Golovyashkina Nataliya, Penazzi Lorène, Ballatore Carlo, Smith Amos B, Bakota Lidia, Brandt Roland
Department of Neurobiology, University of Osnabrück, Barbarastrasse 11, 49076, Osnabrück, Germany.
Department of Chemistry, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, 19014, USA.
Mol Neurodegener. 2015 Nov 5;10:60. doi: 10.1186/s13024-015-0049-0.
Dendritic simplification, a key feature of the neurodegenerative triad of Alzheimer's disease (AD) in addition to spine changes and neuron loss, occurs in a region-specific manner. However, it is unknown how changes in dendritic complexity are mediated and how they relate to spine changes and neuron loss.
To investigate the mechanisms of dendritic simplification in an authentic CNS environment we employed an ex vivo model, based on targeted expression of enhanced green fluorescent protein (EGFP)-tagged constructs in organotypic hippocampal slices of mice. Algorithm-based 3D reconstruction of whole neuron morphology in different hippocampal regions was performed on slices from APPSDL-transgenic and control animals. We demonstrate that induction of dendritic simplification requires the combined action of amyloid beta (Aβ) and human tau. Simplification is restricted to principal neurons of the CA1 region, recapitulating the region specificity in AD patients, and occurs at sites of Schaffer collateral input. We report that γ-secretase inhibition and treatment with the NMDA-receptor antagonist, CPP, counteract dendritic simplification. The microtubule-stabilizing drug epothilone D (EpoD) induces simplification in control cultures per se. Similar morphological changes were induced by a phosphoblocking tau construct, which also increases microtubule stability. In fact, low nanomolar concentrations of naturally secreted Aβ decreased phosphorylation at S262 in a cellular model, a site which is known to directly modulate tau-microtubule interactions.
The data provide evidence that dendritic simplification is mechanistically distinct from other neurodegenerative events and involves microtubule stabilization by dendritic tau, which becomes dephosphorylated at certain sites. They imply that treatments leading to an overall decrease of tau phosphorylation might have a negative impact on neuronal connectivity.
树突简化是阿尔茨海默病（AD）神经退行性三联征的一个关键特征，除了脊柱变化和神经元丢失外，它以区域特异性的方式发生。然而，尚不清楚树突复杂性的变化是如何介导的，以及它们与脊柱变化和神经元丢失有何关系。
为了在真实的中枢神经系统环境中研究树突简化的机制，我们采用了一种离体模型，该模型基于在小鼠器官型海马切片中靶向表达增强型绿色荧光蛋白（EGFP）标记的构建体。对来自APPSDL转基因和对照动物的切片进行了基于算法的不同海马区域全神经元形态的三维重建。我们证明，树突简化的诱导需要淀粉样β蛋白（Aβ）和人tau蛋白的联合作用。简化仅限于CA1区域的主要神经元，重现了AD患者的区域特异性，并发生在谢弗侧支输入部位。我们报告说，γ-分泌酶抑制和用NMDA受体拮抗剂CPP治疗可抵消树突简化。微管稳定药物埃坡霉素D（EpoD）本身在对照培养物中诱导简化。一种磷酸化阻断tau构建体也诱导了类似的形态变化，该构建体也增加了微管稳定性。事实上，在细胞模型中，低纳摩尔浓度的天然分泌Aβ降低了S262位点的磷酸化，该位点已知可直接调节tau-微管相互作用。
数据提供了证据，表明树突简化在机制上与其他神经退行性事件不同，涉及树突tau介导的微管稳定，tau在某些位点发生去磷酸化。这意味着导致tau磷酸化总体降低的治疗可能会对神经元连接产生负面影响。
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