About

Christopher D. Link is an Associate Professor in the Department of Integrative Physiology at the University of Colorado Boulder. His research focuses on understanding the cellular and molecular basis of age-associated neurodegenerative diseases, such as Alzheimer's disease (AD) and Amyotrophic Lateral Sclerosis (ALS). His primary approach involves developing transgenic C. elegans strains that express human proteins central to these diseases, like the beta amyloid peptide in AD and TDP-43 in ALS, to identify mechanisms by which these proteins induce pathology. These invertebrate models facilitate pilot studies that are challenging in other systems. Additionally, his research complements these studies with mammalian cell culture and bioinformatic analysis of mouse and human deep sequencing data. For more detailed information, his laboratory's Molecular Biology of Neurodegeneration website is available.

Research topics

• Neuroscience
• Biology
• Medicine
• Immunology
• Bioinformatics
• Pathology
• Psychology
• Computer Science
• Biochemistry
• Pharmacology
• Environmental health
• Cell biology
• Chemistry

Selected publications

• Multielectrode array characterization of human induced pluripotent stem cell derived neurons in co-culture with primary human astrocytes

  PLoS ONE · 2024-06-25 · 6 citations

  articleOpen accessSenior authorCorresponding

  Human induced pluripotent stem cells (hiPSCs) derived into neurons offer a powerful in vitro model to study cellular processes. One method to characterize functional network properties of these cells is using multielectrode arrays (MEAs). MEAs can measure the electrophysiological activity of cellular cultures for extended periods of time without disruption. Here we used WTC11 hiPSCs with a doxycycline-inducible neurogenin 2 (NGN2) transgene differentiated into neurons co-cultured with primary human astrocytes. We achieved a synchrony index ∼0.9 in as little as six-weeks with a mean firing rate of ∼13 Hz. Previous reports show that derived 3D brain organoids can take several months to achieve similar strong network burst synchrony. We also used this co-culture to model aspects of blood-brain barrier breakdown by using human serum. Our fully human co-culture achieved strong network burst synchrony in a fraction of the time of previous reports, making it an excellent first pass, high-throughput method for studying network properties and neurodegenerative diseases.

  PublisherOA PDFDOI

• Early pandemic in-hospital outcomes and mortality risk factors in COVID-19 solid organ transplant patients

  Baylor University Medical Center Proceedings · 2024-03-19 · 2 citations

  articleOpen accessSenior author

  Background: Solid organ transplant (SOT) recipients with COVID-19 have a higher risk of mortality than those without COVID-19. However, it is unclear how SOT patient outcomes compare to the general population without SOT who contract COVID-19. Methods: We used the National Inpatient Sample from January to December 2020 to investigate inpatient outcomes seen in SOT recipients after contracting COVID-19 compared to nontransplant patients. We identified our study sample using ICD-10 CM and excluded those <18 years of age and those with dual organ transplants. Inpatient outcomes were compared in SOT and non-SOT COVID cohorts, and we further evaluated predictors of mortality in the SOT with COVID population. Results: < 0.01), and similar rates of cardiac arrest, pulmonary embolism, circulatory shock, cerebrovascular events, and in-hospital mortality. Age >65 was associated with mortality in SOT patients. Conclusion: In this nationally representative sample, SOT patients presenting with COVID-19 experienced similar rates of mortality compared to those without SOT. SOT patients were more likely to develop acute kidney injury. Further research is needed to understand the complex relationship between transplant patient outcomes and COVID-19.

  PublisherOA PDFDOI

• Acclimation of Right Ventricular Function After Durable Left Ventricular Assist Device Support

  The Journal of Heart and Lung Transplantation · 2024-04-01

  articleOpen access
  PublisherOA PDFDOI

• Multielectrode array characterization of human induced pluripotent stem cell derived neurons in co-culture with primary human astrocytes

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-03-08 · 2 citations

  preprintOpen accessSenior authorCorresponding

  model to study cellular processes. One method to characterize functional network properties of these cells is using multielectrode arrays (MEAs). MEAs can measure the electrophysiological activity of cellular cultures for extended periods of time without disruption. Here we used WTC11 hiPSCs with a doxycycline-inducible neurogenin 2 (NGN2) transgene differentiated into neurons co-cultured with primary human astrocytes. We achieved a synchrony index ~0.9 in as little as six-weeks with a mean firing rate of ~13 Hz. Previous reports show that derived 3D brain organoids can take several months to achieve similar strong network burst synchrony. We also used this co-culture to model aspects of sporadic Alzheimer's disease by mimicking blood-brain barrier breakdown using a human serum. Our fully human co-culture achieved strong network burst synchrony in a fraction of the time of previous reports, making it an excellent first pass, high-throughput method for studying network properties and neurodegenerative diseases.

  PublisherOA PDFDOI

• Sleep-wake behavior and responses to sleep deprivation and immune challenge of protein kinase RNA-activated knockout mice

  Brain Behavior and Immunity · 2024-07-21 · 5 citations

  articleOpen access

  Protein Kinase RNA-activated (PKR) is an enzyme that plays a role in many systemic processes, including modulation of inflammation, and is implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD). PKR phosphorylation results in the production of several cytokines involved in the regulation / modulation of sleep, including interleukin-1β, tumor necrosis factor-α and interferon-γ. We hypothesized targeting PKR would alter spontaneous sleep of mice, attenuate responses to sleep deprivation, and inhibit responses to immune challenge. To test these hypotheses, we determined the sleep-wake phenotype of mice lacking PKR (knockout; PKR-/-) during undisturbed baseline conditions; in responses to six hours of sleep deprivation; and after immune challenge with lipopolysaccharide (LPS). Adult male mice (C57BL/6J, n = 7; PKR-/-, n = 7) were surgically instrumented with EEG recording electrodes and an intraperitoneal microchip to record core body temperature. During undisturbed baseline conditions, PKR -/- mice spent more time in non-rapid eye movement sleep (NREMS) and rapid-eye movement sleep (REMS), and less time awake at the beginning of the dark period of the light:dark cycle. Delta power during NREMS, a measure of sleep depth, was less in PKR-/- mice during the dark period, and core body temperatures were lower during the light period. Both mouse strains responded to sleep deprivation with increased NREMS and REMS, although these changes did not differ substantively between strains. The initial increase in delta power during NREMS after sleep deprivation was greater in PKR-/- mice, suggesting a faster buildup of sleep pressure with prolonged waking. Immune challenge with LPS increased NREMS and inhibited REMS to the same extent in both mouse strains, whereas the initial LPS-induced suppression of delta power during NREMS was greater in PKR-/- mice. Because sleep regulatory and immune responsive systems in brain are redundant and overlapping, other mediators and signaling pathways in addition to PKR are involved in the responses to acute sleep deprivation and LPS immune challenge.

  PublisherDOI

• PKR regulates sleep-wake behavior and its homeostatic responses to sleep deprivation and LPS administration in mice

  Brain Behavior and Immunity · 2023-11-01

  article
  PublisherDOI

• The reverse transcriptase inhibitor <scp>3TC</scp> protects against age‐related cognitive dysfunction

  Aging Cell · 2023-03-22 · 34 citations

  articleOpen access

  Abstract Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age‐related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild‐type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans ; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age‐related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy.

  PublisherOA PDFDOI

• COVID-19 IN-HOSPITAL OUTCOMES AND PREDICTORS OF MORTALITY IN PATIENTS WITH SOLID ORGAN TRANSPLANT

  CHEST Journal · 2023-10-01

  articleOpen access
  PublisherOA PDFDOI

• NEUROFILAMENT LIGHT CHAIN (NFL) AND GENERAL COGNITIVE ABILITY IN ADULTS APPROACHING MIDLIFE

  Innovation in Aging · 2022-11-01 · 2 citations

  articleOpen access

  Abstract Neurofilament light chain (NfL) is a biomarker indexing axonal integrity where small NfL variations may be associated with cognitive performance in early adulthood and high values associated with neurodegenerative disorders such as Alzheimer’s disease. In the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1) individuals were tested at 28–49 years (M=33.1, SD=4.9). Quanterix Simoa assays of plasma NfL (pNfL) were measured in duplicate, and we included values for 1159 individuals where 1098 had available general cognitive ability scores and sociodemographic covariates. Unadjusted NfL values were consistent with other studies of early-mid adulthood (M = 5.9, SD = 3.1, range = 1.14 – 40.1 pg/mL) and 6% showed values outside expected normal reference limits (&amp;gt;10 pg/mL). After adjusting for technical covariates and skew, higher natural log-transformed pNfL was associated with age (r = 0.27) and female sex (r = 0.07). Moreover, adjusting for sociodemographic covariates, higher pNfL was associated with lower general cognitive ability (GCA) (r = -.06), where associations were more pronounced above the mean pNfL value (r = -.08). Multi-level regression analyses suggested that GCA-NfL associations were modified by age, whereby the worse performance was observed at higher ages and pNfL values (p &amp;lt;= 0.03), accounting for sibling relatedness and sociodemographic covariates. We observed small negative associations of higher plasma NfL and lower cognitive performance, where associations may become magnified with increasing age in early- to mid-adulthood.

  PublisherOA PDFDOI

• Identifying Optimal Neuroinflammation Treatment Using Nanoligomer™ Discovery Engine

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-08-25 · 1 citations

  preprintOpen access

  ABSTRACT Acute activation of innate immune response in the brain, or neuroinflammation, protects this vital organ from a range of external pathogens and promotes healing after traumatic brain injury. However, chronic neuroinflammation leads to the activation of immune cells like microglia and astrocytes causes damage to the nervous tissue, and is causally linked to a range of neurodegenerative diseases such as Alzheimer’s diseases (AD), Multiple Sclerosis (MS), Parkinson’s diseases (PD), and many others. While neuroinflammation is a key target for a range of neuropathological diseases, there is a lack of effective countermeasures to tackle it, and existing experimental therapies require fairly invasive intracerebral and intrathecal delivery due to difficulty associated with the therapeutic crossover between the blood-brain barrier (BBB), making such treatments impractical to treat neuroinflammation long-term. Here, we present the development of an optimal neurotherapeutic using our Nanoligomer™ discovery engine, by screening downregulation of several proinflammatory cytokines (e.g., Interleukin-1β or IL-1β, tumor necrosis factor-alpha or TNF-α, TNF receptor 1 or TNFR1, Interleukin 6 or IL-6), inflammasomes (e.g., NLRP1), key transcription factors (e.g., nuclear factor kappa-B or NF-κβ) and their combinations, as upstream regulators and canonical pathway targets, to identify and validate the best-in-class treatment. Using our high-throughput drug discovery, target validation, and lead molecule identification via a bioinformatics and AI-based ranking method to design sequence-specific peptide molecules to up-or down-regulate gene expression of the targeted gene at will, we used our discovery engine to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse neuroinflammation. The lead neurotherapeutic was a combination of Nanoligomers™ targeted to NF-κβ (SB.201.17D.8_ NF-κβ1) and TNFR1 (SB.201.18D.6_TNFR1), which were identified using in vitro cell-based screening in donor-derived human astrocytes, and further validated in vivo using a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation. The combination treatment SB_NI_111 was delivered without any special formulation using a simple intraperitoneal injection of low-dose (5mg/kg) and was found to significantly suppress the expression of LPS-induced neuroinflammation in mouse hippocampus. These results point to the broader applicability of this approach towards the development of therapies for chronic neuroinflammation-linked neurodegenerative diseases, sleep countermeasures, and others, and the potential for further investigation of the lead neurotherapeutic molecule as reversible gene therapy.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01AG012423

  NIH · $4.5M · 2013

• NIH Grant R29HD026087

  NIH · $499k · 1995

• TDP-43, RNA Metabolism, and ALS/FTD Pathology

  NIH · $3.5M · 2009–2020

• NIH Grant R01AG021037

  NIH · $1.1M · 2008

• NIH Grant R21AG049693

  NIH · $411k · 2018

Frequent coauthors

• Christine M. Roberts

  26 shared

• Leonard Petrucelli

  Mayo Clinic in Florida

  24 shared

• Patrick Gonzales

  19 shared

• Virginia Fonte

  University of Colorado Anschutz Medical Campus

  15 shared

• Gretchen H. Stein

  14 shared

• Tania F. Gendron

  Mayo Clinic in Florida

  13 shared

• Dennis W. Dickson

  Mayo Clinic in Florida

  11 shared

• Yong‐Jie Zhang

  Mayo Clinic in Florida

  11 shared