Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer's disease.
Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer's disease.
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DOI：
10.1186/s13024-017-0199-3
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发表时间：
2017-08-03
影响因子：
15.1
通讯作者：
Di Polo A
中科院分区：
文献类型：
--
作者：
Chiasseu M;Alarcon-Martinez L;Belforte N;Quintero H;Dotigny F;Destroismaisons L;Vande Velde C;Panayi F;Louis C;Di Polo A
Tau是一种富含轴突的蛋白质，它结合并稳定微管，因此在神经元功能中起着至关重要的作用。在阿尔茨海默病（AD）中，病理性tau蛋白积累与认知能力下降相关。在受AD影响的个体中发现大量的视觉缺陷，包括视网膜神经节细胞（RGC）的优先损失，所述视网膜神经节细胞是将视觉信息从视网膜传递到大脑的神经元。然而，目前对这些患者视力变化的机制还知之甚少。在这里，我们询问tau蛋白是否在AD的早期视网膜病理和神经元功能障碍中起作用。通过蛋白质印迹、qPCR和免疫组织化学研究了在编码早老素1（PS1M146 V）、淀粉样前体蛋白（APPSwe）和tau（MAPTP301 L）的基因中携带突变的三重转基因小鼠（3xTg）的视网膜和视觉通路中tau蛋白和基因表达、磷酸化和定位的改变。通过眼内注射霍乱毒素β亚单位，然后定量对侧上级丘中的示踪剂积聚来评估顺行轴突运输。使用细胞特异性标记物在整体安装的视网膜上分析RGC存活。在玻璃体内注射靶向siRNA后实现tau表达的降低。我们的数据表明，在3xTg小鼠中，内源性视网膜tau蛋白的年龄相关性增加，其特征在于表位特异性低磷酸化和高磷酸化。早在三个月大时就观察到视网膜tau积聚，在报告的行为缺陷发作之前，并且在脑中tau聚集之前。有趣的是，tau蛋白在RGC索马和树突中积累，而在视神经中的RGC轴突中的tau蛋白被耗尽。Tau蛋白磷酸化改变和错配与RGC死亡前的顺行轴突运输的实质性缺陷相关。重要的是，靶向siRNA介导的内源性tau蛋白敲低改善了沿着RGC轴突的顺行转运。我们的研究揭示了视觉系统中深刻的tau病理学，导致AD小鼠模型中的早期视网膜神经元损伤。重要的是，我们表明，tau蛋白的积累促进体内顺行轴突运输障碍，并确定这种反应作为AD视网膜细胞死亡之前的神经元功能障碍的早期特征。这些发现提供了第一个概念验证，即减少tau积累的全球策略有利于改善轴突运输并减轻AD和tau蛋白病中的功能缺陷。
Tau is an axon-enriched protein that binds to and stabilizes microtubules, and hence plays a crucial role in neuronal function. In Alzheimer’s disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood. Here, we asked whether tau plays a role in early retinal pathology and neuronal dysfunction in AD. Alterations in tau protein and gene expression, phosphorylation, and localization were investigated by western blots, qPCR, and immunohistochemistry in the retina and visual pathways of triple transgenic mice (3xTg) harboring mutations in the genes encoding presenilin 1 (PS1M146 V), amyloid precursor protein (APPSwe), and tau (MAPTP301L). Anterograde axonal transport was assessed by intraocular injection of the cholera toxin beta subunit followed by quantification of tracer accumulation in the contralateral superior colliculus. RGC survival was analyzed on whole-mounted retinas using cell-specific markers. Reduction of tau expression was achieved following intravitreal injection of targeted siRNA. Our data demonstrate an age-related increase in endogenous retinal tau characterized by epitope-specific hypo- and hyper-phosphorylation in 3xTg mice. Retinal tau accumulation was observed as early as three months of age, prior to the reported onset of behavioral deficits, and preceded tau aggregation in the brain. Intriguingly, tau build up occurred in RGC soma and dendrites, while tau in RGC axons in the optic nerve was depleted. Tau phosphorylation changes and missorting correlated with substantial defects in anterograde axonal transport that preceded RGC death. Importantly, targeted siRNA-mediated knockdown of endogenous tau improved anterograde transport along RGC axons. Our study reveals profound tau pathology in the visual system leading to early retinal neuron damage in a mouse model of AD. Importantly, we show that tau accumulation promotes anterograde axonal transport impairment in vivo, and identify this response as an early feature of neuronal dysfunction that precedes cell death in the AD retina. These findings provide the first proof-of-concept that a global strategy to reduce tau accumulation is beneficial to improve axonal transport and mitigate functional deficits in AD and tauopathies.
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影响因子：
1.4
作者：
CRONINGOLOMB, A;CORKIN, S;GROWDON, JH
通讯作者：
GROWDON, JH
影响因子：
5.3
作者：
Burkhart, KK;Beard, DC;Billingsley, ML
通讯作者：
Billingsley, ML
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
2.9
作者：
BLANKS, JC;HINTON, DR;MILLER, CA
通讯作者：
MILLER, CA
影响因子：
3.3
作者：
Biernat, J;Wu, YZ;Mandelkow, EM
通讯作者：
Mandelkow, EM