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Region-specific dendritic simplification induced by Aβ, mediated by tau via dysregulation of microtubule dynamics: a mechanistic distinct event from other neurodegenerative processes.
Molecular Neurodegeneration ( IF 14.9 ) Pub Date : 2015-11-07 , DOI: 10.1186/s13024-015-0049-0
Nataliya Golovyashkina 1 , Lorène Penazzi 1 , Carlo Ballatore 2, 3 , Amos B Smith 2 , Lidia Bakota 1 , Roland Brandt 1
Affiliation  

BACKGROUND 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. RESULTS 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. CONCLUSIONS 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.

中文翻译:

由Tau通过微管动力学失调介导的Aβ诱导的区域特异性树突简化:与其他神经退行性过程的机制不同。

背景技术树突简化是除脊柱改变和神经元丢失之外的阿尔茨海默氏病(AD)的神经退行性三联征的关键特征,其以区域特定的方式发生。但是,尚不知道如何介导树突状复杂性的变化以及它们与脊柱变化和神经元丢失之间的关系。结果为了研究在真实的中枢神经系统环境中树突简化的机制,我们采用了一种体外模型,该模型基于增强型绿色荧光蛋白(EGFP)标记的构建体在小鼠器官型海马切片中的靶向表达。对来自APPSDL转基因和对照动物的切片进行了基于算法的3D重建,在不同海马区域中的整个神经元形态。我们证明,诱导树突状简化需要淀粉样蛋白β(Aβ)和人类tau的组合作用。简化仅限于CA1区的主要神经元,概括了AD患者的区域特异性,并且发生在Schaffer侧支输入部位。我们报道γ分泌酶抑制和NMDA受体拮抗剂,CPP的治疗抵消树突状的简化。稳定微管的药物埃坡霉素D(EpoD)本身可简化对照培养物。磷酸阻断tau构建体诱导了相似的形态变化,这也增加了微管的稳定性。实际上,在细胞模型中,低纳摩尔浓度的自然分泌的Aβ降低了S262处的磷酸化作用,这是一个直接调节tau-微管相互作用的位点。结论数据提供了证据,表明树突状简化在机制上不同于其他神经退行性事件,并且涉及树突状tau引起的微管稳定作用,该树突状tau在某些部位被去磷酸化。他们暗示导致tau磷酸化总体降低的治疗方法可能会对神经元连通性产生负面影响。
更新日期:2019-11-01
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