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1. A cell junction pathology of neural stem cells leads to abnormal neurogenesis and hydrocephalus

Author

Esteban M Rodríguez, María M Guerra, Karin Vío, César González, Alexander Ortloff, Luis F Bátiz, Sara Rodríguez, María C Jara, Rosa I Muñoz, Eduardo Ortega, Jaime Jaque, Francisco Guerra, Deborah A Sival, Wilfred F. A. den Dunnen, Antonio J Jiménez, María D Domínguez-Pinos, José M Pérez-Fígares, James P McAllister, and Conrad Johanson

Subjects
hydrocephalus, abnormal neurogenesis, neural stem cells, stem cell transplantation, Biology (General), QH301-705.5
Abstract

Most cells of the developing mammalian brain derive from the ventricular (VZ) and the subventricular (SVZ) zones. The VZ is formed by the multipotent radial glia/neural stem cells (NSCs) while the SVZ harbors the rapidly proliferative neural precursor cells (NPCs). Evidence from human and animal models indicates that the common history of hydrocephalus and brain maldevelopment starts early in embryonic life with disruption of the VZ and SVZ. We propose that a "cell junction pathology" involving adherent and gap junctions is a final common outcome of a wide range of gene mutations resulting in proteins abnormally expressed by the VZ cells undergoing disruption. Disruption of the VZ during fetal development implies the loss of NSCs whereas VZ disruption during the perinatal period implies the loss of ependyma. The process of disruption occurs in specific regions of the ventricular system and at specific stages of brain development. This explains why only certain brain structures have an abnormal development, which in turn results in a specific neurological impairment of the newborn. Disruption of the VZ of the Sylvian aqueduct (SA) leads to aqueductal stenosis and hydrocephalus, while disruption of the VZ of telencephalon impairs neurogenesis. We are currently investigating whether grafting of NSCs/neurospheres from normal rats into the CSF of hydrocephalic mutants helps to diminish/repair the outcomes of VZ disruption.

Published
2012

2. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits.

Author

Nicholas J Izzo, Agnes Staniszewski, Lillian To, Mauro Fa, Andrew F Teich, Faisal Saeed, Harrison Wostein, Thomas Walko, Anisha Vaswani, Meghan Wardius, Zanobia Syed, Jessica Ravenscroft, Kelsie Mozzoni, Colleen Silky, Courtney Rehak, Raymond Yurko, Patricia Finn, Gary Look, Gilbert Rishton, Hank Safferstein, Miles Miller, Conrad Johanson, Edward Stopa, Manfred Windisch, Birgit Hutter-Paier, Mehrdad Shamloo, Ottavio Arancio, Harry LeVine, and Susan M Catalano

Subjects
Medicine, Science
Abstract

Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic beta amyloid (Abeta) 1-42 oligomers is proposed to underlie cognitive decline in Alzheimer's disease (AD). Alterations in membrane trafficking induced by Abeta oligomers mediates reduction in neuronal surface receptor expression that is the basis for inhibition of electrophysiological measures of synaptic plasticity and thus learning and memory. We have utilized phenotypic screens in mature, in vitro cultures of rat brain cells to identify small molecules which block or prevent the binding and effects of Abeta oligomers. Synthetic Abeta oligomers bind saturably to a single site on neuronal synapses and induce deficits in membrane trafficking in neuronal cultures with an EC50 that corresponds to its binding affinity. The therapeutic lead compounds we have found are pharmacological antagonists of Abeta oligomers, reducing the binding of Abeta oligomers to neurons in vitro, preventing spine loss in neurons and preventing and treating oligomer-induced deficits in membrane trafficking. These molecules are highly brain penetrant and prevent and restore cognitive deficits in mouse models of Alzheimer's disease. Counter-screening these compounds against a broad panel of potential CNS targets revealed they are highly potent and specific ligands of the sigma-2/PGRMC1 receptor. Brain concentrations of the compounds corresponding to greater than 80% receptor occupancy at the sigma-2/PGRMC1 receptor restore cognitive function in transgenic hAPP Swe/Ldn mice. These studies demonstrate that synthetic and human-derived Abeta oligomers act as pharmacologically-behaved ligands at neuronal receptors--i.e. they exhibit saturable binding to a target, they exert a functional effect related to their binding and their displacement by small molecule antagonists blocks their functional effect. The first-in-class small molecule receptor antagonists described here restore memory to normal in multiple AD models and sustain improvement long-term, representing a novel mechanism of action for disease-modifying Alzheimer's therapeutics.

Published
2014
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3. Contributors

Author

Reidunn B. Aalen, Yasser H.A. Abdel-Wahab, Michael E. Adams, Roger A.H. Adan, Rexford S. Ahima, Naima Ahmed, Omar Al-Massadi, Miriam Altstein, Youssef Anouar, Laura Anselmi, Siegfried Ansorge, Nikolinka Antcheva, Yevgeniya Antonova-Koch, Jon R. Appel, Anam J. Arik, Alison L. Arter, Peter Arvan, Avraham Ashkenazi, P.W. Baas, André Bado, Andrew Baird, Monica Baiula, Lauren O. Bakaletz, Earl E. Bakken, Márta Balaskó, Graham S. Baldwin, William A. Banks, Donatella Barra, Jessica R. Barson, Magali Basille, Natalie N. Bauer, Andrea Bedini, Christine Beeton, David J. Begley, Margery C. Beinfeld, William G. Bendena, Stephen C. Benoit, Itay Bentov, Howard Bern, Gabriele Bierbaum, Charles J. Billington, Anna Blasiak, Norman L. Block, Stephen. R. Bloom, Iwona Bonney, John H. Bowie, Sunny K. Boyd, Susan D. Brain, Dag A. Brede, Jozef Vanden Broeck, Kelly L. Brown, Mark R. Brown, James M. Bugni, Jens R. Bundgaard, Delphine Burel, Melinka A. Butenko, Melissa J. Call, Girolamo Calò, Duncan John Campbell, Anna Carlsson, Daniel B. Carr, Robert E. Carraway, Marcos C. Carreira, Felipe F. Casanueva, Sarah N. Cassella, Stuart A. Casson, Justo P. Castaño, Marek Cebrat, Valerie Chappe, David Chatenet, Keqiang Chen, Chen Chen, Longchuan Chen, Duan Chen, Carrie Y.Y. Cheng, Sung Ki Cho, Billy K.C. Chow, Arthur Christopoulos, Shijian Chu, Iain J. Clarke, Geoffrey M. Coast, Vincent Compere, Gisela P. Concepcion, Roger D. Cone, J. Michael Conlon, Germaine Cornélissen, Maité Courel, Réjean Couture, W.A. Cramer, Nathan P. Croft, Ana B. Crujeiras, Frank Cuttitta, Holger Cynis, F. D’Acquisto, Jon F. Davis, Thomas P. Davis, Claire Barbier de La Serre, Guillaume de Lartigue, Luis de Lecea, Marcelo de Oliveira Santos, Michel De Waard, Carolyn F. Deacon Bolette Hartmann, Charlène Delestre, Mario Delgado, Hans-Ulrich Demuth, Xiaoming Deng, Palitha Dharmawardhana, Anna Di Cosmo, Simoni Campos Dias, Jonathan W. Dickerson, Dzung B. Diep, H. Dircksen, Jasmin Dischinger, Jean-Claude do Rego, Paul R. Dobner, Graham J. Dockray, Robert M. Dores, Robert Ducroc, Nadine L. Dudek, Yvan Dumont, Celine Duraffourd, Dominique Duterte-Boucher, Alex N. Eberlé, Richard D. Egleton, Betty A. Eipper, Jorg B. Engel, Ella W. Englander, Jacques Epelbaum, Charlotte Erlanson-Albertsson, S. Evangelista, Karen A. Fagan, Joshua M. Farber, Klára Farkasfalvi, Csaba Fekete, Peter R. Flatt, R.J. Flower, Wolf-Georg Forssmann, Alain Fournier, Kevin Chu Foy, Octávio Luiz Franco, Dan Frenkel, Lloyd D. Fricker, César de la Fuente-Núñez, Hiroo Fukuda, Gerd Gäde, Ludovic Galas, Patricia E. Gallagher, Pierrick Gandolfo, Maria A. Garcia-Espinosa, Josune García-Sanmartín, Nori Geary, Hua Geng, Patrizia M. Germano, Jens P. Goetze, Alexis A. Gonzalez, Ana Gonzalez, Blake A. Gosnell, Katsutoshi Goto, Guillaume Gourcerol, I. Gozes, Francisco Gracia-Navarro, Bernadette E. Grayson, George H. Greeley, Megan Greenwald-Yarnell, Pierre Gressens, John R. Grider, Jan Grünewald, Juliano R. Guerreiro, Remo Guerrini, Filomena Guida, Laure Guilhaudis, Sandra Guilmeau, Andrew L. Gundlach, Jolanta Gutkowska, Clifton Hackbarth, Y. Haim Ohana, Franz Halberg, Mathias Hallberg, Sayyed A. Hamidi, Song Han, Ji-Sheng Han, Robert E.W. Hancock, Samer-ul Haque, Ikuko Hara-Nishimura, Aliza Hariton, Wendy J. Hartsock, Alan L. Harvey, Itaru Hasunuma, Robert J. Henning, Kristy M. Heppner, Kate L. Hertweck, Herbert Herzog, Tetsuya Higashiyama, Shuji Hinuma, Stefan Hippenstiel, Yuki Hirakawa, Shuichi Hirose, Jochen R. Hirsch, Andreas C. Hocke, Robert S. Hodges, Werner Hoffmann, Tomas Hökfelt, Jens Juul Holst, Peter Holzer, Frank M. Horodyski, Hiroshi Hosoda, Xiaowen Hou, Alisa Huffaker, Norio Iijima, Momoko Ikeuchi, Julita S. Imperial, Giovanna Improta, Akio Inui, Nigel Irwin, Munehiro Ishii, Xavier Iturrioz, Ljubica Ivanisevic, Hiroshi Iwao, Takeo Iwata, Yasukatsu Izumi, Hajime Izumiyama, Marek Jankowski, Tom Janssen, Sylvie Jégou, Robert T. Jensen, Preeti H. Jethwa, Helene Johannessen, Conrad Johanson, Valeria Judkowski, Przemyslaw Kaczmarek, Haruaki Kageyama, Tatsuo Kakimoto, Ki Sung Kang, Kenji Kangawa, Abba J. Kastin, Johji Kato, Pravin T.P. Kaumaya, Richard F. Keep, William R. Kem, Tetyana Khomenko, Sakae Kikuyama, Young-Joon Kim, Sadao Kimura, Ross King, Paul Kiptoo, Ichiro Kishimoto, Kazuo Kitamura, Alicja Kluczyk, Hiroyuki Kobori, Yosuke Kodama, Masayasu Kojima, Yuki Kondo, Meike Körner, Piotr Kosson, Catherine M. Kotz, Bhavani Krishnan, Bård Kulseng, Robert Kumpf, Marc Laburthe, Hélène Lacaille, Ellen E. Ladenheim, Ali Ladram, Marlyn D. Laksitorini, David G. Lambert, Angela B. Lange, Wolfgang Langhans, Muriel Larauche, Dan Larhammar, Ignacio M. Larráyoz, Roberta Lattanzi, Ronald M. Lechan, Benjamin Lefranc, Sarah F. Leibowitz, Vincent Lelièvre, Jérôme Leprince, Allen S. Levine, Qun Li, Veronica Lifshitz, Isabelle Lihrmann, James Chi-Jen Lin, Iris Lindberg, Keith Lindsey, Andrzej W. Lipkowski, T. Liron, Junli Liu, Ying Liu, Min Liu, Catherine Llorens-Cortes, Marilena Loizidou, C. Lopez, David A. Lovejoy, Vincenzo Luca, Thomas A. Lutz, Sherie Ma, Richard E. Mains, Maria M. Malagon, Ludwik K. Malendowicz, Jennifer Man-Fan Wan, Maria Luisa Mangoni, Michaele B Manigrasso, Mohamed A. Marahiel, Heather G. Marco, Christine Maric-Bilkan, Nikki J. Marks, Roland Martin, Vicente Martinez, Alfredo Martínez, Antonio J. Martinez-Fuentes, Edward P. Masler, Yoshikatsu Matsubayashi, Harman S. Mattu, Aaron G. Maule, Patricia J. McLaughlin, Ivan F. McMurtry, Ellen Meelkop, Saher Mehdi, Pietro Melchiorri, R.P. Millar, Laurence J. Miller, Miles Miller, Mulugeta Million, Naoto Minamino, M. Mittelman, Takashi Miyauchi, Mikiya Miyazato, Hirokazu Mizoguchi, Malte Mohme, Maité Montero-Hadjadje, Terry W. Moody, Neeloffer Mookherjee, Timothy H. Moran, Irene Morganstern, Masatomo Mori, Fabrice Morin, John F. Morris, Daniel S. Moura, Anna J. Mudge, Joram D. Mul, Karnam S. Murthy, Martin G. Myers, Ronald J. Nachman, Jean-Louis Nahon, Sushma Naithani, Tomoaki Nakada, Tomoya Nakamachi, Yuki Nakamura, Natalia N. Nalivaeva, June B. Nasrallah, Dick R. Nässel, L. Gabriel Navar, Pratap Neelakantan, Lucia Negri, Ingolf F. Nes, D. Neumann, Cindy Neveu, Tzi Bun Ng, Stephanie Y.L. Ng, Graham M. Nicholson, Pierre Nicolas, Toshio Nishikimi, Mariko Nishiyama, Rubén Nogueiras, Raymond S. Norton, Laura A. Novotny, Krzysztof W. Nowak, Fred Nyberg, Laura Ochoa-Callejero, Sven Ove Ögren, Hideko Ohgusu, Shinsuke Oh-I, Opeolu O. Ojo, Baldomero M. Olivera, Francisco E. Olucha-Bordonau, Joost J. Oppenheim, Ian Orchard, André J. Ouellette, Gustavo Pacheco-López, Nigel M. Page, Mario Sergio Palma, Weihong Pan, Yoonseong Park, Marc Parmentier, Sandrine Passemard, Michael Patterson, Brankica Paunovic, Gregory Pearce, Jens Pedersen, Theo L. Peeters, A. Eugene Pekary, Georges Pelletier, Simona Perboni, Diego Pérez-Tilve, Ábel Perjés, M. Perretti, Erika Pétervári, Clemencia Pinilla, Jacek Pinskim, Joseph R. Pisegna, Kristof Plankensteiner, Sonia Podvin, Pierre Poitras, Gianluca Polese, David M. Pollock, William Farias Porto, Lourival D. Possani, Charalabos Pothoulakis, Françoise Presse, Minolfa C. Prieto, S. Prutchi-Sagiv, Anthony W. Purcell, Louise Purtell, Rémi Quirion, Catalina Abad Rabat, Miriam Rademaker, Gautam Rajpal, Harpal S. Randeva, Sylvie Rebuffat, Joseph R. Reeve, Jens F. Rehfeld, Dirk Reinhold, Rainer K. Reinscheid, Jean Claude Reubi, Katayoun Rezvani, Suzana Meira Ribeiro, D. Richard, Mark Richards, Michael A. Riehle, Andrea C. Rinaldi, Bernd M. Rode, Ricardo C. Rodríguez de la Vega, Susan Rotzinger, Marcin Rucinski, Heikki Ruskoaho, Philip J. Ryan, Jean-Marc Sabatier, Hans-Georg Sahl, Sami I. Said, Tsukasa Sakurada, Shinobu Sakurada, David S. Salomon, Willis K. Samson, Zsuzsanna Sandor, H. Uri Saragovi, Kazuki Sasaki, Takahiro Sato, Ryousuke Satou, Shinichiro Sawa, Ayman I. Sayegh, Andrew V. Schally, Stephan Schilling, Liliane Schoofs, David A. Schooley, Mitchell L. Schubert, Isabelle Segalas-Milazzo, Nabil G. Seidah, Michael E. Selsted, Kim B. Seroogy, Cinzia Severini, Patrick M. Sexton, Yechiel Shai, O. Sharma, Masayoshi Shichiri, Tomoo Shimada, Hiroyuki Shimizu, Seiji Shioda, Arthur Shulkes, Teruna J. Siahaan, Ignacy Z. Siemion, Osmar Nascimento Silva, Marcio C. Silva-Filho, Mariusz Skwarczynski, Caroline. J. Small, Craig M. Smith, David E. Smith, A. Ian Smith, Beka Solomon, Travis E. Solomon, Mireia Sospedra, M.C. Souroujon, Santi Spampinato, Eliot R. Spindel, A. Steiger, Andreas Stengel, Catia Sternini, Frederik J. Steyn, Edward Stopa, Mathias Z. Strowski, Shigeo S. Sugano, Görel Sundström, J. Gregor Sutcliffe, Norbert Suttorp, Jonathan V. Sweedler, Sandor Szabo, Miklós Székely, István Szokodi, Yvette Taché, Kazuhiro Takahashi, Yoshio Takei, Fumiko Takenoya, Sébastien Talbot, E. Ann Tallant, Tricia M. Tan, Liesbet Temmerman, Bettina Temmesfeld-Wollbrück, Manuel Tena-Sempere, Annika Thorsell, Nanda Tilakaratne, Stephen S. Tobe, Takeshi Tokudome, Ganna Tolstanova, Marie-Christine Tonon, Jennifer F. Topping, Alessandro Tossi, Hervé Tostivint, Istvan Toth, Kazuhito Totsune, Fumiyo Toyoda, Rachel Troke, Matthias H. Tschöp, Patrick Tso, Hirokazu Tsukaya, Kazuyoshi Tsutsui, Hong Tu, Anthony J. Turner, Takayoshi Ubuka, Elene R. Valdivia, Hans Peter Vandersmissen, David Vaudry, Hubert Vaudry, Rafael Vazquez-Martinez, Joseph G. Verbalis, Daniele Vicari, Nicolas Vidal, Marzia Vignoni, Cécile Viollet, K.S. Vishwanatha, Mirella Vivoli, Thierry Voisin, John P. Vu, John C. Walker, B.A. Wallace, Ji Ming Wang, Lixin Wang, Jonathan H. Wardman, Takuya Watanabe, Hazel Welch, Haim Werner, L. Whitmore, Imke Wiedemann, Raphaelle Winsky-Sommerer, Ken A. Witt, Tatiana Wojciechowicz, Jack Ho Wong, Stephen C. Woods, Denise Wootten, Vincent Wu, Olivier Wurtz, Ximing Xiong, Zhi-Qing David Xu, Yube Yamaguchi, Takahiro Yamaguchi, Kazutoshi Yamamoto, E. Yamashita, Hiroyuki Yamazaki, De Yang, Masaaki Yoshikawa, Pu-Qing Yuan, Sunny C. Yung, Ian S. Zagon, S.D. Zakharov, Mehfuz Zaman, M.V. Zhalnina, Ning Zhang, Lixin Zhang-Auberson, Chun-Mei Zhao, Agnieszka Ziolkowska, and Dusan Zitnan

Published
2013
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4. Atrial natriuretic peptide: its putative role in modulating the choroid plexus-CSF system for intracranial pressure regulation

Author

Conrad Johanson, Je, Donahue, Spangenberger A, Eg, Stopa, Ja, Duncan, and Hs, Sharma

Subjects
Rats, Sprague-Dawley, Intracranial Pressure, Blood-Brain Barrier, Choroid Plexus, Animals, Brain, Tissue Distribution, Atrial Natriuretic Factor, Rats
Abstract

Evidence continues to build for the role of atrial natriuretic peptide (ANP) in reducing cerebrospinal fluid (CSF) formation rate, and thus, intracranial pressure. ANP binds to choroid plexus (CP) epithelial cells. This generates cGMP, which leads to altered ion transport and the slowing of CSF production. Binding sites for ANP in CP are plentiful and demonstrate plasticity in fluid imbalance disorders; however, specific ANP receptors in epithelial cells need confirmation. Using antibodies directed against NPR-A and NPR-B, we now demonstrate immunostaining not only in the choroidal epithelium (including cytoplasm), but also in the ependyma and some endothelial cells of cerebral microvessels in adult rats (Sprague-Dawley). The choroidal and ependymal cells stained almost universally, thus substantiating the initial autoradiographic binding studies with 125I-ANP. Because ANP titers in human CSF have previously been shown to increase proportionally to increments in ICP, we propose a compensatory ANP modulation of CP function to down-regulate ICP in hydrocephalus. Further evidence for this notion comes from the current finding of increased frequency of "dark" epithelial cells in CP of hydrocephalic (HTx) rats, which fits our earlier observation that the "dark" choroidal cells, associated with states of reduced CSF formation, are increased by elevated ANP in CSF. Altogether, ANP neuroendocrine-like regulation at CSF transport interfaces and blood-brain barrier impacts brain fluid homeostasis.

Published
2006

5. Whole-body hyperthermia in the rat disrupts the blood-cerebrospinal fluid barrier and induces brain edema

Author

Hs, Sharma, Ja, Duncan, and Conrad Johanson

Subjects
Male, Oxygen, Rats, Sprague-Dawley, Hot Temperature, Blood-Brain Barrier, Animals, Water, Brain Edema, Hyperthermia, Induced, Rats
Abstract

The present investigation was undertaken to find out whether whole-body hyperthermia (WBH) alters blood-cerebrospinal fluid barrier (BCSFB) permeability to exogenously-administered tracers and whether choroid plexus and ependymal cells exhibit morphological alterations in hyperthermia. Rats subjected to 4 hours of heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator exhibited a profound increase in the BCSFB to Evans blue and radioiodine. Blue staining of the dorsal surface of the hippocampus and caudate nucleus and a significant increase in Evans blue and [131]Iodine in cisternal cerebrospinal fluid were seen following 4-hour heat stress compared to control. Degeneration of choroidal epithelial cells and underlying ependyma, a dilated ventricular space, and degenerative changes in the underlying neuropil were frequent. Hippocampus, caudate nucleus, thalamus, and hypothalamus exhibited profound increases in water content after 4 hours of heat stress. These observations suggest that hyperthermia induced by WBH is capable of breaking down the BCSFB and contributing to cell and tissue injury in the central nervous system.

Published
2006

6. Homeostatic capabilities of the choroid plexus epithelium in Alzheimer's disease

Author

Conrad, Johanson, Paul, McMillan, Rosemarie, Tavares, Anthony, Spangenberger, John, Duncan, Gerald, Silverberg, and Edward, Stopa

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

As the secretory source of vitamins, peptides and hormones for neurons, the choroid plexus (CP) epithelium critically provides substances for brain homeostasis. This distributive process of cerebrospinal fluid (CSF) volume transmission reaches many cellular targets in the CNS. In ageing and ageing-related dementias, the CP-CSF system is less able to regulate brain interstitial fluid. CP primarily generates CSF bulk flow, and so its malfunctioning exacerbates Alzheimers disease (AD). Considerable attention has been devoted to the blood-brain barrier in AD, but more insight is needed on regulatory systems at the human blood-CSF barrier in order to improve epithelial function in severe disease. Using autopsied CP specimens from AD patients, we immunocytochemically examined expression of heat shock proteins (HSP90 and GRP94), fibroblast growth factor receptors (FGFr) and a fluid-regulatory protein (NaK2Cl cotransporter isoform 1 or NKCC1). CP upregulated HSP90, FGFr and NKCC1, even in end-stage AD. These CP adjustments involve growth factors and neuropeptides that help to buffer perturbations in CNS water balance and metabolism. They shed light on CP-CSF system responses to ventriculomegaly and the altered intracranial pressure that occurs in AD and normal pressure hydrocephalus. The ability of injured CP to express key regulatory proteins even at Braak stage V/VI, points to plasticity and function that may be boosted by drug treatment to expedite CSF dynamics. The enhanced expression of human CP 'homeostatic proteins' in AD dementia is discussed in relation to brain deficits and pharmacology.

Published
2004

9. Vasopressin gene expression in rat choroid plexus

Author

Chodobski A, Be, Wojcik, Yp, Loh, Ka, Dodd, Szmydynger-Chodobska J, Conrad Johanson, Dm, Demers, Zg, Chun, and Np, Limthong

Subjects
Male, Rats, Sprague-Dawley, Transcription, Genetic, Reverse Transcriptase Polymerase Chain Reaction, Vasopressins, Protein Biosynthesis, Choroid Plexus, Animals, Epithelial Cells, RNA, Messenger, Rats
Abstract

Vasopressin (VP) levels in cerebrospinal fluid (CSF) change in response to physiological stimuli and under various pathological conditions. The sources of CSF VP have yet to be clarified, however. In the present study, we provide evidence indicating that VP is synthesized in the choroid plexus, the primary site of CSF formation. All experiments were performed on adult male Sprague-Dawley rats. The presence of VP mRNA in choroid plexus epithelium was demonstrated by in situ hybridization histochemistry using the 35S-labeled riboprobe that was complementary to cDNA fragment of rat VP encoding the C-terminus part of proVP. In situ hybridization findings were confirmed by reverse transcriptase-polymerase chain reaction analysis. Immunohistochemistry for VP-associated neurophysin (VP-NP), a polypeptide component of proVP, revealed subapical accumulation of VP-NP-immunopositive product in choroidal epithelial cells. Immunoprecipitation and immunoblotting of choroidal protein extracts with anti-VP-NP antibody demonstrated the presence of a approximately 10-kD polypeptide that was also detected in hypothalamus. We hypothesize that the choroid plexus-derived VP exerts autocrine and/or paracrine effects on tissues near the CSF system.

Published
1999

10. The Origin of Deoxynucleosides in Brain: Implications for the Study of Neurogenesis and Stem Cell Therapy.

Author

Reynold Spector and Conrad Johanson

Subjects
*CEREBROSPINAL fluid, *CELLULAR therapy, *STEM cells, *DNA
Abstract

Abstract Abstract  Detection of DNA synthesis in brain employing (3H)thymidine ((3H)dT) or bromo deoxyuridine (BrdU) is widely used as a measure of the “birth” of cells in brain development, adult neurogenesis and neuronal stem cell replacement strategies. However, recent studies have raised serious questions about whether this methodology adequately measures the “birth” of cells in brain either quantitatively or in an interpretable way in comparative studies, or in stem cell investigations. To place these questions in perspective, we review deoxynucleoside synthesis and pharmacokinetics focusing on the barriers interfacing the blood-brain (cerebral capillaries) and blood-cerebrospinal fluid (choroid plexus), and the mechanisms, molecular biology and location of the deoxynucleoside transport systems in the central nervous system. Brain interstitial fluid and CSF nucleoside homeostasis depend upon the activity of concentrative nucleoside transporters (CNT) on the ‘central side’ of the barrier cells and equilibrative nucleoside transporters (ENT) on their ‘plasma side.’ With this information about nucleoside transporters, blood/CSF concentrations and metabolic pathways, we discuss the assumptions and weaknesses of using (3H)dT or BrdU methodologies alone for studying DNA synthesis in brain in the context of neurogenesis and potential stem cell therapy. We conclude that the use of (3H)dT and/or BrdU methodologies can be useful if their limitations are recognized and they are used in conjunction with independent methods. [ABSTRACT FROM AUTHOR]

Published
2007
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