Department of Biology and Center for Developmental Neuroscience, College of Staten Island, Graduate Center, The City University of New York, Staten Island, NY, USA.
J Alzheimers Dis. 2013;37(3):539-50. doi: 10.3233/JAD-130617.
A key characteristic of Alzheimer's disease and other tauopathies is the progressive accumulation of neurofibrillary tangles mainly composed of hyperphosphorylated tau protein. In the present study, we use transgenic Drosophila melanogaster as a model to analyze in vivo the effect of expressing pseudophosphorylated tau (S199E/T212E/T231E/S262E tau) on pathological human tau (PH-tau) and on the FTDP-17 mutant R406W (PH-tauR406W). We used two different inducers that produced different levels of tau expression. The expression of these forms of tau did not significantly affect the lifespan of the flies. Flies expressing PH-tau displayed a clear locomotor dysfunction compared to those expressing normal tau regardless of the level of expression. At lower level of expression, this pathological phenotype was found to be age-dependent. At 35 days old, PH-tau flies showed the strongest locomotor impairment compare to flies expressing human tau or control flies (46%, 18% and 18% of flies remained on the bottom of the vials, respectively). At higher levels of expression, PH-tau flies showed these defects at seven days of age and the dysfunction also became significant for flies expressing tauR406W and PH-tauR406W. Whole brain immunochemistry analysis revealed that PH-tau as well as PH-tauR406W appeared to have abnormal mushroom body structures, critical structures involved in olfactory learning and memory in Drosophila. Severe olfactory learning deficits were induced by the expression of PH-tau. Taken together, our findings demonstrate that PH-tau induced a toxic effect in Drosophila, as flies develop both an abnormal motor deficit, associated with disruption of the mushroom body neurons, and impaired olfactory learning.
阿尔茨海默病和其他 tau 病的一个关键特征是神经原纤维缠结的进行性积累，主要由过度磷酸化的 tau 蛋白组成。在本研究中，我们使用转基因黑腹果蝇作为模型，分析体内表达假磷酸化 tau（S199E/T212E/T231E/S262E tau）对病理性人类 tau（PH-tau）和 FTDP-17 突变体 R406W（PH-tauR406W）的影响。我们使用了两种不同的诱导剂，产生了不同水平的 tau 表达。这些 tau 形式的表达并没有显著影响苍蝇的寿命。与表达正常 tau 的苍蝇相比，表达 PH-tau 的苍蝇表现出明显的运动功能障碍，无论表达水平如何。在较低的表达水平下，这种病理表型被发现是年龄依赖性的。在 35 天时，与表达人类 tau 或对照苍蝇的苍蝇相比，PH-tau 苍蝇表现出最强的运动障碍（分别有 46%、18%和 18%的苍蝇留在瓶底）。在较高的表达水平下，PH-tau 苍蝇在七天大时就出现了这些缺陷，tauR406W 和 PH-tauR406W 的苍蝇也出现了功能障碍。全脑免疫化学分析显示，PH-tau 以及 PH-tauR406W 似乎具有异常的蘑菇体结构，这是果蝇嗅觉学习和记忆中关键的结构。PH-tau 的表达诱导了严重的嗅觉学习缺陷。总之，我们的研究结果表明，PH-tau 在果蝇中诱导了毒性作用，因为苍蝇不仅表现出异常的运动缺陷，与蘑菇体神经元的破坏有关，而且嗅觉学习也受到损害。
