER）、内质网-高尔基体中间腔室（ERGIC）、高尔基体、高尔基体后囊泡以及一条回收-降解途径。在本研究中，我们利用对表达pGOLT的囊泡进行实时成像（这表明存在高尔基体驻点和卫星），来研究淀粉样β（Aβ）寡聚体如何影响培养的大鼠海马神经元不同树突区室中类高尔基体细胞器的运输。我们发现，用Aβ进行短期（4小时）处理会导致静息和受刺激（用50 mM KCl）神经元树突中高尔基体囊泡的顺向运输减少。我们还研究了米氮平（一种去甲肾上腺素能和特异性5-羟色胺能四环抗抑郁药（NaSSA））挽救树突中高尔基体动力学的能力。米氮平处理（10 μM）增加了高尔基体囊泡的数量以及顺向和逆向运动能力，减少了静止高尔基体囊泡的百分比。最后，米氮平逆转了用Aβ寡聚体处理24小时所诱导的神经突萎缩，这表明该药物能够通过改善与高尔基体相关囊泡的树突运输来抵消Aβ的作用。
