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首页> 美国卫生研究院文献>Wiley-Blackwell Online Open >Delivery of an anti‐transthyretin Nanobody to the brain through intranasal administration reveals transthyretin expression and secretion by motor neurons
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Delivery of an anti‐transthyretin Nanobody to the brain through intranasal administration reveals transthyretin expression and secretion by motor neurons

机译：通过鼻内给药将抗运甲状腺素蛋白纳米抗体递送至大脑可揭示运甲状腺素蛋白的表达和运动神经元的分泌

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摘要

Transthyretin (TTR) is a transport protein of retinol and thyroxine in serum and CSF, which is mainly secreted by liver and choroid plexus, and in smaller amounts in other cells throughout the body. The exact role of TTR and its specific expression in Central Nervous System (CNS) remains understudied. We investigated TTR expression and metabolism in CNS, through the intranasal and intracerebroventricular delivery of a specific anti‐TTR Nanobody to the brain, unveiling Nanobody pharmacokinetics to the CNS. In TTR deficient mice, we observed that anti‐TTR Nanobody was successfully distributed throughout all brain areas, and also reaching the spinal cord. In wild‐type mice, a similar distribution pattern was observed. However, in areas known to be rich in TTR, reduced levels of Nanobody were found, suggesting potential target‐mediated effects. Indeed, in wild‐type mice, the anti‐TTR Nanobody was specifically internalized in a receptor‐mediated process, by neuronal‐like cells, which were identified as motor neurons. Whereas in KO TTR mice Nanobody was internalized by all cells, for late lysosomal degradation. Moreover, we demonstrate that in vivo motor neurons also actively synthesize TTR. Finally, in vitro cultured primary motor neurons were also found to synthesize and secrete TTR into culture media. Thus, through a novel intranasal CNS distribution study with an anti‐ style="fixed-case">TTR Nanobody, we disclose a new cell type capable of synthesizing style="fixed-case">TTR, which might be important for the understanding of the physiological role of style="fixed-case">TTR, as well as in pathological conditions where style="fixed-case">TTR levels are altered in style="fixed-case">CSF, such as amyotrophic lateral sclerosis.
机译：运甲状腺素蛋白（TTR）是视黄醇和甲状腺素在血清和脑脊液中的转运蛋白，主要由肝和脉络丛分泌，在全身其他细胞中的含量也较低。 TTR的确切作用及其在中枢神经系统（CNS）中的特定表达仍未得到研究。我们通过将特定的抗TTR纳米抗体经鼻内和脑室内向大脑输送，研究了CNS中TTR的表达和代谢，揭示了CNS的纳米抗体药代动力学。在TTR缺陷型小鼠中，我们观察到抗TTR纳米抗体成功地分布在所有脑部区域，也到达了脊髓。在野生型小鼠中，观察到类似的分布模式。但是，在已知富含TTR的地区，发现纳米抗体的含量降低，表明潜在的靶介导作用。的确，在野生型小鼠中，抗TTR纳米抗体在受体介导的过程中被神经元样细胞特异性内化，后者被鉴定为运动神经元。而在KO TTR小鼠中，纳米抗体被所有细胞内在化，用于后期溶酶体降解。此外，我们证明了在体内运动神经元也可以积极合成TTR。最后，在体外培养的原代运动神经元也被发现可以合成TTR并将其分泌到培养基中。因此，通过具有抗 style =“ fixed-case”> TTR 纳米抗体的新型鼻内CNS分布研究，我们揭示了一种能够合成 style =“ fixed-case”> TTR的新型细胞类型，这对于理解 style =“ fixed-case”> TTR 的生理作用以及在 style =“ fixed-case”> TTR 水平在 style =“ fixed-case”> CSF 中会发生变化，例如肌萎缩性侧索硬化症。

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