Transthyretin (TTR) is a protein whose function has been associated to binding and distribution of thyroid hormones in the body and brain. However, little is known regarding the downstream signaling pathways triggered by wild-type TTR in the CNS either in neuroprotection of cerebral ischemia or in physiological conditions. In this study, we investigated how TTR affects hippocampal neurons in physiologic/pathologic conditions. Recombinant TTR significantly boosted neurite outgrowth in mice hippocampal neurons, both in number and length, independently of its ligands. This TTR neuritogenic activity is mediated by the megalin receptor and is lost in megalin-deficient neurons. We also found that TTR activates the mitogen-activated protein kinase (MAPK) pathways (ERK1/2) and Akt through Src, leading to the phosphorylation of transcription factor CREB. In addition, TTR promoted a transient rise in intracellular calcium through NMDA receptors, in a Src/megalin-dependent manner. Moreover, under excitotoxic conditions, TTR stimulation rescued cell death and neurite loss in TTR KO hippocampal neurons, which are more sensitive to excitotoxic degeneration than WT neurons, in a megalin-dependent manner. CREB was also activated by TTR under excitotoxic conditions, contributing to changes in the balance between Bcl2 protein family members, toward anti-apoptotic proteins (Bcl2/BclXL versus Bax). Finally, we clarify that TTR KO mice subjected to pMCAO have larger infarcts than WT mice, because of TTR and megalin neuronal downregulation. Our results indicate that TTR might be regarded as a neurotrophic factor, because it stimulates neurite outgrowth under physiological conditions, and promotes neuroprotection in ischemic conditions.

The hallmark of familial amyloid polyneuropathy (FAP) is the presence of extracellular deposits of transthyretin (TTR) aggregates and amyloid fibers in several tissues, particularly in the peripheral nervous system. The molecular pathways to neurodegeneration in FAP still remain elusive; activation of nuclear factor κB, pro-inflammatory cytokines, oxidative stress, and pro-apoptotic caspase-3 has been demonstrated “in vivo” in clinical samples and in cell culture systems. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress response in FAP by showing activation of the classical unfolded protein response pathways in tissues not specialized in TTR synthesis but presenting extracellular TTR aggregate and fibril deposition. We also proved cytotoxicity by Ca²⁺ efflux from the ER in cell cultures incubated with TTR oligomers. Taken together, these studies evidence ER stress associated with a extracellular signal in a misfolding disorder.

Dendrimers have emerged as a powerful class of nanomaterials in the nanomedicine field due to their unique structural features: globular, well‐defined, highly branched and controllable structure, nanosize‐scale, low polydispersity, and the presence of several terminal groups that can be functionalized with different ligands simulating the multivalency present in different biological systems. Although in its infancy, the application of dendrimers as therapeutics or theranostic tools in central nervous system (CNS) disorders is already significant and has opened promising avenues in the treatment of many conditions where the inherent “smartness” of the dendritic structures is being explored to effectively target the CNS. Here we present an overview of the past and future challenges of the use of dendrimers to respond to one of the ultimate challenges in the (nano)medicine field: to attain CNS repair and regeneration.