Molecular and Cellular Neuroscience Commons^™

The Effects Of Nuclear Factor Erythroid 2 (Nfe2)-Related Factor 2 (Nrf2) Activation In Preclinical Models Of Peripheral Neuropathic Pain, Paramita Basu, Dayna L. Averitt, Camelia Maier, Arpita Basu

Kinesiology and Nutrition Sciences Faculty Research

Oxidative stress, resulting from an imbalance between the formation of damaging free radicals and availability of protective antioxidants, can contribute to peripheral neuropathic pain conditions. Reactive oxygen and nitrogen species, as well as products of the mitochondrial metabolism such as superoxide anions, hydrogen peroxide, and hydroxyl radicals, are common free radicals. Nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) is a transcription factor encoded by the NFE2L2 gene and is a member of the cap ‘n’ collar subfamily of basic region leucine zipper transcription factors. Under normal physiological conditions, Nrf2 remains bound to Kelch-like ECH-associated protein 1 in the cytoplasm …

Rare And Low Frequency Genomic Variants Impacting Neuronal Functions Modify The Dup7q11.23 Phenotype, Farah Qaiser, Yue Yin, Carolyn B. Mervis, Colleen A. Morris, Bonita P. Klein-Tasman, Elaine Tam, Lucy R. Osborne, Ryan K.C. Yuen

School of Medicine Faculty Research

© 2021, The Author(s). Background: 7q11.23 duplication (Dup7) is one of the most frequent recurrent copy number variants (CNVs) in individuals with autism spectrum disorder (ASD), but based on gold-standard assessments, only 19% of Dup7 carriers have ASD, suggesting that additional genetic factors are necessary to manifest the ASD phenotype. To assess the contribution of additional genetic variants to the Dup7 phenotype, we conducted whole-genome sequencing analysis of 20 Dup7 carriers: nine with ASD (Dup7-ASD) and 11 without ASD (Dup7-non-ASD). Results: We identified three rare variants of potential clinical relevance for ASD: a 1q21.1 microdeletion (Dup7-non-ASD) and two deletions which …

Single-Cell Rna Sequencing Deconvolutes The In Vivo Heterogeneity Of Human Bone Marrow-Derived Mesenchymal Stem Cells, Zun Wang, Xiaohua Li, Junxiao Yang, Yun Gong, Huixi Zhang, Xiang Qiu, Ying Liu, Cui Zhou, Yu Chen, Jonathan Greenbaum, Liang Cheng, Yihe Hu, Jie Xie, Xucheng Yang, Yusheng Li, Martin R. Schiller

Life Sciences Faculty Research

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent stromal cells that have a critical role in the maintenance of skeletal tissues such as bone, cartilage, and the fat in bone marrow. In addition to providing microenvironmental support for hematopoietic processes, BM-MSCs can differentiate into various mesodermal lineages including osteoblast/osteocyte, chondrocyte, and adipocyte that are crucial for bone metabolism. While BM-MSCs have high cell-to-cell heterogeneity in gene expression, the cell subtypes that contribute to this heterogeneity in vivo in humans have not been characterized. To investigate the transcriptional diversity of BM-MSCs, we applied single-cell RNA sequencing (scRNA-seq) on freshly isolated CD271+ …

The Amyloid-Β Pathway In Alzheimer’S Disease, Harald Hampel, John Hardy, Kaj Blennow, Christopher Chen, George Perry, Seung Hyun Kim, Victor L. Villemagne, Paul Aisen, Michele Vendruscolo, Takeshi Iwatsubo, Colin L. Masters, Min Cho, Lars Lannfelt, Jeffrey L. Cummings, Andrea Vergallo

School of Medicine Faculty Research

Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer’s disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of …

Severe Covid-19 In Alzheimer’S Disease: Apoe4’S Fault Again?, Nian Xiong, Martin R. Schiller, Jingwen Li, Xiaowu Chen, Zhicheng Lin

Life Sciences Faculty Research

Challenges have been recognized in healthcare of patients with Alzheimer’s disease (AD) in the COVID-19 pandemic, given a high infection and mortality rate of COVID-19 in these patients. This situation urges the identification of underlying risks and preferably biomarkers for evidence-based, more effective healthcare. Towards this goal, current literature review and network analysis synthesize available information on the AD-related gene APOE into four lines of mechanistic evidence. At a cellular level, the risk isoform APOE4 confers high infectivity by the underlying coronavirus SARS-CoV-2; at a genetic level, APOE4 is associated with severe COVID-19; at a pathway level, networking connects APOE …

Validation Of Induced Microglia-Like Cells (Img Cells) For Future Studies Of Brain Diseases, Atoshi Banerjee, Yimei Lu, Kenny Do, Travis Mize, Xiaogang Wu, Xiangning Chen, Jingchun Chen

School of Medicine Faculty Research

Microglia are the primary resident immune cells of the central nervous system that maintain physiological homeostasis in the brain and contribute to the pathogenesis of many psychiatric disorders and neurodegenerative diseases. Due to the lack of appropriate human cellular models, it is difficult to study the basic pathophysiological processes linking microglia to brain diseases. In this study, we adopted a microglia-like cellular model derived from peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-34 (IL-34). We characterized and validated this in vitro cellular model by morphology, immunocytochemistry, gene expression profiles, and functional study. Our results indicated that the iMG …

Influence Of Previous Covid-19 And Mastitis Infections On The Secretion Of Brain-Derived Neurotrophic Factor And Nerve Growth Factor In Human Milk, Veronique Demers-Mathieu, Dustin J. Hines, Rochelle M. Hines, Sirima Lavangnananda, Shawn Fels, Elena Medo

Psychology Faculty Research

Background: Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) play a critical role in neurodevelopment, where breast milk is a significant dietary source. The impact of previous COVID-19 infection and mastitis on the concentration of BDNF and NGF in human milk was investigated. Methods: Concentrations of BDNF and NGF were measured via ELISA in human milk samples collected from 12 mothers with a confirmed COVID-19 PCR, 13 mothers with viral symptoms suggestive of COVID-19, and 22 unexposed mothers (pre-pandemic Ctl-2018). These neurotrophins were also determined in 12 mothers with previous mastitis and 18 mothers without mastitis. Results: The NGF …

Multimodal Single-Cell/Nucleus Rna Sequencing Data Analysis Uncovers Molecular Networks Between Disease-Associated Microglia And Astrocytes With Implications For Drug Repurposing In Alzheimer’S Disease, Jielin Xu, Pengyue Zhang, Yin Huang, Yadi Zhou, Yuan Hou, Lynn M. Bekris, Justin Lathia, Chien-Wei Chiang, Lang Li, Andrew A. Pieper, James B. Leverenz, Jeffrey Cummings, Feixiong Cheng

School of Medicine Faculty Research

Because disease-associated microglia (DAM) and disease-associated astrocytes (DAA) are involved in the pathophysiology of Alzheimer's disease (AD), we systematically identified molecular networks between DAM and DAA to uncover novel therapeutic targets for AD. Specifically, we develop a network-based methodology that leverages single-cell/nucleus RNA sequencing data from both transgenic mouse models and AD patient brains, as well as drug-target network, metaboliteenzyme associations, the human protein-protein interactome, and large-scale longitudinal patient data. Through this approach, we find both common and unique gene network regulators between DAM (i.e., PAK1, MAPK14, and CSF1R) and DAA (i.e., NFKB1, FOS, and JUN) that are significantly enriched …

Behavioral Arrest And A Characteristic Slow Waveform Are Hallmark Responses To Selective 5-Ht2a Receptor Activation, April Contreras, Matthew Khumnark, Rochelle M. Hines, Dustin J. Hines

Psychology Faculty Research

© 2021, The Author(s). Perception, emotion, and mood are powerfully modulated by serotonin receptor (5-HTR) agonists including hallucinogens. The 5-HT2AR subtype has been shown to be central to hallucinogen action, yet the precise mechanisms mediating the response to 5-HT2AR activation remain unclear. Hallucinogens induce the head twitch response (HTR) in rodents, which is the most commonly used behavioral readout of hallucinogen pharmacology. While the HTR provides a key behavioral signature, less is known about the meso level changes that are induced by 5-HT2AR activation. In response to administration of the potent and highly selective 5-HT2AR agonist 25I-NBOH in mice, we …

Alzgps: A Genome-Wide Positioning Systems Platform To Catalyze Multi-Omics For Alzheimer’S Drug Discovery, Yadi Zhou, Jiansong Fang, Lynn M. Bekris, Yeon Heon Kim, Andrew A. Pieper, James B. Leverenz, Jeffrey Cummings, Feixiong Cheng

School of Medicine Faculty Research

Background: Recent DNA/RNA sequencing and other multi-omics technologies have advanced the understanding of the biology and pathophysiology of AD, yet there is still a lack of disease-modifying treatments for AD. A new approach to integration of the genome, transcriptome, proteome, and human interactome in the drug discovery and development process is essential for this endeavor. Methods: In this study, we developed AlzGPS (Genome-wide Positioning Systems platform for Alzheimer’s Drug Discovery, https://alzgps.lerner.ccf.org), a comprehensive systems biology tool to enable searching, visualizing, and analyzing multi-omics, various types of heterogeneous biological networks, and clinical databases for target identification and development of effective prevention …

Molecular Specialization Of Gabaergic Synapses On The Soma And Axon In Cortical And Hippocampal Circuit Function And Dysfunction, April Contreras, Dustin J. Hines, Rochelle M. Hines

Psychology Faculty Research

The diversity of inhibitory interneurons allows for the coordination and modulation of excitatory principal cell firing. Interneurons that release GABA (γ-aminobutyric acid) onto the soma and axon exert powerful control by virtue of proximity to the site of action potential generation at the axon initial segment (AIS). Here, we review and examine the cellular and molecular regulation of soma and axon targeting GABAergic synapses in the cortex and hippocampus. We also describe their role in controlling network activity in normal and pathological states. Recent studies have demonstrated a specific role for postsynaptic dystroglycan in the formation and maintenance of cholecystokinin …

Presenilin Is Necessary For The Function Of Cbp In The Adult Drosophila Cns, Randy S. Boyles

UNLV Theses, Dissertations, Professional Papers, and Capstones

Dominant mutations in Presenilin (Psn) have been correlated with the formation of Aß- containing plaques in patients with inherited forms of Alzheimer's disease (AD). However, a clear mechanism directly linking amyloid plaques to the pathology of familial or sporadic forms of AD has remained elusive. Thus, recent discoveries of several new substrates for Psn protease activity have sparked alternative hypotheses to explain the preclinical symptoms of AD. CBP (CREB-binding protein) is a haplo- insufficient transcriptional co-activator with histone acetyltransferase (HAT) activity that has been proposed to be a downstream target for Psn signaling. Individuals with reduced CBP levels have cognitive …

Genes Involved In Mushroom Body Development And Behavior In Drosophila, Christine Nicole Serway

UNLV Theses, Dissertations, Professional Papers, and Capstones

Mushroom bodies (MBs) are the site of multi modal sensory integration critical for associative conditioning in Drosophila. They have been central to research on the structure function relationship in the brain for over one hundred years due to their unique shape and readily accessible physiology. This dissertation incorporates three different approaches to further elucidate the genetic and molecular nature of this structure function relationship.

First, the suite of genetic and molecular tools available in Drosophila melanogaster, facilitated the molecular mapping of a 25-year old MB structural mutant called mushroom body miniature B (mbmB) to the gene Pendulin [Pen, also known …