Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN 55455

Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115

Tau oligomers have recently emerged as the principal toxic species in Alzheimer’s disease (AD) and tauopathies. Tau oligomers are spontaneously self-assembled soluble tau proteins that are formed prior to fibrils, and they have been shown to play a central role in neuronal cell death and in the induction of neurodegeneration in animal models. As the therapeutic paradigm shifts to targeting toxic tau oligomers, this suggests the focus to study tau oligomerization in species that are less susceptible to fibrillization. While truncated and mutation containing tau as well as the isolated repeat domains are particularly prone to fibrillization, the wild-type (WT) tau proteins have been shown to be resistant to fibril formation in the absence of aggregation inducers. In this review, we will summarize and discuss the toxicity of WT tau both in vitro and in vivo, as well as its involvement in tau oligomerization and cell-to-cell propagation of pathology. Understanding the role of WT tau will enable more effective biomarker development and therapeutic discovery for treatment of AD and tauopathies.

ISTAustria (Institute of Science and Technology Austria), Cellular Neuroscience,Am Campus 1

A-3400 Klosterneuburg, Austria

Abstract

The hippocampus is the key site for learning and memory and for processing of spatial information in the brain. It is divided into three main subregions: the dentate gyrus (DG), the CA3 area, and the CA1 region, which are linearly interconnected to form a so-called trisynaptic circuit. Thus, the DG sits in a strategic position to gate the flow of information from the neocortex into the hippocampal network. The granule cells (GCs), the main cell type in the DG, receive ‘where’ and ‘what’ information from the medial and lateral entorhinal cortex, respectively. How they process this mixed information remains enigmatic. By characterizing the spatial information encoded by the excitatory postsynaptic potentials (EPSPs) in GCs, we demonstrated that the majority of GCs received spatially tuned synaptic input. However, only a minority of GCs successfully converted spatially tuned input to spatially tuned output. Furthermore, we found that mature GCs were highly heterogeneous in terms of their dendritic morphology and intrinsic excitability, which contributes to the sparse and heterogeneous firing of GCs. Finally, we discuss the possible origin of this neural heterogeneity and its potential role in enlarging the computational power of the DG, facilitating pattern separation in this network.

Barbara Davis Center for Diabetes, University ofColorado, Aurora, CO, USA, 80045

T cells are an integral component of the adaptive immune response via the recognition of peptides by the cell surface-expressed T cell receptor (TCR). Rearrangement of the TCR genes results in a highly polymorphic repertoire on the T cells within a given individual. Although the diverse repertoire is beneficial for immune responses to foreign pathogens, recognition of self-peptides by T cells can contribute to the development of autoimmune disorders. Increasing evidence supports a pathogenic role for T cells in autoimmune pathology, and it is of interest to determine the TCR repertoires involved in autoimmune disease development. In this review, we summarize methodologies and advancements in the TCR sequencing field and discuss recent studies focused on TCR sequencing in a variety of autoimmune conditions. The rapidly evolving methodology of TCR sequencing has the potential to allow for a better understanding of autoimmune disease pathogenesis, identify disease-specific biomarkers, and aid in developing therapies to prevent and treat a number of these disorders.

Lysosomes, membrane-bound organelles, play important roles in cellular processes including endocytosis, phagocytosis, and autophagy. Lysosomes maintain cellular homeostasis by generating a highly acidic environment of pH 4.5 – 5.0 and by housing hydrolytic enzymes that degrade engulfed biomolecules. Impairment of lysosomal function, especially in its acidification, is a driving force in the pathogenesis of diseases including neurodegeneration, cancer, metabolic disorders, and infectious diseases. Therefore, lysosomal pH is an attractive and targetable site for therapeutic intervention. Currently, there is a dearth of strategies or materials available to specifically modulate lysosomal acidification. This review focuses on the key aspects of how lysosomal pH is implicated in various diseases and discusses design strategies and molecular or nanoscale agents for lysosomal pH modulation, with the ultimate goal of developing novel therapeutic solutions. 

Diabetes and Beta CellBiology Center, Division of Endocrinology and Metabolism, University ofPittsburgh, Pittsburgh, PA, USA.

microRNAs (miRNAs) are small non-coding RNAs '22nt in length that regulate gene expression post transcriptionally by binding to their 3’UTR. In the last 27 years, since its discovery, tremendous progress has been made to determine its functional significance in the spatio-temporal regulation of gene expression; they act cordially to regulate gene networks or pathways. miRNA being stable, are also found in body fluid serving as a potential biomarker. Despite knowing a lot about miRNAs function, its use in clinical phase is still in its infancy- with poor outcome in clinical trials and difficulty in its tissue-specific delivery. This review provides a snapshot of the progress of miRNA field in past few years and challenges associated with its clinical applications.