PDF(Pubmed)
Abstract：
Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer\'s disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases or 3R tau pathologies less commonly in Pick\'s disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick\'s disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of mEPSCs in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin-dependent whereas that caused by P301L 4R tau is dynamin-independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE.
摘要：
在一些最常见的神经退行性疾病（包括阿尔茨海默病（AD））的大脑中检测到Tau病理，路易体痴呆（LBD），慢性创伤性脑病（CTE），额颞叶痴呆（FTD）。由于选择性RNA剪接，Tau蛋白以具有三个或四个微管结合重复序列（3Rtau或4Rtau）的六种同种型表达。AD,LBD,CTE脑含有3R和4Rtau的病理性沉积物。在大多数情况下，FTD患者可以表现出4Rtau病理，或3Rtau病理在皮克病中不常见，这是FTD的一个亚科。这里,我们报道了tau在FTD中的同工型特异性作用。P301L突变,与家族性4RtauFTD有关，在由两种性别的新生大鼠幼崽制备的原代海马培养物中，诱导4Rtau在树突棘上的错误定位。相反，G272V突变,与家族性Pick病有关,诱导3Rtau而不是4Rtau蛋白在树突棘上的磷酸化依赖性错定位。在5周龄的原代大鼠海马培养物中，G272V3Rtau蛋白而不是4Rtau蛋白的过表达导致树突棘密度降低和微小兴奋性突触电流（mEPSCs）抑制。由G272V3Rtau引起的mEPSC振幅的降低与动态蛋白有关，而由P301L4Rtau引起的mEPSC振幅的降低与动态蛋白无关，这表明这两种tau亚型激活了不同的信号通路，导致兴奋性突触功能障碍。我们在这里的3R和4Rtau研究将为FTD背后的各种机制提供新的启示，AD,LBD,和CTE。重要性声明额颞叶痴呆是由神经变性引起的第三大最常见的痴呆形式，具有不同的临床表现。这里,我们报道了不同的细胞机制,这些机制可能解释了额颞叶痴呆不同形式之间的一些异同.Tau蛋白由六种同工型组成。我们发现尽管所有的同工型都会导致神经缺陷,每种同工型都可能损害具有不同时间动力学或通过不同机制的神经元的结构和功能。本文报道的同工型特异性tau介导的突触损伤的机理研究将为当前的分子和细胞框架增加有价值的信息，不同的tau亚型导致额颞叶痴呆和其他神经退行性疾病包括阿尔茨海默病的脑缺陷，路易体痴呆,慢性创伤性脑病.
