Department of Neuroscience and Centre de recherche du centre hospitalier de l'Université de Montréal (CRCHUM), Université de Montréal, 900 Rue Saint-Denis, Tour Viger, Room R09.720, Montréal, QC, H2X 0A9, Canada.
Institut de Recherches Servier, 78290, Croissy-sur-Seine, France.
Mol Neurodegener. 2017 Aug 3;12(1):58. doi: 10.1186/s13024-017-0199-3.
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.
Tau 是一种富含轴突的蛋白质，可与微管结合并稳定微管，因此在神经元功能中发挥着关键作用。在阿尔茨海默病（AD）中，病理性 Tau 积累与认知能力下降相关。在受 AD 影响的个体中发现了大量视觉缺陷，包括视网膜神经节细胞（RGCs）的优先损失，RGCs 是将视觉信息从视网膜传递到大脑的神经元。然而，目前这些患者视力变化的机制尚不清楚。在这里，我们询问 Tau 是否在 AD 的早期视网膜病变和神经元功能障碍中发挥作用。
通过 Western blot、qPCR 和免疫组织化学，在携带编码早老素 1（PS1M146 V）、淀粉样前体蛋白（APPSwe）和 Tau（MAPTP301L）基因突变的三重转基因小鼠（3xTg）的视网膜和视觉通路中研究 Tau 蛋白和基因表达、磷酸化和定位的改变。通过在眼内注射霍乱毒素 beta 亚基，然后定量检测对侧上丘中的示踪剂积累，评估顺行轴突运输。使用细胞特异性标记物在整个视网膜上分析 RGC 存活。通过玻璃体内注射靶向 siRNA 实现 Tau 表达的减少。
我们的数据表明，在 3xTg 小鼠中，内源性视网膜 Tau 呈年龄相关性增加，表现为表位特异性低磷酸化和高磷酸化。早在行为缺陷报道之前的三个月，就观察到视网膜 Tau 积累，并且早于大脑中的 Tau 聚集。有趣的是，Tau 积累发生在 RGC 体和树突中，而在视神经中的 RGC 轴突中的 Tau 耗尽。Tau 磷酸化变化和错误分类与 RGC 死亡之前的顺行轴突运输的严重缺陷相关。重要的是，靶向 siRNA 介导的内源性 Tau 敲低改善了 RGC 轴突中的顺行运输。
我们的研究揭示了 AD 小鼠模型中视觉系统中严重的 Tau 病理学，导致早期视网膜神经元损伤。重要的是，我们表明 Tau 积累促进体内顺行轴突运输损伤，并确定这一反应是 AD 视网膜神经元功能障碍的早期特征，早于细胞死亡。这些发现首次证明了一种全局策略，即减少 Tau 积累可改善 AD 和 Tau 病中的轴突运输并减轻功能缺陷。
