Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer’s disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer’s disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer’s disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer’s disease.
Neurological disorder is a general term used for diseases affecting the function of the brain and nervous system. Those include a broad range of diseases from developmental disorders (e.g., Autism) over injury related disorders (e.g., stroke and brain tumors) to age related neurodegeneration (e.g., Alzheimer's disease), affecting up to 1 billion people worldwide. For most of those disorders, no curative treatment exists leaving symptomatic treatment as the primary mean of alleviation. Human induced pluripotent stem cells (hiPSC) in combination with animal models have been instrumental to foster our understanding of underlying disease mechanisms in the brain. Of specific interest are patient derived hiPSC which allow for targeted gene editing in the cases of known mutations. Such personalized treatment would include (1) acquisition of primary cells from the patient, (2) reprogramming of those into hiPSC via non-integrative methods, (3) corrective intervention via CRISPR-Cas9 gene editing of mutations, (4) quality control to ensure successful correction and absence of off-target effects, and (5) subsequent transplantation of hiPSC or pre-differentiated precursor cells for cell replacement therapies. This would be the ideal scenario but it is time consuming and expensive. Therefore, it would be of great benefit if transplanted hiPSC could be modulated to become invisible to the recipient's immune system, avoiding graft rejection and allowing for allogenic transplantations. This review will focus on the current status of gene editing to generate non-immunogenic hiPSC and how these cells can be used to treat neurological disorders by using cell replacement therapy. By providing an overview of current limitations and challenges in stem cell replacement therapies and the treatment of neurological disorders, this review outlines how gene editing and non-immunogenic hiPSC can contribute and pave the road for new therapeutic advances. Finally, the combination of using non-immunogenic hiPSC and in vivo animal modeling will highlight the importance of models with translational value for safety efficacy testing; before embarking on human trials.
,I dunnP restholm, IlirianaQ oqaj, ChristinaB.R iel, To bias V. Rostgaard, Nora Saleh, HannibalM.S chultz, Mark Standland,Jens S. Svenningsen, RasmusTruels Sørensen, JesperV isby,E milie L. Wolff-Sneedorff, Malte Hee Zachariassen, Edmond A. Ziari, Henning O. Sørensen, and Thomas Just Sørensen* [a] To Professor Klaus Bechgaard and Professor ThomasB jørnholm for always teaching to think outside the box Abstract: Ionic self-assembly (ISA) is ap rovenm ethod that exploits non-covalenti nteractions to generate supramolecular materials. Here, we have expanded the scope of this approach fabricating thin films with nanoscopic order maintained over centimeters. Cationiclayers of benzalkonium surfactants form al amellar template. The template is able to host layers of negatively charged polyaromatic functional units, hered emonstrated with b-naphthol-derived azo-dyes. We show that av arietyo ft hese functional building blocks can be incorporated in the lamellar templatet hrough ISA. Sixteen different materials were produced,c haracterized, and processedi nto thin films, with lamellar order perpendicular to the substrate. Thus, ad esign concept is demonstrated in which diverse functional motifs can be isolated and ordered in a2 Dl attice between layers of alkyl chains in bulk and in thin films, in which the molecular orderi sm aintained and alignedt othe substrate.
Aims
Variants in SCN5A encoding Nav1.5 are associated with cardiac arrhythmias. We aimed to determine the mechanism by which c.638G>A in SCNA5 resulting in p.Gly213Asp (G213D) in Nav1.5 altered Na+ channel function and how flecainide corrected the defect in a family with multifocal ectopic Purkinje-related premature contractions (MEPPC)-like syndrome.
Methods and results
Five patients carrying the G213D variant were treated with flecainide. Gating pore currents were evaluated in Xenopus laevis oocytes. The 638G>A SCN5A variant was introduced to human-induced pluripotent stem cell (hiPSC) by CRISPR–Cas9 gene editing and subsequently differentiated to cardiomyocytes (hiPSC-CM). Action potentials and sodium currents were measured in the absence and presence of flecainide. Ca2+ transients were measured by confocal microscopy. The five patients exhibited premature atrial and ventricular contractions which were suppressed by flecainide treatment. G213D induced gating pore current at potentials negative to −50 mV. Voltage-clamp analysis in hiPSC-CM revealed the activation threshold of INa was shifted in the hyperpolarizing direction resulting in a larger INa window current. The G213D hiPSC-CMs had faster beating rates compared with wild-type and frequently showed Ca2+ waves and alternans. Flecainide applied to G213D hiPSC-CMs decreased window current by shifting the steady-state inactivation curve and slowed the beating rate.
Conclusion
The G213D variant in Nav1.5 induced gating pore currents and increased window current. The changes in INa resulted in a faster beating rate and Ca2+ transient dysfunction. Flecainide decreased window current and inhibited INa, which is likely responsible for the therapeutic effectiveness of flecainide in MEPPC patients carrying the G213D variant.
Current debate and policy surrounding the use of genetic editing in humans often relies on a binary distinction between therapy and human enhancement. In this paper, we argue that this dichotomy fails to take into account perhaps the most significant potential uses of CRISPR-Cas9 gene editing in humans. We argue that genetic treatment of sporadic Alzheimer's disease, breastand ovarian-cancer causing BRCA1/2 mutations and the introduction of HIV resistance in humans should be considered within a new category of genetic protection treatments. We find that if this category is not introduced, life-altering research might be unnecessarily limited by current or future policy. Otherwise ad hoc decisions might be made, which introduce a risk of unforeseen moral costs, and might overlook or fail to address some important opportunities.
Self‐Assembly. Self‐organizing materials allow for fabrication of functional nanostructures. A two‐component approach to self‐assembled nanostructures has been developed, which allows for simple preparation of thin films with lamellar molecular order. The nanoscale molecular order is maintained over centimeters and is a direct result of the tailored chemical properties of the materials. Furthermore, the two‐component approach allows for different functions to be incorporated in the thin films. For more information, see the Full Paper on page 253 by Thomas Just Sørensen and co‐workers, which is featured on the back cover. Cover image kindly provided by Merlin von Soosten.
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