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102. Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis

Author

Kunkle, Brian W., Schmidt, Michael, Klein, Hans-Ulrich, Naj, Adam C., Hamilton-Nelson, Kara L., Larson, Eric B., Evans, Denis A., De Jager, Phil L., Crane, Paul K., Buxbaum, Joe D., Ertekin-Taner, Nilufer, Barnes, Lisa L., Fallin, M. Daniele, Manly, Jennifer J., Go, Rodney C. P., Obisesan, Thomas O., Kamboh, M. Ilyas, Bennett, David A., Hall, Kathleen S., Goate, Alison M., Foroud, Tatiana M., Martin, Eden R., Wang, Li-San, Byrd, Goldie S., Farrer, Lindsay A., Haines, Jonathan L., Schellenberg, Gerard D., Mayeux, Richard, Pericak-Vance, Margaret A., Reitz, Christiane, Graff-Radford, Neill R., Martinez, Izri, Ayodele, Temitope, Logue, Mark W., Cantwell, Laura B., Jean-Francois, Melissa, Kuzma, Amanda B., Adams, L.D., Vance, Jeffery M., Cuccaro, Michael L., Chung, Jaeyoon, Mez, Jesse, Lunetta, Kathryn L., Jun, Gyungah R., Lopez, Oscar L., Hendrie, Hugh C., Reiman, Eric M., Kowall, Neil W., Leverenz, James B., Small, Scott A., Levey, Allan I., Golde, Todd E., Saykin, Andrew J., Starks, Takiyah D., Albert, Marilyn S., Hyman, Bradley T., Petersen, Ronald C., Sano, Mary, Wisniewski, Thomas, Vassar, Robert, Kaye, Jeffrey A., Henderson, Victor W., DeCarli, Charles, LaFerla, Frank M., Brewer, James B., Miller, Bruce L., Swerdlow, Russell H., Van Eldik, Linda J., Paulson, Henry L., Trojanowski, John Q., Chui, Helena C., Rosenberg, Roger N., Craft, Suzanne, Grabowski, Thomas J., Asthana, Sanjay, Morris, John C., Strittmatter, Stephen M., and Kukull, Walter A.

Abstract

IMPORTANCE: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. OBJECTIVE: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. MAIN OUTCOMES AND MEASURES: Diagnosis of Alzheimer disease. RESULTS: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10−7), near the immune response gene ALCAM (3q13; P = 9.3 × 10−7), within GPC6 (13q31; P = 4.1 × 10−7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10−7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10−9) and 6 additional loci with suggestive significance (P ≤ 5 × 10−7) such as API5 at 11p12 (P = 8.8 × 10−8) and RBFOX1 at 16p13 (P = 5.4 × 10−7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. CONCLUSIONS AND RELEVANCE: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

Published
2021
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104. Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice

Author

Liu, Peng, primary, Reichl, John H., additional, Rao, Eshaan R., additional, McNellis, Brittany M., additional, Huang, Eric S., additional, Hemmy, Laura S., additional, Forster, Colleen L., additional, Kuskowski, Michael A., additional, Borchelt, David R., additional, Vassar, Robert, additional, Ashe, Karen H., additional, and Zahs, Kathleen R., additional

Published
2017
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105. HIV Protease Inhibitors Alter Amyloid Precursor Protein Processing via β-Site Amyloid Precursor Protein Cleaving Enzyme-1 Translational Up-Regulation

Author

Gannon, Patrick J., primary, Akay-Espinoza, Cagla, additional, Yee, Alan C., additional, Briand, Lisa A., additional, Erickson, Michelle A., additional, Gelman, Benjamin B., additional, Gao, Yan, additional, Haughey, Norman J., additional, Zink, M. Christine, additional, Clements, Janice E., additional, Kim, Nicholas S., additional, Van De Walle, Gabriel, additional, Jensen, Brigid K., additional, Vassar, Robert, additional, Pierce, R. Christopher, additional, Gill, Alexander J., additional, Kolson, Dennis L., additional, Diehl, J. Alan, additional, Mankowski, Joseph L., additional, and Jordan-Sciutto, Kelly L., additional

Published
2017
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116. Pyroglutamate-3 amyloid-v deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models

Author

Frost, Jeffrey L., Le, Kevin X., Cynis, H., Ekpo, Elisabeth, Kleinschmidt, Martin, Palmour, Roberta M., Ervin, Frank R., Snigdha, Shikha, Cotman, Carl W., Saido, Takaomi C., Vassar, Robert J., George-Hyslop, Peter S., Ikezu, Tsuneya, Schilling, Stephan, Demuth, Hans-Ulrich, Lemere, Cynthia A., and Publica

Abstract

Amyloid-v (Av) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Av), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Av peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Av deposition in humans and animal models. PyroGlu-3 Av immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Av IR. PyroGlu-3 Av is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Av deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Av deposition preceding pyroGlu-3 Av deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Av is a major species of v-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 Av peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.

Published
2013

117. Dimebon alters hippocampal amyloid pathology in 3xTg-AD mice

Author

Perez, Sylvia E, Nadeem, Muhammad, Sadleir, Katherine R, Matras, Joanna, Kelley, Christy M, Counts, Scott E, Vassar, Robert, and Mufson, Elliott J

Subjects
Original Article
Abstract

A double blind, placebo-controlled phase II study revealed that the antihistamine, Dimebon® (dimebolin, latrepirdine) improved cognition in Alzheimer disease (AD) patients compared to placebo controls. However, the Phase III CONNECTION trial failed to demonstrate significant differences between dimebon and placebo treatments. Despite the controversial therapeutic outcomes in the treatment of AD, dimebon's mechanism(s) of action within the brain remain unclear. In the present study, we evaluated the effects of dimebon upon β-amyloid (Aβ), tau and astrocytes in the hippocampus of triple transgenic (3xTg-AD) mice, which develop AD-like pathology in an age-dependent manner. At age 6.5 months, prior to the development of Aβ plaques in the hippocampus, male and female 3xTg-AD mice, received a daily intraperitoneal injection of 0.1 % dimebon or saline for 1.5 months. At 8 months, quantitative immunohistochemistry revealed a significant reduction in hippocampal/subicular APP/Aβ in dimebon-treated mice, whereas protein bioassay found no change in full length APP, soluble Aβ(1-40) and Aβ(1-42), Aβ oligomers, BACE1 and GFAP levels between groups. Interestingly, the number of the hippocampal APP/Aβ plaques in female and male dimebon-treated mice was higher compared to gender-matched control mice. Dimebon did not alter hippocampal tau levels. Furthermore, dimebon protects SH-SY5Y neurons against Aβ toxicity and promotes GFAP expression in primary mouse astrocyte cultures. Our findings demonstrate that dimebon in vivo modifies hippocampal APP/Aβ pathology and in vitro protects against Aβ toxicity promoting cell survival and activates astrocytes.

Published
2012

123. Quantitative Comparison of Dense-Core Amyloid Plaque Accumulation in Amyloid-β Protein Precursor Transgenic Mice.

Author

Peng Liu, Reichl, John H., Rao, Eshaan R., McNellis, Brittany M., Huang, Eric S., Hemmy, Laura S., Forster, Colleen L., Kuskowski, Michael A., Borchelt, David R., Vassar, Robert, Ashe, Karen H., Zahs, Kathleen R., and Liu, Peng

Subjects
AMYLOID, LABORATORY mice, TRANSGENIC mice, HIPPOCAMPUS (Brain), AMYLOIDOSIS
Abstract

There exist several dozen lines of transgenic mice that express human amyloid-β protein precursor (AβPP) with Alzheimer's disease (AD)-linked mutations. AβPP transgenic mouse lines differ in the types and amounts of Aβ that they generate and in their spatiotemporal patterns of expression of Aβ assemblies, providing a toolkit to study Aβ amyloidosis and the influence of Aβ aggregation on brain function. More complete quantitative descriptions of the types of Aβ assemblies present in transgenic mice and in humans during disease progression should add to our understanding of how Aβ toxicity in mice relates to the pathogenesis of AD. Here, we provide a direct quantitative comparison of amyloid plaque burdens and plaque sizes in four lines of AβPP transgenic mice. We measured the fraction of cortex and hippocampus occupied by dense-core plaques, visualized by staining with Thioflavin S, in mice from young adulthood through advanced age. We found that the plaque burdens among the transgenic lines varied by an order of magnitude: at 15 months of age, the oldest age studied, the median cortical plaque burden in 5XFAD mice was already ∼4.5 times that of 21-month-old Tg2576 mice and ∼15 times that of 21-24-month-old rTg9191 mice. Plaque-size distributions changed across the lifespan in a line- and region-dependent manner. We also compared the dense-core plaque burdens in the mice to those measured in a set of pathologically-confirmed AD cases from the Nun Study. Cortical plaque burdens in Tg2576, APPSwePS1ΔE9, and 5XFAD mice eventually far exceeded those measured in the human cohort. [ABSTRACT FROM AUTHOR]

Published
2017
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126. Characterization of Alzheimer's β-Secretase Protein BACE: Processing and Other Post-translational Modifications

Author

Haniu, Mitsuru, primary, Bennett, Brian D., additional, Denis, Paul, additional, Young, Yunjen, additional, Mendiaz, Elizabeth A., additional, Fuller, Janis, additional, Hui, John O., additional, Kahn, Steven, additional, Babu-Khan, Safura, additional, Ross, Sandra, additional, Burgess, Teresa, additional, Katta, Viswanatham, additional, Nicolson, Margery, additional, Lull, Jonathan, additional, Wang, Shue-Yuan, additional, Rogers, Gary, additional, Vassar, Robert, additional, and Citron, Martin, additional

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133. A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer’s Disease Aβ Production

Author

Buggia-Prévot, Virginie, primary, Fernandez, Celia G., additional, Udayar, Vinod, additional, Vetrivel, Kulandaivelu S., additional, Elie, Aureliane, additional, Roseman, Jelita, additional, Sasse, Verena A., additional, Lefkow, Margaret, additional, Meckler, Xavier, additional, Bhattacharyya, Sohinee, additional, George, Manju, additional, Kar, Satyabrata, additional, Bindokas, Vytautas P., additional, Parent, Angèle T., additional, Rajendran, Lawrence, additional, Band, Hamid, additional, Vassar, Robert, additional, and Thinakaran, Gopal, additional

Published
2013
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135. Regulation of dynamic BACE1 trafficking in neurons

Author

Buggia-Prévot, Virginie, primary, Fernandez, Celia G, additional, Riordan, Sean, additional, Vetrivel, Kulandaivelu S, additional, Udayar, Vinod, additional, Elie, Aureliane, additional, Lefkow, Margaret, additional, Roseman, Jelita, additional, Meckler, Xavier, additional, Bhattacharyya, Sohinee, additional, George, Manju, additional, Waters, Jack, additional, Bindokas, Vytautas P, additional, Parent, Angèle T, additional, Rajendran, Lawrence, additional, Band, Hamid, additional, Vassar, Robert, additional, and Thinakaran, Gopal, additional

Published
2013
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137. Comment on “ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models”

Author

Veeraraghavalu, Karthikeyan, primary, Zhang, Can, additional, Miller, Sean, additional, Hefendehl, Jasmin K., additional, Rajapaksha, Tharinda W., additional, Ulrich, Jason, additional, Jucker, Mathias, additional, Holtzman, David M., additional, Tanzi, Rudolph E., additional, Vassar, Robert, additional, and Sisodia, Sangram S., additional

Published
2013
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140. Proteomic Substrate Identification for Membrane Proteases in the Brain.

Author

Müller, Stephan A., Scilabra, Simone D., Lichtenthaler, Stefan F., Vassar, Robert, Kins, Stefan, and Keller, Ulrich Auf Dem

Subjects
PROTEOMICS, PROTEOLYTIC enzymes, BRAIN proteins
Abstract

Cell-cell communication in the brain is controlled by multiple mechanisms, including proteolysis. Membrane-bound proteases generate signaling molecules from membranebound precursor proteins and control the length and function of cell surface membrane proteins. These proteases belong to different families, including members of the "a disintegrin and metalloprotease" (ADAM), the beta-site amyloid precursor protein cleaving enzymes (BACE), membrane-type matrix metalloproteases (MT-MMP) and rhomboids. Some of these proteases, in particular ADAM10 and BACE1 have been shown to be essential not only for the correct development of the mammalian brain, but also for myelination and maintaining neuronal connections in the adult nervous system. Additionally, these proteases are considered as drug targets for brain diseases, including Alzheimer's disease (AD), schizophrenia and cancer. Despite their biomedical relevance, the molecular functions of these proteases in the brain have not been explored in much detail, as little was known about their substrates. This has changed with the recent development of novel proteomic methods which allow to identify substrates of membrane-bound proteases from cultured cells, primary neurons and other primary brain cells and even in vivo from minute amounts of mouse cerebrospinal fluid (CSF). This review summarizes the recent advances and highlights the strengths of the individual proteomic methods. Finally, using the example of the Alzheimer-related proteases BACE1, ADAM10 and g-secretase, as well as ADAM17 and signal peptide peptidase like 3 (SPPL3), we illustrate how substrate identification with novel methods is instrumental in elucidating broad physiological functions of these proteases in the brain and other organs. [ABSTRACT FROM AUTHOR]

Published
2016
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141. A new biochemical method for ultra‐purification of amyloids from Alzheimer's disease brain tissues.

Author

Upadhyay, Arun, Siemer, Ansgar, Langen, Ralf, Vassar, Robert J., and Savas, Jeffrey N

Abstract

Background: The deposition of amyloids is the fundamental feature of several neurodegenerative diseases, including Alzheimer's disease (AD). Amyloid‐beta 42 (Aβ42) peptides are the primary constituents of amyloid deposits in the extracellular spaces within AD brains. Over the years, scientists have identified multiple biochemical features and elucidated several structural arrangements of the amyloidic deposits in the brain. Until now, many previous structural studies have been limited by barriers to isolate highly pure amyloid fibrils and plaques from diseased brains. Despite all the technological progress, detailed solid‐state NMR structures of naturally occurring Aβ42 amyloid fibrils have yet to be deduced due to the lack in our ability to isolate highly pure material. Method: We recently developed a robust protocol to isolate amyloid threads by using ultrasonication to remove non‐specific interacting protein from SDS insoluble fraction of APP‐KI brains. This protocol utilizes previously described sucrose gradient ultracentrifugation‐based enrichment methods, followed by high shearing energy generated by the advanced Bioruptor Pico Plus sonicator system. Result: We observed a high‐efficiency purification of multiple amyloid species from the APP knock‐in mice brains. The presence and purity of long fibrils were verified through negative staining electron microscopy and biochemical methods using Aβ42 and fibril‐specific antibodies. Immunoblot analyses using different antibodies provide complementary information about the structural and compositional differences among multiple amyloidic formations. The ultrasensitive ELISA values showed enrichment of Aβ42 in a range significantly higher than the previously reported values. Conclusion: Owing to the heterogeneity among the amyloidogenic structures in the extracellular spaces of brain tissues, no clear understanding of the fundamental process of in vivo fibril formation prevails. The lack of biochemical, structural, and clinical correlations further hampers the therapeutic advancement in AD biology. This new method of amyloid purification may help further biochemical and structural characterization of the disease‐causing proteinaceous formations in different brain regions. [ABSTRACT FROM AUTHOR]

Published
2021
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148. Orally Administrated Cinnamon Extract Reduces β-Amyloid Oligomerization and Corrects Cognitive Impairment in Alzheimer's Disease Animal Models

Author

Frydman-Marom, Anat, primary, Levin, Aviad, additional, Farfara, Dorit, additional, Benromano, Tali, additional, Scherzer-Attali, Roni, additional, Peled, Sivan, additional, Vassar, Robert, additional, Segal, Daniel, additional, Gazit, Ehud, additional, Frenkel, Dan, additional, and Ovadia, Michael, additional

Published
2011
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