A5022252180- Neuroinflammation and Neurodegeneration Mechanisms
- Prion Diseases and Protein Misfolding
- Alzheimer's disease research and treatments
- Neuroscience and Neuropharmacology Research
- Neurological diseases and metabolism
- RNA regulation and disease
- Inflammasome and immune disorders
- Tryptophan and brain disorders
- Endoplasmic Reticulum Stress and Disease
- Heavy Metal Exposure and Toxicity
- Participatory Visual Research Methods
- Human-Animal Interaction Studies
- Reflective Practices in Education
- Digital Storytelling and Education
- Trace Elements in Health
- Peroxisome Proliferator-Activated Receptors
- Immune Response and Inflammation
- Parkinson's Disease Mechanisms and Treatments
- Barrier Structure and Function Studies
- Neurogenesis and neuroplasticity mechanisms
- NF-κB Signaling Pathways
- Neuroendocrine regulation and behavior
- Biochemical Acid Research Studies
- Macrophage Migration Inhibitory Factor
- Signaling Pathways in Disease
Colorado State University
2015-2025
University of Colorado Anschutz Medical Campus
2018
Texas A&M University
2018
MRC Toxicology Unit
2010-2017
University of Leicester
2010-2016
Medical Research Council
2015
During prion disease, an increase in misfolded protein (PrP) generated by replication leads to sustained overactivation of the branch unfolded response (UPR) that controls initiation synthesis. This results persistent repression translation, resulting loss critical proteins synaptic failure and neuronal death. We have previously reported localized genetic manipulation this pathway rescues shutdown translation prevents neurodegeneration a mouse model suggesting pharmacological inhibition...
Abstract Activation of the PERK branch unfolded protein response (UPR) in to misfolding within endoplasmic reticulum (ER) results transient repression synthesis, mediated by phosphorylation alpha subunit eukaryotic initiation factor 2 (eIF2 α ). This is part a wider integrated physiological maintain proteostasis face ER stress, dysregulation which increasingly associated with wide range diseases, particularly neurodegenerative disorders. In prion-diseased mice, persistently high levels eIF2...
See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article. Signalling through the PERK/eIF2α-P branch of unfolded protein response plays critical role in controlling synthesis rates cells. This pathway is overactivated brains patients with Alzheimer's disease related disorders has recently emerged as promising therapeutic target these currently untreatable conditions. Thus, mouse models neurodegenerative disease, prolonged overactivation signalling causes...
The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates transient shutdown translation in response to rising levels misfolded proteins endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised postmortem analyses patients with neurodegenerative disorders, including Alzheimer's disease, tauopathies prion disorders. These all characterised by accumulation disease-specific brain association specific patterns neuronal loss, but role UPR their pathogenesis is...
Neuroinflammation plays a crucial role in the development of neurodegenerative protein misfolding disorders. This category progressive diseases includes, but is not limited to, Alzheimer's disease, Parkinson's and prion diseases. Shared pathogenesis involves accumulation misfolded proteins, chronic neuroinflammation, synaptic dysfunction, ultimately leading to irreversible neuronal loss, measurable cognitive deficits, death. Presently, there are few no effective treatments halt advancement...
The current frontline symptomatic treatment for Alzheimer's disease (AD) is whole-body upregulation of cholinergic transmission via inhibition acetylcholinesterase. This approach leads to profound dose-related adverse effects. An alternative strategy selectively target muscarinic acetylcholine receptors, particularly the M1 receptor (M1 mAChR), which was previously shown have procognitive activity. However, developing mAChR-selective orthosteric ligands has proven challenging. Here, we that...
Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding host encoded prion protein, PrP C , by its conformation, Sc . Following discovery in captive Colorado deer 1967, uncontrollable contagious transmission chronic wasting disease (CWD) led to an expanded geographic range increasing numbers free-ranging North American (NA) cervids. Some five decades later, detection Norwegian (NO) reindeer...
Abstract Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver both age- tau-associated neuroinflammation NF-κB NLRP3 signaling axis. However, current treatments targeting or may have adverse/systemic effects, most not been clinically translatable. In this study, we tested efficacy a novel, nucleic acid therapeutic (Nanoligomer)...
Chronic exposure to manganese (Mn) produces a spectrum of cognitive and behavioral deficits associated with neurodegenerative disorder resembling Parkinson's disease. The effects high-dose Mn in occupational cohorts adult rodent models the disease are well described but much less is known about neurochemical developing brain. We therefore exposed C57Bl/6 mice by intragastric gavage as juveniles, adults, or both, postulating that juveniles then again adults would exhibit greater neurological...
Although the unifying hallmark of prion diseases is CNS neurodegeneration caused by conformational corruption host protein (PrP) to its infective counterpart, contagious transmission chronic wasting disease (CWD) results from shedding prions produced at high titers in periphery diseased cervids. While deer and elk PrP primary structures are equivalent except residue 226, which glutamate glutamine deer, effect this difference on CWD pathogenesis largely unknown. Using a gene-targeting...
Inflammatory activation of glial cells promotes loss dopaminergic neurons in Parkinson disease. The transcription factor nuclear κB (NF-<i>κ</i>B) regulates the expression multiple neuroinflammatory cytokines and chemokines activated that are damaging to neurons. Thus, inhibition NF-<i>κ</i>B signaling could be a promising therapeutic strategy for prevention injury. Nuclear orphan receptors NR4A family, including NR4A1 (Nur77) NR4A2 (Nurr1), can inhibit inflammatory effects NF-<i>κ</i>B, but...
Mesenchymal stromal cells (MSCs) are an intriguing avenue for the treatment of neurological disorders due to their ability migrate sites neuroinflammation and respond paracrine signaling in those by secreting cytokines, growth factors, other neuromodulators. We potentiated this stimulating MSCs with inflammatory molecules, improving migratory secretory properties. investigated use intranasally delivered adipose-derived (AdMSCs) combating prion disease a mouse model. Prion is rare, lethal...
Immune malfunction or misrecognition of healthy cells and tissue, termed autoimmune disease, is implicated in more than 80 disease conditions multiple other secondary pathologies. While pan-immunosuppressive therapies like steroids can offer limited relief for systemic inflammation some organs, many patients never achieve remission, such drugs do not cross the blood-brain barrier, making them ineffective tackling neuroinflammation. Especially brain, unintended activation microglia astrocytes...
Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages life. This affects the spinal cord brain characterized by severe neuroinflammation, demyelination, subsequent neuronal damage, resulting in symptoms like loss mobility. While untargeted pan-immunosuppressive therapies have proven to be disease-modifying manage (or prolong time between) many...
Abstract Inflammatory activation of glial cells is associated with neuronal injury in several degenerative movement disorders the basal ganglia, including manganese neurotoxicity. Manganese (Mn) potentiates effects inflammatory cytokines on nuclear factor‐κB (NF‐κB)‐dependent expression nitric oxide synthase 2 (NOS2) astrocytes, but signaling mechanisms underlying this effect have remained elusive. It was postulated present studies that direct stimulation cGMP synthesis and mitogen‐activated...
ABSTRACT Multiple Sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages life. This affects the spinal cord brain, characterized by severe neuroinflammation, demyelination, subsequent neuronal damage, resulting in symptoms like loss mobility. While untargeted pan-immunosuppressive therapies have proven to be disease-modifying manage (or prolong time between)...
ABSTRACT Neuroinflammation contributes to impaired cognitive function in brain aging and neurodegenerative disorders like Alzheimer’s disease, which is characterized by the aggregation of pathological tau. One major driver both age- tau-associated neuroinflammation NF-κB NLRP3 signaling axis. However, current treatments targeting or may have adverse/systemic effects, most not been clinically translatable. In this study, we tested efficacy a novel, nucleic acid therapeutic (Nanoligomer)...
Chronic exposure to manganese (Mn) produces a neurodegenerative disorder affecting the basal ganglia characterized by reactive gliosis and expression of neuroinflammatory genes including inducible nitric oxide synthase (NOS2). Induction NOS2 in glial cells causes overproduction (NO) injury neurons that is associated with parkinsonian-like motor deficits. Inflammatory activation glia believed be an early event Mn neurotoxicity, but specific responses microglia astrocytes during development...
Manganese toxicity can cause a neurodegenerative disorder affecting cortical and basal ganglia structures with neurological presentation resembling features of Parkinson's disease. Children are more sensitive to Mn-induced dysfunction than adults, recent studies from our laboratory revealed marked sensitivity male juvenile mice neuroinflammatory injury Mn, relative females. To determine the role estrogen (E2) in mediating sex-dependent vulnerability neurotoxicity, we exposed transgenic...
Binge alcohol use is increasing among aged adults (>65 years). Alcohol-related toxicity in associated with neurodegeneration, yet the molecular underpinnings of this age-related sensitivity to are not well described. Studies utilizing rodent models neurodegenerative disease reveal heightened activation Nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and Nod like receptor 3 (NLRP3) mediate microglia neuronal injury. Our group, others, have implicated hippocampal-resident...
This review synthesizes the emerging understanding of roles glial cells and non-coding RNAs (ncRNAs) in pathogenesis progression Alzheimer’s disease related dementias (ADRDs). ADRDs encompass a spectrum neurodegenerative disorders characterized by cognitive decline, memory impairment, functional deterioration. The interplay between most common types cells—astrocytes, microglia, oligodendrocytes—and ncRNAs is as critical factor development ADRDs. Glial are essential for maintaining...