Reelin is an extracellular protein crucial for adult brain plasticity. Moreover, Reelin is protective against amyloid-β (Aβ) pathology in Alzheimer's Disease (AD), reducing plaque deposition, synaptic loss and cognitive decline. Given that Tau protein plays a key role in AD pathogenesis, and that the Reelin pathway modulates Tau phosphorylation, here we explored the involvement of Reelin in AD-related Tau pathology. We found that Reelin overexpression modulates the levels of Tau phosphorylation in AD-related epitopes in VLW mice expressing human mutant Tau. in vitro, Reelin reduced the Aβ-induced missorting of axonal Tau and neurofilament proteins to dendrites. Reelin also reverted in vivo the toxic somatodendritic localization of phosphorylated Tau. Finally, overexpression of Reelin in VLW mice improved long-term potentiation and long-term memory cognitive performance thus masking the cognitive and physiological deficits in VLW mice. These data suggest that the Reelin pathway, which is also protective against Aβ pathology, modulates fundamental traits of Tau pathology, strengthening the potential of Reelin as a therapeutic target in AD.

中文翻译：

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Reelin可逆转Tauopathy小鼠模型中的生化，生理和认知改变。

Reelin是一种细胞外蛋白，对于成人的大脑可塑性至关重要。此外，Reelin可预防阿尔茨海默氏病（AD）中的淀粉样β（Aβ）病理，减少斑块沉积，突触丧失和认知能力下降。鉴于Tau蛋白在AD发病机理中起关键作用，并且Reelin途径调节Tau磷酸化，在这里我们探讨Reelin在AD相关Tau病理学中的作用。我们发现，Reelin过表达调节表达人突变Tau的VLW小鼠中AD相关表位中Tau磷酸化的水平。在体外，Reelin减少了Aβ诱导的轴突Tau和神经丝蛋白向树突的缺失。Reelin还体内还原了磷酸化Tau的有毒体细胞树突定位。最后，VLW小鼠中Reelin的过表达改善了长期增强和长期记忆的认知表现，从而掩盖了VLW小鼠的认知和生理缺陷。这些数据表明，还对Aβ病理学起保护作用的Reelin途径调节Tau病理学的基本特征，增强了Reelin作为AD治疗靶标的潜力。