Linseman Laboratory

In the Linseman laboratory, biochemical, immunofluorescence, and molecular biological techniques are used to examine the roles of mitochondrial oxidative stress, neuroinflammation, and intrinsic apoptosis in neurodegeneration and neurotrauma. We utilize mouse models of neurodegenerative disorders (e.g., mutant hSOD1 transgenic mouse model of ALS and mutant APP mouse model of AD) and TBI (e.g., controlled cortical impact mouse model of TBI) to study disease processes in vivo. Specific projects include the following: elucidating the relationship between TBI and neurodegeneration, investigating the role of Reelin deficiencies in the pathogenesis of AD, the role of Rho family GTPases in the motor neuron cell death that underlies ALS, the role of mitochondrial glutathione transport in protecting neurons from oxidative stress, involvement of Bcl-2 family proteins in the regulation of mitochondrial susceptibility to oxidative stress, and studies on the antioxidant, anti-neuroinflammatory, and neuroprotective properties of a variety of natural products. We also collaborate with a number of clinicians (neurologists and neurosurgeons) to perform translational clinical studies. The most recent of these is focused on the long-term consequences to brain health in patients who have had SARS-CoV-2 infection, particularly those with a history of head trauma (i.e., concussion).

About Dr. Linesman

Dr. Daniel Linseman is an experienced neuroscientist with expertise in neurodegeneration, neurotrauma, and neuropharmacology. He received his B.S. in Biology and Chemistry from the University of Michigan in 1987 and a Ph.D. in Pharmacology from the University of Michigan in 2000. From 1987-1995, he was a research assistant at the Upjohn Pharmaceutical Company in Kalamazoo, Michigan where he worked in the fields of toxicology and cardiovascular disease. Beginning in 2000, he did 5 years of postdoctoral training at the Denver Veterans Affairs Medical Center studying mechanisms of neuronal apoptosis. Dr. Linseman is currently a Professor in the Department of Biological Sciences and Associate Executive Director of the Knoebel Institute for Healthy Aging at the University of Denver. He is also a Senior Scientist and Vice President of the Eleanor Roosevelt Institute. For the past 15 years, he has ran his own research program focused on elucidating molecular mechanisms of neuronal cell death in degenerative disorders and episodes of neurotrauma, with a particular emphasis on amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), Alzheimer's disease (AD), and traumatic brain injury (TBI). He has submitted more than 50 independent investigator grant applications and received funding from the NIH (R01NS062766), the VA (10 years of Merit Review funding), and the biotechnology industry. He has published more than 75 peer-reviewed papers. According to Google Scholar, his published works have nearly 4800 citations and he has an author H-index of 37. Dr. Linseman has served as a peer reviewer for nearly 30 journals including a dozen neuroscience journals. He has also served on peer review study sections for the NIH (R01, R21, R15, and Fellowship panels), the VA (Merit Review panels), and the Department of Defense, as well as multiple foundation granting agencies. In addition to his significant research and peer review responsibilities, Dr. Linseman mentors undergraduates, graduate students and postdocs in the laboratory and teaches university courses in neuropharmacology, advanced cell signaling, and ethical dilemmas in neurology.

Graduate Student Research

• Alexandra Sandberg – 5th year PhD Student in the Linseman Lab

  I am currently in my fifth year of graduate studies pursuing a PhD in Cellular & Molecular Biology at DU. Previously, I earned my Professional Science Masters in Biomedical Sciences at DU and BA in Biochemistry at Miami University (Ohio). In my time in the Linseman lab, my research has focused on the mechanisms and treatment of Alzheimer's Disease (AD) onset. I like to say my studies translate from the cell to the patient as my projects have included cell culture work, mouse studies, and clinical evaluations of adults with AD and age-related dementias (ADRD). In regards to cell work, I've worked with hippocampal HT22 cells on several projects to uncover mechanisms of amyloid precursor protein (APP) product toxicity. We have found that two APP cleavage products, amyloid beta (A) and APP intracellular domain (AICD), induce apoptosis through distinct pathways since AICD requires caspase activation, while A requires a functional mitochondrial permeability transitional pore (PTP) to induce cell death. In addition, I've investigated the relationship between polyamines and A in HT22 cells by measuring polyamines, the rate-limiting enzyme ornithine decarboxylase (ODC) in the polyamine synthesis pathway, and A aggregation and induced apoptosis. Through these studies, we found that with increasing concentrations of A, there are increasing levels of polyamines, which is likely through increased expression of ODC; and further, that by inhibiting ODC, there is a reduction in A aggregation and A induced apoptosis. In regards to mouse work, using the J20 AD mouse model, we found that treatment with the whey protein supplement Immunocal protects Reelin expression in an AD mouse model, presumably through preservation of glutathione. In addition, we found that treatment also decreased neuronal loss and decreased amyloid load in the disease state. Lastly, I have worked alongside the Alumia Institute, a clinic which uses a multimodal approach to combating ADRD progression. Throughout this project, we have been investigating the impact of this curriculum and environment on improving behavioral and cognitive measures as well as the impact on the caregivers of these patients as a method of delaying disease onset and improving wellbeing for the patients and their caretakers. By investigating the single cell changes to the development of disease in mouse models, to the treatment of patients affected, the research I have been involved in seeks to uncover new ways to combat AD from multiple angles whether that be through new, multifaceted therapeutics to lifestyle interventions to ultimately delay onset and improve outcomes for those affected by AD.

• Lilia Koza – 4th year PhD Student in the Linseman Lab

  I am a fourth year Cellular and Molecular Biology Ph.D. candidate at the University of Denver. I first received training in the lab while working towards my B.S. in Biology with a concentration in Cognitive Neuroscience at the University of Denver. After receiving my B.S. in 2017, I was eager to continue learning and, that same year, I entered the Ph.D. program I am currently enrolled in. I have a passion for understanding and treating neurodegeneration through my research. My research consists of exploring nutraceuticals, or natural compounds found in everyday foods, as treatment options for neurotrauma and amyotrophic lateral sclerosis (ALS). More specifically, I am analyzing the anti-inflammatory and neuroprotective effect of nutraceuticals, such as protocatechuic acid, in the G93A mutant hSOD1 mouse model of ALS. I have also researched the therapeutic benefit of a whey protein supplement and buckminsterfullerene C60 in single-moderate, repetitive-mild, and repetitive-mild-moderate mouse models of traumatic brain injury. As a part of my research, I am also in collaboration with Resilience Code, a local clinic which focuses on a functional medicine approach to treating traumatic brain injury. Through this collaboration, I hope to publish on nutrient deficiencies in concussed versus non-concussed individuals. I also instruct undergraduate laboratory courses and mentor undergraduate students in research at the University of Denver. I am motivated to find natural treatments for neurodegenerative disorders and to understand the mechanisms underlying neurodegeneration. I hope to translate my findings into helping individuals age healthily and to aid in the treatment of individuals suffering from neurodegenerative diseases or neurotrauma.

• Claudia Pena – 3rd year PhD Student in the Linseman Lab

  Currently, I am in my third year of the Cell and Molecular Biology PhD program at the University of Denver. My research focuses on Parkinson's disease (PD), the second most common neurodegenerative condition affecting people over 60 years of age. I work with a neuroblastoma cell line (BE(2)-M17) that expresses the protein alpha synuclein (αS), which forms aggregates and fibrils in dopaminergic neurons, thus contributing to disease pathology. I am currently investigating the protective antioxidant effects of Protocatechuic Acid (PCA), the major phenolic acid metabolite found in an array of food products, on this cell line when treated with different toxins that exacerbate αS cytotoxicity. Future work with this compound includes assessing its anti-aggregation effects on BE(2)-M17 cells seeded with αS fibrils. I am also involved in another PD study that involves deep brain stimulation (DBS) in rats. This project consists in the surgical implantation of electrodes (recording and stimulating) in the subthalamic nucleus of the brain of a PD transgenic rat model and recording the signal milliseconds before the rat performs a forelimb reaching task. The goal is to integrate the signal into the battery of the DBS electrode to create a closed circuit in which the battery (and stimulation) only activates when it receives an abnormal signal, instead of always being on, as it is the case with the existing DBS systems.

• Allison Grossberg – 2nd year PhD Student in the Linseman Lab

  I am a second year Cellular and Molecular Biology Ph.D. student at the University of Denver. As a graduate student, my research has been primarily focused on the short- and long-term consequences of tramautic brain injury (TBI). I've had the wonderful opportunity to work with a local precision medicine clinic, Resilience Code, to conduct research from a systems biology perspective. I am currently working to compile and analyze a large amount of data from TBI patients who have sustained single or multiple concussions of varying severities. The clinical data includes neurocognitive testing, balance and gait assessment, brain imaging, neurofeedback, genetic analysis, comprehensive blood panels, questionnaires and other measures. We hope to find meaningful clinical differences in these measures between different sub-populations of patients. A first study will investigate blood biomarkers of immune system dysfunction, inflammation and oxidative stress in patients with history of TBI and those without. A second study will investigate the efficacy of holistic, precision medicion based treatments for chronic post-concussion syndrome.
  As my work with Resilience Code continues, I hope to collect blood samples from patients to explore plasma and serum biomarkers related to brain health and neurotrauma and neuron-derived exosomal biomarkers of Alzheimer's Disease including phosphorylated tau and amyloid beta-40 and -42, pro-inflammatory glial markers and cytokines and brain-derived neurotrophic factor. I hope this work will enable researchers and clinicians to better understand the complex and dynamic interrelationships that may exist on molecular, cellular, physiological, psychological, behavioral and psychosocial levels in patients with TBI.
  In addition to my work related to TBI, this year I had the opportunity to collaborate on a publication related to the immune response to COVID-19 infection. We collected data from a group of outpatients in Colorado who were tested for COVID-19 using a novel multiplex serology assay. All patients were asked to respond to a brief survey that included questions related to symptom presentation and severity, recent immunizations, and other demographic information. Antibody titers and symptom data were analyzed to better understand symptom presentation and the immune response in COVID-19-positive patients who were symptomatic or asymptomatic. I am confident that this study provides important information related to COVID-19 infection during a critical period in science and society. This work may pave the way for future studies that investigate the long-term neurological outcomes of COVID-19 infection in individuals with and without TBI.

Undergraduate Student Research 

• Hannah Jackson

  Hello, my name is Hannah Jackson and I am a third year student at the University of Denver. I am majoring in Biology with a concentration in Cognitive Neuroscience and minors in Chemistry and Psychology. My involvement in the lab currently includes training rats to complete certain tasks, which is part of a research project focused on better understanding neurodegenerative diseases and finding new forms of treatment. I am passionate about biology and animal science, and I hope to go into veterinary medicine in the future.

• Alec Smith

  Hey! My name is Alec Smith, and I am currently a third-year honors student here at DU. I am doubling majoring in biochemistry and molecular biology with a minor in mathematics and medical physics. I am currently working alongside a PhD candidate and assisting with a study revolving around an amyotrophic lateral sclerosis (ALS) mouse model with repetitive traumatic brain injury. I am also working on my honors thesis which delves into researching therapeutic effects of a nutraceutical derived from dragon fruit in an hSOD1 ALS mouse model.

• Kensey Bishop

  Hi! My name is Kensey Bishop and I am a third year Biology major also pursuing minors in Leadership Studies, Chemistry, and Health Sciences. As an undergraduate research assistant, I am currently working in partnership with Resilience Code, a functional sports medicine clinic, on a statistical analysis study defining the impact of traumatic brain injuries on an individual's micronutrient levels. This research is important in quantifying the unseen impacts that concussions have on the human body and which direction we should turn to support quicker recovery. I am passionate about health and wellness, and after graduation I will attend medical school and work towards opening my own medical practice as a functional medicine doctor.

• Caitlin Pham

  Hello, my name is Caitlin Pham and I am a third-year pre-med student at the University of Denver. I double major in Molecular Biology and Psychology and minor in Chemistry. I currently participate in the Linseman lab by performing cell culture and cell quantification for Alzheimer's Disease. The purpose for this research is to have a better understanding of the neurological disease in hopes for more advanced methods of treatment in the future. I look forward to continuing my research in the Linseman lab and one day attending medical school.

• Hannah Lardinois

  Hello, my name is Hannah Lardinois, and I am a fourth year at the University of Denver. I am majoring in Molecular Biology and Psychology with concentrations in cognitive neuroscience and minors in Chemistry and Medical Physics. In the lab, I am working on research pertaining to Alzheimer's Disease. Specifically, I am investigating the Icelandic mutation of the amyloid precursor protein to determine the potential of protective characteristics against AD by studying apoptosis in transfected HT22 cell lines.

• Ellie Gozalez

  Hi, my name is Ellie Gonzalez and I am a senior at the University of Denver majoring in Biology and minoring in Chemistry and Psychology with a concentration in Cognitive Neuroscience. I have been a part of Professor Linseman's lab as a Research Assistant since my junior year and have since been assisting multiple graduate students in concussion studies and data analysis. This work aims to further understand how concussion effects the chemistry within individuals through evaluating nutrients, hormones, and many other components within the body. I am currently working on my thesis project which will evaluate the relationship between concussion occurrence and hormonal dysfunction.