Publications
2024
Valencia‑Sánchez, S., Davis, M., Martensen, J., Hoeffer, C., Link, CD., & Opp, M. R. (2024). Sleep-wake behavior and responses to sleep deprivation and immune challenge of protein kinase RNA-activated knockout mice. 121, 74–86.
Abstract
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.
Lemieux MR, Freigassner B, Hanson JL, Thathey Z, Opp MR, Hoeffer CA, Link CD. (2024) Multielectrode array characterization of human induced pluripotent stem cell derived neurons in co‑culture with primary human astrocytes. Jun25;19(6):e0303901.
Abstract
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.
2023
Valencia, S., Hoeffer, C., Link, C. D., & Opp, M. R. (2023). PKR regulates sleep-wake behavior and its homeostatic responses to sleep deprivation and LPS administration in mice. , 114(Suppl), 65.
Milstead, R. A., Link, C. D., Xu, Z., & Hoeffer, C. A. (2023). TDP‑43 knockdown in mouse model of ALS leads to dsRNA deposition, gliosis, and neurodegeneration in the spinal cord. Cerebral Cortex, 33(10), 5808–5816.
Abstract
Transactive response DNA binding protein 43 kilodaltons (TDP-43) is a DNA and RNA binding protein associated with severe neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), primarily affecting motor neurons in the brain and spinal cord. Partial knockdown of TDP-43 expression in a mouse model (the amiR-TDP-43 mice) leads to progressive, age-related motor dysfunction, as observed in ALS patients. Work in Caenorhabditis elegans suggests that TDP-43 dysfunction can lead to deficits in chromatin processing and double-stranded RNA (dsRNA) accumulation, potentially activating the innate immune system and promoting neuroinflammation. To test this hypothesis, we used immunostaining to investigate dsRNA accumulation and other signs of CNS pathology in the spinal cords of amiR-TDP-43 mice. Compared with wild-type controls, TDP-43 knockdown animals show increases in dsRNA deposition in the dorsal and ventral horns of the spinal cord. Additionally, animals with heavy dsRNA expression show markedly increased levels of astrogliosis and microgliosis. Interestingly, areas of high dsRNA expression and microgliosis overlap with regions of heavy neurodegeneration, indicating that activated microglia could contribute to the degeneration of spinal cord neurons. This study suggests that loss of TDP-43 function could contribute to neuropathology by increasing dsRNA deposition and subsequent innate immune system activation.
Wahl, D., Smith, M. E., McEntee, C. M., Cavalier, A. N., Osburn, S. C., Burke, S. D., Grant, R. A., Nerguizian, D., Lark, D. S., Link, C. D., & LaRocca, T. J. (2023). The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction. , 22(5), e13798.
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.
2022
Reynolds, C., Smolen, A., Link, C., Evans, D., Bruellman, R., Evans, L., & Wadsworth, S. (2023, December). Neurofilament light chain (NFL) and general cognitive ability in adults approaching midlife. , 7(Suppl_1), 263.
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 (>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 <= 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.
Schwarze-Taufiq, T. A., Frankowski, H., Lemieux, M., Link, C. D., & Young, J. E. (2022). Investigating the role of tau loss-of-function in Alzheimer’s disease pathogenesis. . Advance online publication.
Sharma, S., Borski, C., Hanson, J., Garcia, M. A., Link, C. D., Hoeffer, C., Chatterjee, A., & Nagpal, P. (2022). Identifying an optimal neuroinflammation treatment using a nanoligomer discovery engine. , 13(23), 3247–3256.
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 leading to the activation of immune cells like microglia and astrocytes causes damage to the nervous tissue, and it is causally linked to a range of neurodegenerative diseases such as Alzheimer’s diseases (AD), Multiple Sclerosis (MS), Parkinson’s disease (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, 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 artificial intelligence-based ranking method to design sequence-specific peptide molecules to up- or downregulate 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 (5 mg/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.
2021
LaRocca, T. J., Cavalier, A. N., Roberts, C. M., Lemieux, M. R., Ramesh, P., Garcia, M. A., & Link, C. D. (2021). Amyloid beta acts synergistically as a pro-inflammatory cytokine. .
Abstract
The (Aβ) peptide is believed to play a central role in (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily selected functions of Aβ are incompletely understood. Here, we report that nanomolar concentrations of Aβ act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using (RNA-seq), we show that Aβ can directly substitute for the C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by Aβ have a transcriptional signature similar to neurotoxic “A1” astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of Aβ at low concentrations is distinct from the changes induced by the high/supraphysiological doses of Aβ often used in . Collectively, our results suggest an important, cytokine-like function for Aβ and a novel mechanism by which it may directly contribute to the associated with brain aging and AD.
Melnick, M., Gonzales, P., LaRocca, T. J., Song, Y., Wuu, J., Benatar, M., Oskarsson, B., Petrucelli, L., Dowell, R. D., Link, C. D., & Prudencio, M. (2021). Application of a bioinformatic pipeline to RNA-seq data identifies novel virus-like sequence in human blood. , 11(9), jkab141.
Abstract
Numerous reports have suggested that infectious agents could play a role in neurodegenerative diseases, but specific etiological agents have not been convincingly demonstrated. To search for candidate agents in an unbiased fashion, we have developed a bioinformatic pipeline that identifies microbial sequences in mammalian RNA-seq data, including sequences with no significant nucleotide similarity hits in GenBank. Effectiveness of the pipeline was tested using publicly available RNA-seq data and in a reconstruction experiment using synthetic data. We then applied this pipeline to a novel RNA-seq dataset generated from a cohort of 120 samples from amyotrophic lateral sclerosis patients and controls, and identified sequences corresponding to known bacteria and viruses, as well as novel virus-like sequences. The presence of these novel virus-like sequences, which were identified in subsets of both patients and controls, were confirmed by quantitative RT-PCR. We believe this pipeline will be a useful tool for the identification of potential etiological agents in the many RNA-seq datasets currently being generated.
Link, C. D. (2021). Is There a Brain Microbiome? , 16, 26331055211018709
Abstract
Numerous studies have identified microbial sequences or epitopes in pathological and non-pathological human brain samples. It has not been resolved if these observations are artifactual, or truly represent population of the brain by microbes. Given the tempting speculation that resident microbes could play a role in the many neuropsychiatric and neurodegenerative diseases that currently lack clear etiologies, there is a strong motivation to determine the “ground truth” of microbial existence in living brains. Here I argue that the evidence for the presence of microbes in diseased brains is quite strong, but a compelling demonstration of resident microbes in the healthy human brain remains to be done. Dedicated animal models studies may be required to determine if there is indeed a “brain microbiome.”
2019
LaRocca TJ, Mariani A, Watkins LR, Link CD. (2019) TDP-43 knockdown causes innate immune activation via protein kinase R in astrocytes. Jun 21;132:104514. doi: 10.1016
Shea D, Hsu CC, Bi TM, Paranjapye N, Childers MC, Cochran J, Tomberlin CP, Wang L, Paris D, Zonderman J, Varani G, Link CD, Mullan M, Daggett V. α-Sheet secondary structure in amyloid β-peptide drives aggregation and toxicity in Alzheimer's disease. (2019) Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):8895-8900. doi: 10.1073/pnas.1820585116. Epub 2019 Apr 19.
Melnick M, Gonzales P, Cabral J, Allen MA, Dowell RD,Link CD. (2019) Heat shock in C. elegans induces downstream of gene transcription and accumulation of double-stranded RNA. Apr 8;14(4):e0206715.
Saldi TK, Gonzales PK, LaRocca TJ, Link CD (2019) Neurodegeneration, Heterochromatin, and Double-Stranded RNA. J. Experimental Neuroscience Feb 14;13:1179069519830697. doi: 10.1177/1179069519830697
Guerrero-Gómez D, Mora-Lorca JA, Sáenz-Narciso B, Naranjo-Galindo FJ, Muñoz-Lobato F, Parrado-Fernández C, Goikolea J, Cedazo-Minguez Á, Link CD, Neri C, Sequedo MD, Vázquez-Manrique RP, Fernández-Suárez E, Goder V, Pané R, Cabiscol E, Askjaer P, Cabello J, Miranda-Vizuete A. (2019) Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation. Feb 15. doi: 10.1038/s41418-018-0270-9.
Zhang YJ, Guo L, Gonzales PK, Gendron TF, Wu Y, Jansen-West K, O'Raw AD, Pickles SR, Prudencio M, Carlomagno Y, Gachechiladze MA, Ludwig C, Tian R, Chew J, DeTure M, Lin WL, Tong J, Daughrity LM, Yue M, Song Y, Andersen JW, Castanedes-Casey M, Kurti A, Datta A, Antognetti G, McCampbell A, Rademakers R, Oskarsson B, Dickson DW, Kampmann M, Ward ME, Fryer JD, Link CD, Shorter J, Petrucelli L. (2019) Heterochromatin anomalies and double-stranded RNA accumulation underlie C9orf72 poly(PR) toxicity. Science Feb 15;363(6428). pii: eaav2606. doi: 10.1126/science.aav2606.
2018
Julien C, Tomberlin C, Roberts CM, Akram A, Stein GH, Silverman MA, Link CD. (2018) In vivo induction of membrane damage by β-amyloid peptide oligomers.
Acta Neuropathol Commun. Nov 29;6(1):131. doi: 10.1186/s40478-018-0634-x.
Gonzales PK, Roberts CM, Fonte V, Jacobsen C, Stein GH, Link CD. (2018) Transcriptome analysis of genetically matched human induced pluripotent stem cells disomic or trisomic for chromosome 21. PLoS One. Mar 27;13(3):e0194581. doi: 10.1371
Saldi TK, Gonzales P, Garrido-Lecca A, Dostal V, Roberts CM, Petrucelli L, Link CD. (2018) The C. elegans ortholog of TDP-43 regulates the chromatin localization of the heterochromatin protein 1 homolog, HPL-2. Mol Cell Biol. May 14. pii: MCB.00668-17. doi: 10.1128
Van Treeck B, Protter DSW, Matheny T, Khong A, Link CD, Parker R. (2018) RNA self-assembly contributes to stress granule formation and defining the stress granule transcriptome. Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2734-2739. doi: 10.1073/pnas.1800038115
2017
Prudencio M, Gonzales PK, Cook CN, Gendron TF, Daughrity LM, Song Y, Ebbert MTW, van Blitterswijk M, Zhang YJ, Jansen-West K, Baker MC, DeTure M, Rademakers R, Boylan KB, Dickson DW, Petrucelli L, Link CD. (2017) Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Hum Mol Genet Jun 16. Sep 1;26(17):3421-3431
2016
Henze A, Homann T, Rohn I, Aschner M, Link CD, Kleuser B, Schweigert FJ, Schwerdtle T, Bornhorst J. (2016) Caenorhabditis elegans as a model system to study post-translational modifications of human transthyretin. Sci Rep. 6:37346. doi: 10.1038/srep37346.
Kramer NJ, Carlomagno Y, Zhang YJ, Almeida S, Cook CN, Gendron TF, Prudencio M, Van Blitterswijk M, Belzil V, Couthouis J, Paul JW 3rd, Goodman LD, Daughrity L, Chew J, Garrett A, Pregent L, Jansen-West K, Tabassian LJ, Rademakers R, Boylan K, Graff-Radford NR, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Boeve BF, Deng N, Feng Y, Cheng TH, Dickson DW, Cohen SN, Bonini NM, Link CD, Gao FB, Petrucelli L, Gitler AD. (2016) Spt4 selectively regulates the expression of C9orf72 sense and antisense mutant transcripts. Science. 353(6300):708-12. doi:10.1126/science.aaf7791.
Munkácsy E, Khan MH, Lane RK, Borror MB, Park JH, Bokov AF, Fisher AL, Link CD, Rea SL. (2016) DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans. (2016) PLoS Genet. 12(7):e1006133. doi: 10.1371/journal.pgen.1006133.
Kokona B, May CA, Cunningham NR, Richmond L, Jay Garcia F, Durante JC, Ulrich KM, Roberts CM, Link CD, Stafford WF, Laue TM, Fairman R. (2016) Studying polyglutamine aggregation in Caenorhabditis elegans using an analytical ultracentrifuge equipped with fluorescence detection. Protein Sci. (3):605-17. doi: 10.1002/pro.2854.
Zhang YJ, Gendron TF, Grima JC, Sasaguri H, Jansen-West K, Xu YF, Katzman RB, Gass J, Murray ME, Shinohara M, Lin WL, Garrett A, Stankowski JN, Daughrity L, Tong J, Perkerson EA, Yue M, Chew J, Castanedes-Casey M, Kurti A, Wang ZS, Liesinger AM, Baker JD, Jiang J, Lagier-Tourenne C, Edbauer D, Cleveland DW, Rademakers R, Boylan KB, Bu G, Link CD, Dickey CA, Rothstein JD, Dickson DW, Fryer JD, Petrucelli L. (2016) C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nature Neuroscience 19(5):668-677
2015
Prudencio M, Belzil VV, Batra R, Ross CA, Gendron TF, Pregent LJ, Murray ME, Overstreet KK, Piazza-Johnston AE, Desaro P, Bieniek KF, DeTure M, Lee WC, Biendarra SM, Davis MD, Baker MC, Perkerson RB, van Blitterswijk M, Stetler CT, Rademakers R, Link CD, Dickson DW, Boylan KB, Li H, Petrucelli L. (2015) Distinct brain transcriptome profiles in C9orf72-associated and sporadic ALS. Nature Neuroscience 18(8):1175-82.
2014
Saldi TK, Ash PEA, Wilson G, Gonzales P, Garrido-Lecca A, Roberts CM, Dostal V, Gendron TF, Stein LD, Blumenthal T, Petrucelli L, Link CD. (2014) TDP-1, the C. elegans ortholog of TDP-43, limits the accumulation of double-stranded RNA. EMBO J Dec 17;33(24):2947-66.
Hassan WM, Dostal V, Yerg JE, Link CD. Identifying Ab-specific pathogenic mechanisms using a nematode model of Alzheimer's disease. (2014) Neurobiology of Aging Feb;36(2):857-66.
Machino K, Link CD, Wang S, Murakami H, Murakami S. (2014) A semi-automated motion-tracking analysis of locomotion speed in the C. elegans transgenics overexpressing beta-amyloid in neurons. Front Genet. Jul 4;5:202. doi: 10.3389
2013
Muñoz-Lobato F, Rodríguez-Palero MJ, Naranjo-Galindo FJ, Shepard F, Gaffney CJ, Szewczyk NJ, Hamamichi S, Caldwell KA, Caldwell GA, Link CD, Miranda-Vizuete A. (2013) Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases. Jan 10;20(2):217-35.
Lublin, AL and Link, CD. Alzheimer's disease drug discovery: in vivo screening using Caenorhabditis elegans as a model for β-amyloid peptide-induced toxicity. (2013) Drug Discov Today Technol. Spring;10(1):e115-9. doi: 10.1016/j.ddtec.2012.02.002
2012
Gass J, Lee WC, Cook C, Finch N, Stetler C, Jansen-West K, Lewis J, Link CD, Rademakers R, Nykjær A, Petrucelli L. (2012) Mol Neurodegener.. Jul 10;7:33
Cacho-Valadez B, Muñoz-Lobato F, Pedrajas JR, Cabello J, Fierro-González JC, Navas P, Swoboda P, Link C. D, Miranda-Vizuete A. (2012) The characterization of the Caenorhabditis elegans mitochondrial thioredoxin system uncovers an unexpected protective role of thioredoxin reductase 2 in β-amyloid peptide toxicity. Jun 15;16(12):1384-400.
Link C. D, Saldi T. K. Cell death by glutamine repeats? (2012) Feb 24;335(6071):926-7.
Cotella D, Hernandez-Enriquez B, Wu X, Li R, Pan Z, Leveille J, Link C.D., Oddo S, Sesti F. (2012) Toxic role of K+ channel oxidation in mammalian brain. J Neurosci. Mar 21;32(12):4133-44
2011
Fonte V., Dostal V., Roberts C.M., Gonzales P., Lacor P., Magrane J., Dingwell N., Fan E.Y., Silverman M.A., Stein G.H., Link C.D. (2011) A glycine zipper motif mediates the formation of toxic b-amyloid oligomers in vitro and in vivo. Mol Neurodegener. 2011 Aug 23;6(1):61.
Mendenhall A.R., Wu D., Park S.K., Cypser JR, Tedesco PM, Link C.D., Phillips P.C., Johnson T.E. (2011) Genetic dissection of late-life fertility in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci. Aug;66(8):842-54.
2010
McColl, G., Rogers, A.N., Alavez, S., Hubbard, A.E., Melov, S., Link, C.D., Bush, A.I., Kapahi, P., Lithgow, G.J. (2010) Insulin-like Signaling Determines Survival during Stress via Posttranscriptional Mechanisms in C. elegans. Cell Metab;12(3):260-72.
Ash, P.E., Zhang, Y.J., Roberts, C.M., Saldi, T., Hutter. H., Buratti, E., Petrucelli, L., Link, C.D. (2010) Neurotoxic effects of TDP-43 overexpression in C. elegans Hum Mol Genet. 2010 Aug 15;19(16):3206-18.
Dostal, V. and Link C.D. (2010) Assaying b-amyloid toxicity using a transgenic C. elegans model. J Vis Exp. Oct 9;(44).
Dostal, V., Roberts, C.M., Link, C.D. (2010) Genetic Mechanisms of Coffee Extract Protection in a Caenorhabditis elegans Model of b-amyloid Peptide Toxicity. Genetics Nov;186(3):857-66.
Dosanjh, L.E., Brown, M. K., Rao, G, Link C. D., Luo Y. (2010) Behavioral phenotyping of a transgenic Caenorhabditis elegans expressing neuronal amyloid-beta. J Alzheimers Dis. 19(2):681-90
2009
Teschendorf, D. and Link, C. D. (2009) What have worm models told us about the mechanisms of neuronal dysfunction in human neurodegenerative diseases? Molecular Neurodegeneration Sept 28;4(1):38
Park S. K., Link C. D., Johnson T. E. (2009) Life-span extension by dietary restriction is mediated by NLP-7 signaling and coelomocyte endocytosis in C. elegans. FASEB J. Feb;24(2):383-92.
Hassan, W. M., Merin, D. A., Fonte V., Link, C. D. (2009) AIP-1 ameliorates b-amyloid peptide toxicity in a Caenorhabditis elegans Alzheimer's disease model. Hum Mol Genet. Aug 1;18(15):2739-47.
Zhang, Y. J., Xu Y. .F, Cook, C., Gendron, T. F., Roettges, P., Link, C. D., Lin, W. L., Tong, J., Castanedes-Casey, M., Ash, P., Gass, J., Rangachari, V., Buratti, E., Baralle, F., Golde, T. E., Dickson, D. W., Petrucelli, L. (2009) Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. Proc Natl Acad Sci U S A. May 5;106(18):7607-12.
2008
Link, C.D., Fonte, V., Roberts C.M., Hiester, B., Silverman, M.A., Stein. G. (2008) The b amyloid peptide can act as a modular aggregation domain. Neurobiology of Disease,32(3):420-5
Fonte V., Kipp D.R., Yerg J., Merin D., Forrestal M., Wagner E., Link C.D. (2008) Suppression of in vivo b amyloid peptide toxicity by overexpression of the HSP-16 small chaperone protein. J Biol Chem. 283(2):784-91
2007
Florez-McClure M.L., Fonte G., Hohsfield L., Bealor M., Link C.D. (2007) Decreased insulin signaling promotes the autophagic degradation of b-amyloid peptide in C. elegans. Autophagy 3(6):569-80.
2006
Wu Y., Wu Z., Butko P., Christeen Y., Lambert, M.P., Klein W.L., Link C.D., Luo Y. (2006) Ab-induced pathological behaviors are suppressed by Ginkgo biloba extract and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 26(50):13102-13.
Link C.D., (2006) C. elegans models of age-associated neurodegenerative diseases: Lessons from transgenic worm models of Alzheimer's disease. Exp Gerontol. 41(10):1007-13.
Link C.D., Fonte V., Hiester B., Yerg J., Ferguson J., Csontos S., Silverman MA., Stein G. H. (2006) Conversion of Green Fluorescent Protein into a Toxic, Aggregation-prone Protein by C-terminal Addition of a Short Peptide. J Biol Chem. Jan 20;281(3):1808-16
Boyd-Kimball D, Poon HF, Lynn BC, Cai J, Pierce Jr WM, Klein JB, Ferguson J, Link CD, Butterfield DA. (2006) Proteomic identification of proteins specifically oxidized in Caenorhabditis elegans expressing human Abeta(1-42): Implications for Alzheimer's disease. Neurobiol Aging. 27(9):1239-49
2005
Cottrell BA, Galvan V, Banwait S, Gorostiza O, Lombardo CR, Williams T, Schilling B, Peel A, Gibson B, Koo EH, Link CD, Bredesen DE. (2005) A pilot proteomic study of amyloid precursor interactors in Alzheimer's disease. Ann Neurol. 58(2):277-89.
Link, C.D. (2005). Invertebrate models of Alzheimer’s Disease. Genes, Brain and Behavior, 4(3):147-56.
Gutierrez-Zepeda A, Santell R, Wu Z, Brwon M, Wu Y, Khan I, Link CD, Zhao B, Luo Y. (2005) Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans. BMC Neurosci. 6(1):54.
Kapulkin V., Hiester B. G., Link C. D. (2005) Compensatory regulation among ER chaperones in C. elegans.
FEBS Lett. 579(14):3063-8.
2003
Strayer, A., Wu, Z., Christen, Y., Link. C.D., & Luo, Y. (2003). Expression of the small heat-shock protein Hsp16-2 in Caenorhabditis elegans is suppressed by Ginko biloba extract EGb761. FASEBJ, 17, 2305-2307.
Drake J., Link C.D., Butterfield D.A. (2003) Oxidative stress precedes fibrillar deposition of Alzheimer's disease amyloid beta-peptide (1-42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 24:415-420.
Kampkotter A., Volkmann T.E., de Castro S.H., Leiers B., Klotz L.O., Johnson T.E., Link C.D., Henkle-Duhrsen K. (2003) Functional analysis of the glutathione S-transferase 3 from Onchocerca volvulus (Ov-GST-3): a parasite GST confers increased resistance to oxidative stress in Caenorhabditis elegans. J Mol Biol 325:25-37.
Leiers B., Kampkotter A., Grevelding C.G., Link C.D., Johnson T.E., Henkle-Duhrsen K. (2003) A stress-responsive glutathione S-transferase confers resistance to oxidative stress in Caenorhabditis elegans. Free Radic Biol Med 34:1405-1415.
Link C.D., Taft A., Kapulkin V., Duke K., Kim S., Fei Q., Wood D.E., Sahagan B.G. (2003) Gene expression analysis in a transgenic Caenorhabditis elegans Alzheimer's disease model. Neurobiol Aging 24:397-413.
Strayer A., Wu Z., Christen Y., Link C.D., Luo Y. (2003) Expression of the small heat-shock protein Hsp16-2 in Caenorhabditis elegans is suppressed by Ginkgo biloba extract EGb 761. Faseb J 17:2305-2307.
Borgonie G., Link C.D., Claeys M., Coomans A. (2003) Lysosomal and pseudocoelom routing protects Caenorhabditis elegans from ricin toxicity. Nematology 5: 339-350
2002
Blumenthal T., Evans D., Link C.D., Guffanti A., Lawson D., Thierry-Mieg J., Thierry-Mieg D., Chiu W.L., Duke K., Kiraly M., Kim S.K. (2002) A global analysis of Caenorhabditis elegans operons. Nature 417:851-854.
Fonte V., Kapulkin V., Taft A., Fluet A., Friedman D., Link C.D. (2002) Interaction of intracellular beta amyloid peptide with chaperone proteins. Proc Natl Acad Sci U S A 99:9439-9444.
GuhaThakurta D., Palomar L., Stormo G.D., Tedesco P., Johnson T.E., Walker D.W., Lithgow G., Kim S., Link C.D. (2002) Identification of a novel cis-regulatory element involved in the heat shock response in Caenorhabditis elegans using microarray gene expression and computational methods. Genome Res 12:701-712.
Link C.D., Johnson C.J. (2002) Reporter transgenes for study of oxidant stress in Caenorhabditis elegans. Methods Enzymol 353:497-505.
Johnson T.E., Henderson S., Murakami S., de Castro E., de Castro S.H., Cypser J., Rikke B., Tedesco P, Link C.D, (2002) Longevity genes in the nematode Caenorhabditis elegans also mediate increased resistance to stress and prevent disease. Journal of Inherited Metabolic Disease 25: 197-206
2001
Link C.D. (2001) Transgenic invertebrate models of age-associated neurodegenerative diseases. Mech Ageing Dev 122:1639-1649.
Link C.D., Johnson C.J., Fonte V., Paupard M., Hall D.H., Styren S., Mathis C.A., Klunk W.E. (2001) Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34. Neurobiol Aging 22:217-226.
2000
Johnson T.E., Cypser J., de Castro E., de Castro S., Henderson S., Murakami S., Rikke B., Tedesco P., Link C.D. (2000) Gerontogenes mediate health and longevity in nematodes through increasing resistance to environmental toxins and stressors. Experimental Gerontology 35: 687-694
1999
Butterfield D.A., Yatin S.M., Link C.D. (1999) In vitro and in vivo protein oxidation induced by Alzheimer's disease amyloid beta-peptide (1-42). Ann N Y Acad Sci 893:265-268.
Link C.D., Cypser J.R., Johnson C.J., Johnson T.E. (1999) Direct observation of stress response in Caenorhabditis elegans using a reporter transgene. Cell Stress Chaperones 4:235-242.
Yatin S.M., Varadarajan S., Link C.D., Butterfield D.A. (1999) In vitro and in vivo oxidative stress associated with Alzheimer's amyloid beta-peptide (1-42). Neurobiol Aging 20:325-330; discussion 339-342.
1998
Fay D.S., Fluet A., Johnson C.J., Link C.D. (1998) In vivo aggregation of beta-amyloid peptide variants. J Neurochem 71:1616-1625.
1997
Silverman, M., M. L. Blaxter and Link C.D. (1997). "Biochemical analysis of Caenorhabditis elegans surface mutants." Journal of
Nematology 29: 296-305.
1995
Link C.D. (1995) Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans. Proc Natl Acad Sci U S A 92:9368-9372.
1994
Borgonie G., van Driessche E., Link C.D., de Waele D., Coomans A. (1994) Tissue treatment for whole mount internal lectin staining in the nematodes Caenorhabditis elegans, Panagrolaimus superbus and Acrobeloides maximus. Histochemistry 101:379-384.
1992
Link C.D., Silverman M.A., Breen M., Watt K.E., Dames S.A. (1992) Characterization of Caenorhabditis elegans lectin-binding mutants. Genetics 131:867-881.
1988
Link C.D., Ehrenfels C.W., Wood W.B. (1988) Mutant expression of male copulatory bursa surface markers in Caenorhabditis elegans. Development 103:485-495.
1987
Link C.D., Graf-Whitsel J., Wood W.B. (1987) Isolation and characterization of a nematode transposable element from Panagrellus redivivus. Proc Natl Acad Sci U S A 84:5325-5329.
1983
Link C.D., Reiner A.M. (1983) Genotypic exclusion: a novel relationship between the ribitol-arabitol and galactitol genes of E. coli. Mol Gen Genet 189:337-339.
1982
Link C.D., Reiner A.M. (1982) Inverted repeats surround the ribitol-arabitol genes of E. coli C. Nature 298:94-96.
1977
Beam C.A., Himes M., Himelfarb J., Link C.D., Shaw K. (1977) Genetic evidence of unusual meiosis in the dinoflagellate Crypthecodinium cohnii. Genetics 87:19-32