Search

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. Herein, we accentuate some of the contemporary translational approaches made in characterizing the underlying mechanisms of neurodegeneration. Melatonin-induced cognitive enhancement and inhibition of oxidative signaling substantiates the efficacy of melatonin in combating neurodegenerative processes. Our review considers in detail the possible roles of melatonin in understanding the synergistic pathogenic mechanisms between aggregated proteins and in regulating, modulating, and preventing the altered signaling mechanisms discovered in cellular and animal models along with clinical evaluations pertaining to neurodegeneration. Furthermore, this review showcases the therapeutic potential of melatonin in preventing and treating neurodegenerative diseases with optimum prognosis.

International audience; 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. Double+ NPCs, at the hierarchical apex, are least lineage restricted due to Neurog2-Ascl1 cross-repression and display unique features of multipotency (more open chromatin, complex gene regulatory network, G2 pausing). Strikingly, selectively eliminating double+ NPCs by crossing Neurog2-Ascl1 split-Cre mice with diphtheria toxin-dependent "deleter" strains locally disrupts Notch signaling, perturbs neurogenic symmetry, and triggers cortical folding. In support of our discovery that double+ NPCs are Notch-ligand-expressing "niche" cells that control neurogenic periodicity and cortical folding, NEUROG2, ASCL1, and HES1 transcript distribution is modular (adjacent high/low zones) in gyrencephalic macaque cortices, prefiguring future folds.

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. Finally, we develop a fluorescence-activated cell-sorting strategy to isolate interneuron progenitors from SFEBs to allow development of a purified population of these cells. Identification of this critical neuronal cell type within iPSC-derived SFEBs is an important and novel step in describing cortical development in this iPSC preparation.

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. Pre-treatment with 10-00nM PT-3 significantly attenuated neuronal cell death induced by 10μM Aβ1-42. PT-3 was found to enhance cell viability through a significant reduction in the level of reactive oxygen species, down-regulated expression of pro-apoptotic activated caspase-3 and Bax, increased expression of anti-apoptotic Bcl-2, and mitigation of Aβ-induced morphological alterations. Regarding its effects on inflammatory responses, PT-3 pre-treatment decreased the expression of pro-inflammatory cytokines IL-1β and IL-6. The mechanisms of PT-3 neuronal protection against inflammation may be associated with the mitogen-activated protein kinases (MAPK) pathway. Aβ1-42-induced phosphorylation of JNK and p38 MAPK was inhibited by pretreatment with PT-3 in a dose-dependent manner. However, phosphorylation of ERK1/2 was not affected by either PT-3 or Aβ1-42. PT-3 did not stimulate Akt phosphorylation, which was inhibited by Aβ1-42. These findings suggest that PT-3 protects neurons from Aβ1-42-induced neurotoxicity through its anti-apoptotic, anti-oxidative, and anti-inflammatory properties with inhibition of JNK and p38 MAPK phosphorylation as the potential underlying mechanism.

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. Therefore, we analyzed the basic electrophysiological parameters of forebrain neurons differentiated from human iPSCs, from day 31 to day 55 after the initiation of neuronal differentiation. We assayed the developmental progression of various properties, including resting membrane potential, action potential, sodium and potassium channel currents, somatic calcium transients and synaptic activity. During the maturation of iPSC-derived neurons, the resting membrane potential became more negative, the expression of voltage-gated sodium channels increased, the membrane became capable of generating action potentials following adequate depolarization and, at day 48-55, 50% of the cells were capable of firing action potentials in response to a prolonged depolarizing current step, of which 30% produced multiple action potentials. The percentage of cells exhibiting miniature excitatory post-synaptic currents increased over time with a significant increase in their frequency and amplitude. These changes were associated with an increase of Ca2+ transient frequency. Co-culturing iPSC-derived neurons with mouse glial cells enhanced the development of electrophysiological parameters as compared to pure iPSC-derived neuronal cultures. This study demonstrates the importance of properly evaluating the electrophysiological status of the newly generated neurons when using stem cell technology, as electrophysiological properties of iPSC-derived neurons mature over time.