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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‐ TTR  Nanobody, we disclose a new cell type capable of synthesizing  TTR , which might be important for the understanding of the physiological role of  TTR , as well as in pathological conditions where  TTR  levels are altered in  CSF , such as amyotrophic lateral sclerosis.

journal of neurochemistry

Delivery of an anti‐transthyretin Nanobody to the brain through intranasal administration reveals transthyretin expression and secretion by motor neurons