Examining the NEUROG2-lineage and associated-gene expression in human cortical organoids.

Proneural genes are conserved drivers of neurogenesis across the animal kingdom. How their functions have adapted to guide human-specific neurodevelopmental features is poorly understood. Here, we mined transcriptomic data from human fetal cortices and generated from human embryonic stem cell (hESC)-derived cortical organoids (COs) to show that NEUROG1 and NEUROG2 are most highly expressed in basal neural progenitor cells, with pseudotime trajectory analyses indicating that NEUROG1-derived lineages predominate early and NEUROG2 lineages later.

Primitive and Definitive Neural Precursor Cells Are Present in Human Cerebral Organoids.

Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively characterized and comprise (1) primitive NSCs (pNSCs) and (2) definitive NSCs (dNSCs). pNSCs are the earliest cells in the NSC lineage giving rise to dNSCs in the embryonic and adult mouse brain.

Pten regulates endocytic trafficking of cell adhesion and Wnt signaling molecules to pattern the retina.

The retina is exquisitely patterned, with neuronal somata positioned at regular intervals to completely sample the visual field. Here, we show that phosphatase and tensin homolog (Pten) controls starburst amacrine cell spacing by modulating vesicular trafficking of cell adhesion molecules and Wnt proteins. Single-cell transcriptomics and double-mutant analyses revealed that Pten and Down syndrome cell adhesion molecule Dscam) are co-expressed and function additively to pattern starburst amacrine cell mosaics.

Ascl1 phospho-site mutations enhance neuronal conversion of adult cortical astrocytes .

Direct neuronal reprogramming, the process whereby a terminally differentiated cell is converted into an induced neuron without traversing a pluripotent state, has tremendous therapeutic potential for a host of neurodegenerative diseases. While there is strong evidence for astrocyte-to-neuron conversion studies in the adult brain are less supportive or controversial. Here, we set out to enhance the efficacy of neuronal conversion of adult astrocytes by optimizing the neurogenic capacity of a driver transcription factor encoded by the proneural gene Ascl1.

Proneural genes define ground-state rules to regulate neurogenic patterning and cortical folding.

Asymmetric neuronal expansion is thought to drive evolutionary transitions between lissencephalic and gyrencephalic cerebral cortices. We report that Neurog2 and Ascl1 proneural genes together sustain neurogenic continuity and lissencephaly in rodent cortices. Using transgenic reporter mice and human cerebral organoids, we found that Neurog2 and Ascl1 expression defines a continuum of four lineage-biased neural progenitor cell (NPC) pools.

Melatonin Prevents Neddylation Dysfunction in Aβ42-Exposed SH-SY5Y Neuroblastoma Cells by Regulating the Amyloid Precursor Protein- Binding Protein 1 Pathway.

Background: Amyloid Precursor Protein (APP)-Binding Protein 1 (APP-BP1) is a crucial regulator of many key signaling pathways and functions mainly as a scaffold protein to enhance molecular interactions and facilitate catalytic reactions. The interaction of APP-BP1 with Amyloid Precursor Protein (APP) plays a role in cell cycle transit control, which determines the mechanism behind the loss of cell cycle regulation in Alzheimer's Disease (AD). In contrast, neddylation, a posttranslational modification mediated by conjugation of ubiquitin-like protein neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), is activated by a heterodimer composed of APP-BP1 and NEDD8-activating enzyme E1 catalytic subunit (Uba3).

The role of melatonin in targeting cell signaling pathways in neurodegeneration.

Neurodegenerative diseases are typified by neuronal loss associated with progressive dysfunction and clinical presentation. Neurodegenerative diseases are characterized by the intra- and extracellular conglomeration of misfolded proteins that occur because of abnormal protein dynamics and genetic manipulations; these trigger processes of cell death in these disorders. The disrupted signaling mechanisms involved are oxidative stress-mediated mitochondrial and calcium signaling deregulation, alterations in immune and inflammatory signaling, disruption of autophagic integrity, proteostasis dysfunction, and anomalies in the insulin, Notch, and Wnt/β-catenin signaling pathways.

Melatonin ameliorates Aβ -induced alteration of βAPP-processing secretases via the melatonin receptor through the Pin1/GSK3β/NF-κB pathway in SH-SY5Y cells.

Melatonin is involved in the physiological regulation of the β-amyloid precursor protein (βAPP)-cleaving secretases which are responsible for generation of the neurotoxic amyloid beta (Aβ) peptide, one of the hallmarks of Alzheimer's disease (AD) pathology. In this study, we aimed to determine the underlying mechanisms of this regulation under pathological conditions. We establish that melatonin prevents Aβ -induced downregulation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) as well as upregulation of β-site APP-cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) in SH-SY5Y cell cultures.

Connectivity and circuitry in a dish versus in a brain.

In order to understand and find therapeutic strategies for neurological disorders, disease models that recapitulate the connectivity and circuitry of patients' brain are needed. Owing to many limitations of animal disease models, in vitro neuronal models using patient-derived stem cells are currently being developed. However, prior to employing neurons as a model in a dish, they need to be evaluated for their electrophysiological properties, including both passive and active membrane properties, dynamics of neurotransmitter release, and capacity to undergo synaptic plasticity.

Characterization of a subpopulation of developing cortical interneurons from human iPSCs within serum-free embryoid bodies.

Production and isolation of forebrain interneuron progenitors are essential for understanding cortical development and developing cell-based therapies for developmental and neurodegenerative disorders. We demonstrate production of a population of putative calretinin-positive bipolar interneurons that express markers consistent with caudal ganglionic eminence identities. Using serum-free embryoid bodies (SFEBs) generated from human inducible pluripotent stem cells (iPSCs), we demonstrate that these interneuron progenitors exhibit morphological, immunocytochemical, and electrophysiological hallmarks of developing cortical interneurons.

A time course analysis of the electrophysiological properties of neurons differentiated from human induced pluripotent stem cells (iPSCs).

Many protocols have been designed to differentiate human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs) into neurons. Despite the relevance of electrophysiological properties for proper neuronal function, little is known about the evolution over time of important neuronal electrophysiological parameters in iPSC-derived neurons. Yet, understanding the development of basic electrophysiological characteristics of iPSC-derived neurons is critical for evaluating their usefulness in basic and translational research.

N-benzylcinnamide protects rat cultured cortical neurons from β-amyloid peptide-induced neurotoxicity.

The pathogenesis of Alzheimer's disease involves an amyloid β-peptide (Aβ)-induced cascade of elevated oxidative damage and inflammation. The present study investigates the protective effects and the underlying mechanisms of N-benzylcinnamide (PT-3), purified from Piper submultinerve. Against Aβ-induced oxidative stress and inflammation in rat primary cortical cell cultures.