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465 results on '"Mathews, Paul M."'

51. Human ATP1AL1 gene encodes a ouabain-sensitive H-K-ATPase

Author

Modyanov, Nikolai N., Mathews, Paul M., Grishin, Alexander V., Beguin, Pascal, Beggah, Ahmed T., Rossier, Bernard C., Horisberger, Jean-Daniel, and Geering, Kathi

Subjects
Xenopus -- Physiological aspects, Adenosine triphosphatase -- Research, Proteins -- Research, Potassium metabolism -- Research, Biological sciences
Abstract

A study conducted on the activity of the ATP1AL1 protein, encoded by the ATP1AL1 gene, in the Xenopus laevis oocyte shows that the ATP1AL1 protein is the alpha subunit of the human X-K-ATPase family (X = Na, H). This protein is able to perform the partially ouabain- and SCH-28080-sensitive exchange of extracellular K+ for intracellular protons. The ATPase regulated substitution of intracellular protons with extracellular potassium makes the oocytes' cytoplasm alkaline. The intracellular function of Na-K-ATPase is totally suppressed by the presence of ouabain.

Published
1995

52. Mutation of a conserved proline residue in the beta-subunit ectodomain prevents Na+-K+-ATPase oligomerization

Author

Geering, Kathi, Jaunin, Philippe, Jaisser, Frederic, Merillat, Anne-Marie, Horisberger, Jean-Daniel, Mathews, Paul M., Lemas, Victor, Fambrough, Douglas M., and Rossier, Bernard C.

Subjects
Sodium in the body -- Research, Xenopus -- Physiological aspects, Adenylate cyclase -- Physiological aspects, Biological sciences
Abstract

A sequence motif of Na+-K+-adenosinetriphosphatase (ATPase) beta-1-subunit ectodomain is mutagenized to determine its involvement in the alpha/beta-assembly and sodium pump activity. Functional Na-K pumps at the plasma membrane are formed when single and double tyrosine mutants of Xenopus laevis beta-1-subunits react with alpha-1-subunits. Correct grouping and behaviour of Na+-K+-ATPase is decreased by an exclusive proline mutation despite a regular speed of synthesis and core glycosylation. Correct folding of the beta-subunit and its capacity to connect properly with the alpha-1-subunit in the endoplasmic reticulum involves proline-244.

Published
1993

55. FE65 as a link between VLDLR and APP to regulate their trafficking and processing

Author

Dumanis Sonya B, Chamberlain Kelly A, Jin Sohn Yoo, Jin Lee Young, Guénette Suzanne Y, Suzuki Toshiharu, Mathews Paul M, Pak Daniel TS, Rebeck G William, Suh Yoo-hun, Park Hee-Sae, and Hoe Hyang-Sook

Subjects
FE65, VLDLR, APP trafficking, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background Several studies found that FE65, a cytoplasmic adaptor protein, interacts with APP and LRP1, altering the trafficking and processing of APP. We have previously shown that FE65 interacts with the ApoE receptor, ApoER2, altering its trafficking and processing. Interestingly, it has been shown that FE65 can act as a linker between APP and LRP1 or ApoER2. In the present study, we tested whether FE65 can interact with another ApoE receptor, VLDLR, thereby altering its trafficking and processing, and whether FE65 can serve as a linker between APP and VLDLR. Results We found that FE65 interacted with VLDLR using GST pull-down and co-immunoprecipitation assays in COS7 cells and in brain lysates. This interaction occurs via the PTB1 domain of FE65. Co-transfection with FE65 and full length VLDLR increased secreted VLDLR (sVLDLR); however, the levels of VLDLR C-terminal fragment (CTF) were undetectable as a result of proteasomal degradation. Additionally, FE65 increased cell surface levels of VLDLR. Moreover, we identified a novel complex between VLDLR and APP, which altered trafficking and processing of both proteins. Furthermore, immunoprecipitation results demonstrated that the presence of FE65 increased the interaction between APP and VLDLR in vitro and in vivo. Conclusions These data suggest that FE65 can regulate VLDLR trafficking and processing. Additionally, the interaction between VLDLR and APP altered both protein's trafficking and processing. Finally, our data suggest that FE65 serves as a link between VLDLR and APP. This novel interaction adds to a growing body of literature indicating trimeric complexes with various ApoE Receptors and APP.

Published
2012
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60. Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised

Author

Landreth Gary E, Heneka Michael T, Breidert Tilo, Schmidt Stephen D, Mathews Paul M, Lacombe Pierre, Feinstein Douglas L, and Galea Elena

Subjects
Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Background The over-expression of transforming growth factor β-1(TGF-β1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidβ (Aβ) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-β1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-β1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Aβ-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-β1-induced pathology. Methods Two-month-old TGF-β1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-γ agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Aβ precursor protein (APP) by western blot analysis; Aβ deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means ± SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. Results Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Aβ or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Aβ42- with no change in APP contents – while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. Conclusions i) TGF-β1 over-expressing mice may not be an appropriate model of Aβ-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-β1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-β1 actions in brain.

Published
2004
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61. Apolipoprotein E4 genotype compromises brain exosome production

Author

Peng, Katherine Y, primary, Pérez-González, Rocío, additional, Alldred, Melissa J, additional, Goulbourne, Chris N, additional, Morales-Corraliza, Jose, additional, Saito, Mariko, additional, Saito, Mitsuo, additional, Ginsberg, Stephen D, additional, Mathews, Paul M, additional, and Levy, Efrat, additional

Published
2018
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62. Alzheimer's disease-related overexpression of the cation-dependent mannose 6-phosphate receptor increases Aβ secretion : role for altered lysosomal hydrolase distribution in β-amyloidogenesis

Author

Mathews, Paul M., Guerra, Carolyn B., Jiang, Ying, Grbovic, Olivera M., Kao, Benjamin H., Schmidt, Stephen D., Dinakar, Ravi, Mercken, Marc, Hille-Rehfeld, Annette, Rohrer, Jack, Mehta, Pankaj, Cataldo, Anne M., Nixon, Ralph A., Mathews, Paul M., Guerra, Carolyn B., Jiang, Ying, Grbovic, Olivera M., Kao, Benjamin H., Schmidt, Stephen D., Dinakar, Ravi, Mercken, Marc, Hille-Rehfeld, Annette, Rohrer, Jack, Mehta, Pankaj, Cataldo, Anne M., and Nixon, Ralph A.

Abstract

Prominent endosomal and lysosomal changes are an invariant feature of neurons in sporadic Alzheimer's disease (AD). These changes include increased levels of lysosomal hydrolases in early endosomes and increased expression of the cation-dependent mannose 6-phosphate receptor (CD-MPR), which is partially localized to early endosomes. To determine whether AD-associated redistribution of lysosomal hydrolases resulting from changes in CD-MPR expression affects amyloid precursor protein (APP) processing, we stably transfected APP-overexpressing murine L cells with human CD-MPR. As controls for these cells, we also expressed CD-MPR trafficking mutants that either localize to the plasma membrane (CD-MPRpm) or to early endosomes (CD-MPRendo). Expression of CD-MPR resulted in a partial redistribution of a representative lysosomal hydrolase, cathepsin D, to early endosomal compartments. Turnover of APP and secretion of sAPPalpha and sAPPbeta were not altered by overexpression of any of the CD-MPR constructs. However, secretion of both human Abeta40 and Abeta42 into the growth media nearly tripled in CD-MPR- and CD-MPRendo-expressing cells when compared with parental or CD-MPRpm-expressing cells. Comparable increases were confirmed for endogenous mouse Abeta40 in L cells expressing these CD-MPR constructs but not overexpressing human APP. These data suggest that redistribution of lysosomal hydrolases to early endocytic compartments mediated by increased expression of the CD-MPR may represent a potentially pathogenic mechanism for accelerating Abeta generation in sporadic AD, where the mechanism of amyloidogenesis is unknown.

Published
2018

64. Brain-Wide Insulin Resistance, Tau Phosphorylation Changes, and Hippocampal Neprilysin and Amyloid-β Alterations in a Monkey Model of Type 1 Diabetes

Author

Morales-Corraliza, Jose, primary, Wong, Harrison, additional, Mazzella, Matthew J., additional, Che, Shaoli, additional, Lee, Sang Han, additional, Petkova, Eva, additional, Wagner, Janice D., additional, Hemby, Scott E., additional, Ginsberg, Stephen D., additional, and Mathews, Paul M., additional

Published
2016
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65. Apolipoprotein E4 genotype compromises brain exosome production.

Author

Peng, Katherine Y, Pérez-González, Rocío, Alldred, Melissa J, Goulbourne, Chris N, Morales-Corraliza, Jose, Saito, Mariko, Saito, Mitsuo, Ginsberg, Stephen D, Mathews, Paul M, and Levy, Efrat

Abstract

In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ɛ4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-β and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ɛ3 allele we show that the ɛ4 allele, whether homozygous or heterozygous with an ɛ3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-β precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression. [ABSTRACT FROM AUTHOR]

Published
2019
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66. Endogenous murine A beta increases amyloid deposition in APP23 but not in APPPS1 transgenic mice

Author

Mahler, Jasmin, Morales-Corraliza, Jose, Stolz, Julia, Skodras, Angelos, Radde, Rebecca, Duma, Carmen C., Eisele, Yvonne S., Mazzella, Matthew J., Wong, Harrison, Klunk, William E., Nilsson, Peter, Staufenbiel, Matthias, Mathews, Paul M., Jucker, Mathias, Wegenast-Braun, Bettina M., Mahler, Jasmin, Morales-Corraliza, Jose, Stolz, Julia, Skodras, Angelos, Radde, Rebecca, Duma, Carmen C., Eisele, Yvonne S., Mazzella, Matthew J., Wong, Harrison, Klunk, William E., Nilsson, Peter, Staufenbiel, Matthias, Mathews, Paul M., Jucker, Mathias, and Wegenast-Braun, Bettina M.

Abstract

Endogenous murine amyloid-beta peptide (A beta) is expressed in most A beta precursor protein (APP) transgenic mouse models of Alzheimers disease but its contribution to beta-amyloidosis remains unclear. We demonstrate similar to 35% increased cerebral A beta load in APP23 transgenic mice compared with age-matched APP23 mice on an App-null background. No such difference was found for the much faster A beta-depositing APPPS1 transgenic mouse model between animals with or without the murine App gene. Nevertheless, both APP23 and APPPS1 mice codeposited murine A beta, and immunoelectron microscopy revealed a tight association of murine A beta with human A beta fibrils. Deposition of murine A beta was considerably less efficient compared with the deposition of human A beta indicating a lower amyloidogenic potential of murine A beta in vivo. The amyloid dyes Pittsburgh Compound-B and pentamer formyl thiophene acetic acid did not differentiate between amyloid deposits consisting of human A beta and deposits of mixed human-murine A beta. Our data demonstrate a differential effect of murine A beta on human A beta deposition in different APP transgenic mice. The mechanistically complex interaction of human and mouse A beta may affect pathogenesis of the models and should be considered when models are used for translational preclinical studies., Funding Agencies|German Network in Degenerative Dementias [BMBF-01G10705]; NIA [AG017617]; Hertie Foundation, Frankfurt, Germany; ERC Starting Independent Researcher Grant (Project: MUMID) from the European Research Council

Published
2015
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67. Physiologically generated presenilin 1 lacking exon 8 fails to rescue brain PS1−/− phenotype and forms complexes with wildtype PS1 and nicastrin

Author

Brautigam, Hannah, primary, Moreno, Cesar L., additional, Steele, John W., additional, Bogush, Alexey, additional, Dickstein, Dara L., additional, Kwok, John B.J., additional, Schofield, Peter R., additional, Thinakaran, Gopal, additional, Mathews, Paul M., additional, Hof, Patrick R., additional, Gandy, Sam, additional, and Ehrlich, Michelle E., additional

Published
2015
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73. Physiological mouse brain Abeta levels are not related to the phosphorylation state of threonine-668 of Alzheimer's APP.

Author

Sano, Yoshitake, Nakaya, Tadashi, Pedrini, Steve, Takeda, Shizu, Iijima-Ando, Kanae, Iijima, Koichi, Mathews, Paul M, Itohara, Shigeyoshi, Gandy, Sam, Suzuki, Toshiharu, Sano, Yoshitake, Nakaya, Tadashi, Pedrini, Steve, Takeda, Shizu, Iijima-Ando, Kanae, Iijima, Koichi, Mathews, Paul M, Itohara, Shigeyoshi, Gandy, Sam, and Suzuki, Toshiharu

Abstract

Amyloid-beta peptide species ending at positions 40 and 42 (Abeta40, Abeta42) are generated by the proteolytic processing of the Alzheimer's amyloid precursor protein (APP). Abeta peptides accumulate in the brain early in the course of Alzheimer's disease (AD), especially Abeta42. The cytoplasmic domain of APP regulates intracellular trafficking and metabolism of APP and its carboxyl-terminal fragments (CTFalpha, CTFbeta). The role of protein phosphorylation in general, and that of the phosphorylation state of APP at threonine-668 (Thr668) in particular, has been investigated in detail by several laboratories (including our own). Some investigators have recently proposed that the phosphorylation state of Thr668 plays a pivotal role in governing brain Abeta levels, prompting the current study.

Published
2006

75. Therapeutic effects of remediating autophagy failure in a mouse model of Alzheimer disease by enhancing lysosomal proteolysis

Author

Yang, Dun-Sheng, primary, Stavrides, Philip, additional, Mohan, Panaiyur S., additional, Kaushik, Susmita, additional, Kumar, Asok, additional, Ohno, Masuo, additional, Schmidt, Stephen D., additional, Wesson, Daniel W., additional, Bandyopadhyay, Urmi, additional, Jiang, Ying, additional, Pawlik, Monika, additional, Peterhoff, Corrinne M., additional, Yang, Austin J., additional, Wilson, Donald A., additional, St. George-Hyslop, Peter, additional, Westaway, David, additional, Mathews, Paul M., additional, Levy, Efrat, additional, Cuervo, Ana Maria, additional, and Nixon, Ralph A., additional

Published
2011
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77. Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits

Author

Yang, Dun-Sheng, primary, Stavrides, Philip, additional, Mohan, Panaiyur S., additional, Kaushik, Susmita, additional, Kumar, Asok, additional, Ohno, Masuo, additional, Schmidt, Stephen D., additional, Wesson, Daniel, additional, Bandyopadhyay, Urmi, additional, Jiang, Ying, additional, Pawlik, Monika, additional, Peterhoff, Corrinne M., additional, Yang, Austin J., additional, Wilson, Donald A., additional, St George-Hyslop, Peter, additional, Westaway, David, additional, Mathews, Paul M., additional, Levy, Efrat, additional, Cuervo, Ana M., additional, and Nixon, Ralph A., additional

Published
2010
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78. O4‐05‐05: Modeling familial danish dementia: Implications for the amyloid hypothesis of Alzheimer's disease

Author

Coomaraswamy, Janaky, primary, Kilger, Ellen, additional, Woelfing, Heidrun, additional, Schaefer, Claudia, additional, Kaeser, Stephan A., additional, Wegenast-Braun, Bettina, additional, Hefendehl, Jasmin K., additional, Wolburg, Hartwig, additional, Mazzella, Matthew, additional, Ghiso, Jorge, additional, Goedert, Michel, additional, Akiyama, Haruhiko, additional, Garcia-Sierra, Francisco, additional, Wolfer, David P., additional, Mathews, Paul M., additional, and Jucker, Mathias, additional

Published
2010
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80. O4‐02‐05: In vivo turnover of tau and APP metabolites in the brains of wild‐type and Tg2576 mice: Greater stability of sAPP in the β‐amyloid‐depositing mice

Author

Morales-Corraliza, Jose, primary, Mazzella, Matthew J., additional, Berger, Jason D., additional, Diaz, Nicole S., additional, Choi, Jennifer H.K., additional, Levy, Efrat, additional, Matsuoka, Yasuji, additional, Planel, Emmanuel, additional, and Mathews, Paul M., additional

Published
2010
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83. Formation and maintenance of Alzheimer's disease β-amyloid plaques in the absence of microglia

Author

Grathwohl, Stefan A, primary, Kälin, Roland E, additional, Bolmont, Tristan, additional, Prokop, Stefan, additional, Winkelmann, Georg, additional, Kaeser, Stephan A, additional, Odenthal, Jörg, additional, Radde, Rebecca, additional, Eldh, Therese, additional, Gandy, Sam, additional, Aguzzi, Adriano, additional, Staufenbiel, Matthias, additional, Mathews, Paul M, additional, Wolburg, Hartwig, additional, Heppner, Frank L, additional, and Jucker, Mathias, additional

Published
2009
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86. O4-03-05: Amyloid-beta peptide is required for synaptic plasticity and memory

Author

Puzzo, Daniela, primary, Privitera, Lucia, additional, Leznik, Elena, additional, Fa’, Mauro, additional, Staniszewsky, Agnieszka, additional, Hashimoto, Gakuji, additional, Aziz, Fahad, additional, Sakurai, Mikako, additional, Ribe, Elena M., additional, Mathews, Paul M., additional, Troy, Carol M., additional, Mercken, Marc, additional, Jung, Sonia S., additional, Palmeri, Agostino, additional, and Arancio, Ottavio, additional

Published
2009
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87. P4-029: Formation and maintenance of β-amyloid plaques in the absence of microglia

Author

Grathwohl, Stefan, primary, Kälin, Roland, additional, Bolmont, Tristan, additional, Radde, Rebecca, additional, Odenthal, Joerg, additional, Mazzella, Matthew, additional, Käser, Stephan, additional, Mathews, Paul M., additional, Eldh, Therese, additional, Wolburg, Hartwig, additional, Kohsaka, Shinichi, additional, Heppner, Frank L., additional, and Jucker, Mathias, additional

Published
2009
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89. P1-076: Modeling Familial Danish dementia

Author

Coomaraswamy, Janaky, primary, Woelfing, Heidrun, additional, Schaefer, Claudia, additional, Kaeser, Stephan A., additional, Akiyama, Haruhiko, additional, Goedert, Michel, additional, Mathews, Paul M., additional, Ghiso, Jorge, additional, and Jucker, Mathias, additional

Published
2008
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90. P1-059: Cystatin B deletion in a mouse model of Alzheimer's disease, TgCRND8, ameliorates both autophagic-lysosomal and amyloid pathologies

Author

Yang, Dun-Sheng, primary, Stavrides, Philip, additional, Mohan, Panaiyur, additional, Kumar, Asok, additional, Schmidt, Stephen D., additional, Pawlik, Monika, additional, Bandyopadhyay, Urmi, additional, Mathews, Paul M., additional, Levy, Efrat, additional, Cuervo, Ana M., additional, and Nixon, Ralph A., additional

Published
2008
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95. P-161: Amyloid beta (Aβ) is unaltered with highly elevated peripheral cholesterol in mice lacking the low-density lipoprotein receptor

Author

Franciosi, Sonia, primary, English, Daniel, additional, Cho, Julie, additional, Buxbaum, Adina R., additional, Schmidt, Stephen D., additional, Perez, Gissel, additional, Mathews, Paul M., additional, De Gasperi, Rita, additional, Sosa, Miguel A. Gama, additional, Haroutunian, Vahram, additional, Elder, Gregory A., additional, and Buxbaum, Joseph D., additional

Published
2007
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98. Exogenous Induction of Cerebral ß-Amyloidogenesis Is Governed by Agent and Host

Author

Meyer-Luehmann, Melanie, primary, Coomaraswamy, Janaky, additional, Bolmont, Tristan, additional, Kaeser, Stephan, additional, Schaefer, Claudia, additional, Kilger, Ellen, additional, Neuenschwander, Anton, additional, Abramowski, Dorothee, additional, Frey, Peter, additional, Jaton, Anneliese L., additional, Vigouret, Jean-Marie, additional, Paganetti, Paolo, additional, Walsh, Dominic M., additional, Mathews, Paul M., additional, Ghiso, Jorge, additional, Staufenbiel, Matthias, additional, Walker, Lary C., additional, and Jucker, Mathias, additional

Published
2006
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