by Keyword: Central-nervous-system

Solomon M, Loeck M, Silva-Abreu M, Moscoso R, Bautista R, Vigo M, Muro S, (2022). Altered blood-brain barrier transport of nanotherapeutics in lysosomal storage diseases Journal Of Controlled Release 349, 1031-1044

Treatment of neurological lysosomal storage disorders (LSDs) are limited because of impermeability of the blood-brain barrier (BBB) to macromolecules. Nanoformulations targeting BBB transcytosis are being explored, but the status of these routes in LSDs is unknown. We studied nanocarriers (NCs) targeted to the transferrin receptor (TfR), ganglioside GM1 or ICAM1, associated to the clathrin, caveolar or cell adhesion molecule (CAM) routes, respectively. We used brain endothelial cells and mouse models of acid sphingomyelinase-deficient Niemann Pick disease (NPD), and postmortem LSD patients' brains, all compared to respective controls. NC transcytosis across brain endothelial cells and brain distribution in mice were affected, yet through different mechanisms. Reduced TfR and clathrin expression were found, along with decreased transcytosis in cells and mouse brain distribution. Caveolin-1 expression and GM1 transcytosis were also reduced, yet increased GM1 levels seemed to compensate, providing similar NC brain distribution in NPD vs. control mice. A tendency to lower NHE-1 levels was seen, but highly increased ICAM1 expression in cells and human brains correlated with increased transcytosis and brain distribution in mice. Thus, transcytosis-related alterations in NPD and likely other LSDs may impact therapeutic access to the brain, illustrating the need for these mechanistic studies.Copyright © 2022 Elsevier B.V. All rights reserved.

JTD Keywords: acid sphingomyelinase, antibody-affinity, blood -brain barrier, drug-delivery, icam-1-targeted nanocarriers, in-vivo, mediated endocytosis, model, neurological diseases, niemann-pick, targeted nanocarriers, trafficking, transcytosis pathways, Blood-brain barrier, Central-nervous-system, Lysosomal storage disorders, Neurological diseases, Targeted nanocarriers, Transcytosis pathways

Mesquida-Veny, F, Martinez-Torres, S, Del Rio, JA, Hervera, A, (2022). Nociception-Dependent CCL21 Induces Dorsal Root Ganglia Axonal Growth via CCR7-ERK Activation Frontiers In Immunology 13, 880647

While chemokines were originally described for their ability to induce cell migration, many studies show how these proteins also take part in many other cell functions, acting as adaptable messengers in the communication between a diversity of cell types. In the nervous system, chemokines participate both in physiological and pathological processes, and while their expression is often described on glial and immune cells, growing evidence describes the expression of chemokines and their receptors in neurons, highlighting their potential in auto- and paracrine signalling. In this study we analysed the role of nociception in the neuronal chemokinome, and in turn their role in axonal growth. We found that stimulating TRPV1(+) nociceptors induces a transient increase in CCL21. Interestingly we also found that CCL21 enhances neurite growth of large diameter proprioceptors in vitro. Consistent with this, we show that proprioceptors express the CCL21 receptor CCR7, and a CCR7 neutralizing antibody dose-dependently attenuates CCL21-induced neurite outgrowth. Mechanistically, we found that CCL21 binds locally to its receptor CCR7 at the growth cone, activating the downstream MEK-ERK pathway, that in turn activates N-WASP, triggering actin filament ramification in the growth cone, resulting in increased axonal growth.

JTD Keywords: Actin dynamics, Axonal growth, Ccl21, Ccr7, Cell-migration, Central-nervous-system, Chemokine, Ligands, Mek-erk, Microglia, Neurons, Neuropathic pain, Nociception, Phosphorylation, Regeneration

Lopez-Mengual, A, Segura-Feliu, M, Sunyer, R, Sanz-Fraile, H, Otero, J, Mesquida-Veny, F, Gil, V, Hervera, A, Ferrer, I, Soriano, J, Trepat, X, Farre, R, Navajas, D, del Rio, JA, (2022). Involvement of Mechanical Cues in the Migration of Cajal-Retzius Cells in the Marginal Zone During Neocortical Development Frontiers In Cell And Developmental Biology 10,

Emerging evidence points to coordinated action of chemical and mechanical cues during brain development. At early stages of neocortical development, angiogenic factors and chemokines such as CXCL12, ephrins, and semaphorins assume crucial roles in orchestrating neuronal migration and axon elongation of postmitotic neurons. Here we explore the intrinsic mechanical properties of the developing marginal zone of the pallium in the migratory pathways and brain distribution of the pioneer Cajal-Retzius cells. These neurons are generated in several proliferative regions in the developing brain (e.g., the cortical hem and the pallial subpallial boundary) and migrate tangentially in the preplate/marginal zone covering the upper portion of the developing cortex. These cells play crucial roles in correct neocortical layer formation by secreting several molecules such as Reelin. Our results indicate that the motogenic properties of Cajal-Retzius cells and their perinatal distribution in the marginal zone are modulated by both chemical and mechanical factors, by the specific mechanical properties of Cajal-Retzius cells, and by the differential stiffness of the migratory routes. Indeed, cells originating in the cortical hem display higher migratory capacities than those generated in the pallial subpallial boundary which may be involved in the differential distribution of these cells in the dorsal-lateral axis in the developing marginal zone.

JTD Keywords: Atomic force microscopy, Cajal-retzius cells, Central-nervous-system, Cortical development, Cortical hem, Developing cerebral-cortex, Expression, Growth, Marginal zone, Mechanical cues, Mouse, Neuronal migration, Nogo receptor, Olfactory ensheathing cells, Tangential migration, Traction force microscopy