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162


Sex and Immunogen-Specific Benefits of Immunotherapy Targeting Islet Amyloid Polypeptide in Transgenic and Wild-Type Mice

Krishnamurthy, Pavan K; Rajamohamedsait, Hameetha B; Gonzalez, Veronica; Rajamohamedsait, Wajitha J; Ahmed, Nawal; Krishnaswamy, Senthilkumar; Sigurdsson, Einar M
Type 2 diabetes mellitus is characterized by the deposition of islet amyloid polypeptide (IAPP) as amyloid in islets, a process thought to be toxic to beta-cells. To determine the feasibility of targeting these aggregates therapeutically, we vaccinated transgenic (Tg) mice that overexpress human IAPP and were fed a high-fat diet to promote their diabetic phenotype. Our findings indicate that prophylactic vaccination with IAPP and its derivative IAPP7-19-TT, protects wild-type female mice, but not males, from obesity-induced early mortality, and the derivative showed a strong trend for prolonging the lifespan of Tg females but not males. Furthermore, IAPP7-19-TT-immunized Tg females cleared a glucose bolus more efficiently than controls, while IAPP-immunized Tg females showed an impaired ability to clear a glucose bolus compared to their adjuvant injected Tg controls. Interestingly, IAPP or IAPP7-19-TT treatments had no effect on glucose clearance in Tg males. Overall, these beneficial effects of IAPP targeted immunization depend on Tg status, sex, and immunogen. Hence, future studies in this field should carefully consider these variables that clearly affect the therapeutic outcome. In conclusion, IAPP targeting immunotherapy may have benefits in patients with type 2 diabetes.
PMCID:4907063
PMID: 27379014
ISSN: 1664-2392
CID: 2175782

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) [Guideline]

Klionsky, Daniel J; Abdelmohsen, Kotb; Abe, Akihisa; Abedin, Md Joynal; Abeliovich, Hagai; Acevedo Arozena, Abraham; Adachi, Hiroaki; Adams, Christopher M; Adams, Peter D; Adeli, Khosrow; Adhihetty, Peter J; Adler, Sharon G; Agam, Galila; Agarwal, Rajesh; Aghi, Manish K; Agnello, Maria; Agostinis, Patrizia; Aguilar, Patricia V; Aguirre-Ghiso, Julio; Airoldi, Edoardo M; Ait-Si-Ali, Slimane; Akematsu, Takahiko; Akporiaye, Emmanuel T; Al-Rubeai, Mohamed; Albaiceta, Guillermo M; Albanese, Chris; Albani, Diego; Albert, Matthew L; Aldudo, Jesus; Algul, Hana; Alirezaei, Mehrdad; Alloza, Iraide; Almasan, Alexandru; Almonte-Beceril, Maylin; Alnemri, Emad S; Alonso, Covadonga; Altan-Bonnet, Nihal; Altieri, Dario C; Alvarez, Silvia; Alvarez-Erviti, Lydia; Alves, Sandro; Amadoro, Giuseppina; Amano, Atsuo; Amantini, Consuelo; Ambrosio, Santiago; Amelio, Ivano; Amer, Amal O; Amessou, Mohamed; Amon, Angelika; An, Zhenyi; Anania, Frank A; Andersen, Stig U; Andley, Usha P; Andreadi, Catherine K; Andrieu-Abadie, Nathalie; Anel, Alberto; Ann, David K; Anoopkumar-Dukie, Shailendra; Antonioli, Manuela; Aoki, Hiroshi; Apostolova, Nadezda; Aquila, Saveria; Aquilano, Katia; Araki, Koichi; Arama, Eli; Aranda, Agustin; Araya, Jun; Arcaro, Alexandre; Arias, Esperanza; Arimoto, Hirokazu; Ariosa, Aileen R; Armstrong, Jane L; Arnould, Thierry; Arsov, Ivica; Asanuma, Katsuhiko; Askanas, Valerie; Asselin, Eric; Atarashi, Ryuichiro; Atherton, Sally S; Atkin, Julie D; Attardi, Laura D; Auberger, Patrick; Auburger, Georg; Aurelian, Laure; Autelli, Riccardo; Avagliano, Laura; Avantaggiati, Maria Laura; Avrahami, Limor; Awale, Suresh; Azad, Neelam; Bachetti, Tiziana; Backer, Jonathan M; Bae, Dong-Hun; Bae, Jae-Sung; Bae, Ok-Nam; Bae, Soo Han; Baehrecke, Eric H; Baek, Seung-Hoon; Baghdiguian, Stephen; Bagniewska-Zadworna, Agnieszka; Bai, Hua; Bai, Jie; Bai, Xue-Yuan; Bailly, Yannick; Balaji, Kithiganahalli Narayanaswamy; Balduini, Walter; Ballabio, Andrea; Balzan, Rena; Banerjee, Rajkumar; Banhegyi, Gabor; Bao, Haijun; Barbeau, Benoit; Barrachina, Maria D; Barreiro, Esther; Bartel, Bonnie; Bartolome, Alberto; Bassham, Diane C; Bassi, Maria Teresa; Bast, Robert C Jr; Basu, Alakananda; Batista, Maria Teresa; Batoko, Henri; Battino, Maurizio; Bauckman, Kyle; Baumgarner, Bradley L; Bayer, K Ulrich; Beale, Rupert; Beaulieu, Jean-Francois; Beck, George R Jr; Becker, Christoph; Beckham, J David; Bedard, Pierre-Andre; Bednarski, Patrick J; Begley, Thomas J; Behl, Christian; Behrends, Christian; Behrens, Georg Mn; Behrns, Kevin E; Bejarano, Eloy; Belaid, Amine; Belleudi, Francesca; Benard, Giovanni; Berchem, Guy; Bergamaschi, Daniele; Bergami, Matteo; Berkhout, Ben; Berliocchi, Laura; Bernard, Amelie; Bernard, Monique; Bernassola, Francesca; Bertolotti, Anne; Bess, Amanda S; Besteiro, Sebastien; Bettuzzi, Saverio; Bhalla, Savita; Bhattacharyya, Shalmoli; Bhutia, Sujit K; Biagosch, Caroline; Bianchi, Michele Wolfe; Biard-Piechaczyk, Martine; Billes, Viktor; Bincoletto, Claudia; Bingol, Baris; Bird, Sara W; Bitoun, Marc; Bjedov, Ivana; Blackstone, Craig; Blanc, Lionel; Blanco, Guillermo A; Blomhoff, Heidi Kiil; Boada-Romero, Emilio; Bockler, Stefan; Boes, Marianne; Boesze-Battaglia, Kathleen; Boise, Lawrence H; Bolino, Alessandra; Boman, Andrea; Bonaldo, Paolo; Bordi, Matteo; Bosch, Jurgen; Botana, Luis M; Botti, Joelle; Bou, German; Bouche, Marina; Bouchecareilh, Marion; Boucher, Marie-Josee; Boulton, Michael E; Bouret, Sebastien G; Boya, Patricia; Boyer-Guittaut, Michael; Bozhkov, Peter V; Brady, Nathan; Braga, Vania Mm; Brancolini, Claudio; Braus, Gerhard H; Bravo-San Pedro, Jose M; Brennan, Lisa A; Bresnick, Emery H; Brest, Patrick; Bridges, Dave; Bringer, Marie-Agnes; Brini, Marisa; Brito, Glauber C; Brodin, Bertha; Brookes, Paul S; Brown, Eric J; Brown, Karen; Broxmeyer, Hal E; Bruhat, Alain; Brum, Patricia Chakur; Brumell, John H; Brunetti-Pierri, Nicola; Bryson-Richardson, Robert J; Buch, Shilpa; Buchan, Alastair M; Budak, Hikmet; Bulavin, Dmitry V; Bultman, Scott J; Bultynck, Geert; Bumbasirevic, Vladimir; Burelle, Yan; Burke, Robert E; Burmeister, Margit; Butikofer, Peter; Caberlotto, Laura; Cadwell, Ken; Cahova, Monika; Cai, Dongsheng; Cai, Jingjing; Cai, Qian; Calatayud, Sara; Camougrand, Nadine; Campanella, Michelangelo; Campbell, Grant R; Campbell, Matthew; Campello, Silvia; Candau, Robin; Caniggia, Isabella; Cantoni, Lavinia; Cao, Lizhi; Caplan, Allan B; Caraglia, Michele; Cardinali, Claudio; Cardoso, Sandra Morais; Carew, Jennifer S; Carleton, Laura A; Carlin, Cathleen R; Carloni, Silvia; Carlsson, Sven R; Carmona-Gutierrez, Didac; Carneiro, Leticia Am; Carnevali, Oliana; Carra, Serena; Carrier, Alice; Carroll, Bernadette; Casas, Caty; Casas, Josefina; Cassinelli, Giuliana; Castets, Perrine; Castro-Obregon, Susana; Cavallini, Gabriella; Ceccherini, Isabella; Cecconi, Francesco; Cederbaum, Arthur I; Cena, Valentin; Cenci, Simone; Cerella, Claudia; Cervia, Davide; Cetrullo, Silvia; Chaachouay, Hassan; Chae, Han-Jung; Chagin, Andrei S; Chai, Chee-Yin; Chakrabarti, Gopal; Chamilos, Georgios; Chan, Edmond Yw; Chan, Matthew Tv; Chandra, Dhyan; Chandra, Pallavi; Chang, Chih-Peng; Chang, Raymond Chuen-Chung; Chang, Ta Yuan; Chatham, John C; Chatterjee, Saurabh; Chauhan, Santosh; Che, Yongsheng; Cheetham, Michael E; Cheluvappa, Rajkumar; Chen, Chun-Jung; Chen, Gang; Chen, Guang-Chao; Chen, Guoqiang; Chen, Hongzhuan; Chen, Jeff W; Chen, Jian-Kang; Chen, Min; Chen, Mingzhou; Chen, Peiwen; Chen, Qi; Chen, Quan; Chen, Shang-Der; Chen, Si; Chen, Steve S-L; Chen, Wei; Chen, Wei-Jung; Chen, Wen Qiang; Chen, Wenli; Chen, Xiangmei; Chen, Yau-Hung; Chen, Ye-Guang; Chen, Yin; Chen, Yingyu; Chen, Yongshun; Chen, Yu-Jen; Chen, Yue-Qin; Chen, Yujie; Chen, Zhen; Chen, Zhong; Cheng, Alan; Cheng, Christopher Hk; Cheng, Hua; Cheong, Heesun; Cherry, Sara; Chesney, Jason; Cheung, Chun Hei Antonio; Chevet, Eric; Chi, Hsiang Cheng; Chi, Sung-Gil; Chiacchiera, Fulvio; Chiang, Hui-Ling; Chiarelli, Roberto; Chiariello, Mario; Chieppa, Marcello; Chin, Lih-Shen; Chiong, Mario; Chiu, Gigi Nc; Cho, Dong-Hyung; Cho, Ssang-Goo; Cho, William C; Cho, Yong-Yeon; Cho, Young-Seok; Choi, Augustine Mk; Choi, Eui-Ju; Choi, Eun-Kyoung; Choi, Jayoung; Choi, Mary E; Choi, Seung-Il; Chou, Tsui-Fen; Chouaib, Salem; Choubey, Divaker; Choubey, Vinay; Chow, Kuan-Chih; Chowdhury, Kamal; Chu, Charleen T; Chuang, Tsung-Hsien; Chun, Taehoon; Chung, Hyewon; Chung, Taijoon; Chung, Yuen-Li; Chwae, Yong-Joon; Cianfanelli, Valentina; Ciarcia, Roberto; Ciechomska, Iwona A; Ciriolo, Maria Rosa; Cirone, Mara; Claerhout, Sofie; Clague, Michael J; Claria, Joan; Clarke, Peter Gh; Clarke, Robert; Clementi, Emilio; Cleyrat, Cedric; Cnop, Miriam; Coccia, Eliana M; Cocco, Tiziana; Codogno, Patrice; Coers, Jorn; Cohen, Ezra Ew; Colecchia, David; Coletto, Luisa; Coll, Nuria S; Colucci-Guyon, Emma; Comincini, Sergio; Condello, Maria; Cook, Katherine L; Coombs, Graham H; Cooper, Cynthia D; Cooper, J Mark; Coppens, Isabelle; Corasaniti, Maria Tiziana; Corazzari, Marco; Corbalan, Ramon; Corcelle-Termeau, Elisabeth; Cordero, Mario D; Corral-Ramos, Cristina; Corti, Olga; Cossarizza, Andrea; Costelli, Paola; Costes, Safia; Cotman, Susan L; Coto-Montes, Ana; Cottet, Sandra; Couve, Eduardo; Covey, Lori R; Cowart, L Ashley; Cox, Jeffery S; Coxon, Fraser P; Coyne, Carolyn B; Cragg, Mark S; Craven, Rolf J; Crepaldi, Tiziana; Crespo, Jose L; Criollo, Alfredo; Crippa, Valeria; Cruz, Maria Teresa; Cuervo, Ana Maria; Cuezva, Jose M; Cui, Taixing; Cutillas, Pedro R; Czaja, Mark J; Czyzyk-Krzeska, Maria F; Dagda, Ruben K; Dahmen, Uta; Dai, Chunsun; Dai, Wenjie; Dai, Yun; Dalby, Kevin N; Dalla Valle, Luisa; Dalmasso, Guillaume; D'Amelio, Marcello; Damme, Markus; Darfeuille-Michaud, Arlette; Dargemont, Catherine; Darley-Usmar, Victor M; Dasarathy, Srinivasan; Dasgupta, Biplab; Dash, Srikanta; Dass, Crispin R; Davey, Hazel Marie; Davids, Lester M; Davila, David; Davis, Roger J; Dawson, Ted M; Dawson, Valina L; Daza, Paula; de Belleroche, Jackie; de Figueiredo, Paul; de Figueiredo, Regina Celia Bressan Queiroz; de la Fuente, Jose; De Martino, Luisa; De Matteis, Antonella; De Meyer, Guido Ry; De Milito, Angelo; De Santi, Mauro; de Souza, Wanderley; De Tata, Vincenzo; De Zio, Daniela; Debnath, Jayanta; Dechant, Reinhard; Decuypere, Jean-Paul; Deegan, Shane; Dehay, Benjamin; Del Bello, Barbara; Del Re, Dominic P; Delage-Mourroux, Regis; Delbridge, Lea Md; Deldicque, Louise; Delorme-Axford, Elizabeth; Deng, Yizhen; Dengjel, Joern; Denizot, Melanie; Dent, Paul; Der, Channing J; Deretic, Vojo; Derrien, Benoit; Deutsch, Eric; Devarenne, Timothy P; Devenish, Rodney J; Di Bartolomeo, Sabrina; Di Daniele, Nicola; Di Domenico, Fabio; Di Nardo, Alessia; Di Paola, Simone; Di Pietro, Antonio; Di Renzo, Livia; DiAntonio, Aaron; Diaz-Araya, Guillermo; Diaz-Laviada, Ines; Diaz-Meco, Maria T; Diaz-Nido, Javier; Dickey, Chad A; Dickson, Robert C; Diederich, Marc; Digard, Paul; Dikic, Ivan; Dinesh-Kumar, Savithrama P; Ding, Chan; Ding, Wen-Xing; Ding, Zufeng; Dini, Luciana; Distler, Jorg Hw; Diwan, Abhinav; Djavaheri-Mergny, Mojgan; Dmytruk, Kostyantyn; Dobson, Renwick Cj; Doetsch, Volker; Dokladny, Karol; Dokudovskaya, Svetlana; Donadelli, Massimo; Dong, X Charlie; Dong, Xiaonan; Dong, Zheng; Donohue, Terrence M Jr; Doran, Kelly S; D'Orazi, Gabriella; Dorn, Gerald W 2nd; Dosenko, Victor; Dridi, Sami; Drucker, Liat; Du, Jie; Du, Li-Lin; Du, Lihuan; du Toit, Andre; Dua, Priyamvada; Duan, Lei; Duann, Pu; Dubey, Vikash Kumar; Duchen, Michael R; Duchosal, Michel A; Duez, Helene; Dugail, Isabelle; Dumit, Veronica I; Duncan, Mara C; Dunlop, Elaine A; Dunn, William A Jr; Dupont, Nicolas; Dupuis, Luc; Duran, Raul V; Durcan, Thomas M; Duvezin-Caubet, Stephane; Duvvuri, Umamaheswar; Eapen, Vinay; Ebrahimi-Fakhari, Darius; Echard, Arnaud; Eckhart, Leopold; Edelstein, Charles L; Edinger, Aimee L; Eichinger, Ludwig; Eisenberg, Tobias; Eisenberg-Lerner, Avital; Eissa, N Tony; El-Deiry, Wafik S; El-Khoury, Victoria; Elazar, Zvulun; Eldar-Finkelman, Hagit; Elliott, Chris Jh; Emanuele, Enzo; Emmenegger, Urban; Engedal, Nikolai; Engelbrecht, Anna-Mart; Engelender, Simone; Enserink, Jorrit M; Erdmann, Ralf; Erenpreisa, Jekaterina; Eri, Rajaraman; Eriksen, Jason L; Erman, Andreja; Escalante, Ricardo; Eskelinen, Eeva-Liisa; Espert, Lucile; Esteban-Martinez, Lorena; Evans, Thomas J; Fabri, Mario; Fabrias, Gemma; Fabrizi, Cinzia; Facchiano, Antonio; Faergeman, Nils J; Faggioni, Alberto; Fairlie, W Douglas; Fan, Chunhai; Fan, Daping; Fan, Jie; Fang, Shengyun; Fanto, Manolis; Fanzani, Alessandro; Farkas, Thomas; Faure, Mathias; Favier, Francois B; Fearnhead, Howard; Federici, Massimo; Fei, Erkang; Felizardo, Tania C; Feng, Hua; Feng, Yibin; Feng, Yuchen; Ferguson, Thomas A; Fernandez, Alvaro F; Fernandez-Barrena, Maite G; Fernandez-Checa, Jose C; Fernandez-Lopez, Arsenio; Fernandez-Zapico, Martin E; Feron, Olivier; Ferraro, Elisabetta; Ferreira-Halder, Carmen Verissima; Fesus, Laszlo; Feuer, Ralph; Fiesel, Fabienne C; Filippi-Chiela, Eduardo C; Filomeni, Giuseppe; Fimia, Gian Maria; Fingert, John H; Finkbeiner, Steven; Finkel, Toren; Fiorito, Filomena; Fisher, Paul B; Flajolet, Marc; Flamigni, Flavio; Florey, Oliver; Florio, Salvatore; Floto, R Andres; Folini, Marco; Follo, Carlo; Fon, Edward A; Fornai, Francesco; Fortunato, Franco; Fraldi, Alessandro; Franco, Rodrigo; Francois, Arnaud; Francois, Aurelie; Frankel, Lisa B; Fraser, Iain Dc; Frey, Norbert; Freyssenet, Damien G; Frezza, Christian; Friedman, Scott L; Frigo, Daniel E; Fu, Dongxu; Fuentes, Jose M; Fueyo, Juan; Fujitani, Yoshio; Fujiwara, Yuuki; Fujiya, Mikihiro; Fukuda, Mitsunori; Fulda, Simone; Fusco, Carmela; Gabryel, Bozena; Gaestel, Matthias; Gailly, Philippe; Gajewska, Malgorzata; Galadari, Sehamuddin; Galili, Gad; Galindo, Inmaculada; Galindo, Maria F; Galliciotti, Giovanna; Galluzzi, Lorenzo; Galluzzi, Luca; Galy, Vincent; Gammoh, Noor; Gandy, Sam; Ganesan, Anand K; Ganesan, Swamynathan; Ganley, Ian G; Gannage, Monique; Gao, Fen-Biao; Gao, Feng; Gao, Jian-Xin; Garcia Nannig, Lorena; Garcia Vescovi, Eleonora; Garcia-Macia, Marina; Garcia-Ruiz, Carmen; Garg, Abhishek D; Garg, Pramod Kumar; Gargini, Ricardo; Gassen, Nils Christian; Gatica, Damian; Gatti, Evelina; Gavard, Julie; Gavathiotis, Evripidis; Ge, Liang; Ge, Pengfei; Ge, Shengfang; Gean, Po-Wu; Gelmetti, Vania; Genazzani, Armando A; Geng, Jiefei; Genschik, Pascal; Gerner, Lisa; Gestwicki, Jason E; Gewirtz, David A; Ghavami, Saeid; Ghigo, Eric; Ghosh, Debabrata; Giammarioli, Anna Maria; Giampieri, Francesca; Giampietri, Claudia; Giatromanolaki, Alexandra; Gibbings, Derrick J; Gibellini, Lara; Gibson, Spencer B; Ginet, Vanessa; Giordano, Antonio; Giorgini, Flaviano; Giovannetti, Elisa; Girardin, Stephen E; Gispert, Suzana; Giuliano, Sandy; Gladson, Candece L; Glavic, Alvaro; Gleave, Martin; Godefroy, Nelly; Gogal, Robert M Jr; Gokulan, Kuppan; Goldman, Gustavo H; Goletti, Delia; Goligorsky, Michael S; Gomes, Aldrin V; Gomes, Ligia C; Gomez, Hernando; Gomez-Manzano, Candelaria; Gomez-Sanchez, Ruben; Goncalves, Dawit Ap; Goncu, Ebru; Gong, Qingqiu; Gongora, Celine; Gonzalez, Carlos B; Gonzalez-Alegre, Pedro; Gonzalez-Cabo, Pilar; Gonzalez-Polo, Rosa Ana; Goping, Ing Swie; Gorbea, Carlos; Gorbunov, Nikolai V; Goring, Daphne R; Gorman, Adrienne M; Gorski, Sharon M; Goruppi, Sandro; Goto-Yamada, Shino; Gotor, Cecilia; Gottlieb, Roberta A; Gozes, Illana; Gozuacik, Devrim; Graba, Yacine; Graef, Martin; Granato, Giovanna E; Grant, Gary Dean; Grant, Steven; Gravina, Giovanni Luca; Green, Douglas R; Greenhough, Alexander; Greenwood, Michael T; Grimaldi, Benedetto; Gros, Frederic; Grose, Charles; Groulx, Jean-Francois; Gruber, Florian; Grumati, Paolo; Grune, Tilman; Guan, Jun-Lin; Guan, Kun-Liang; Guerra, Barbara; Guillen, Carlos; Gulshan, Kailash; Gunst, Jan; Guo, Chuanyong; Guo, Lei; Guo, Ming; Guo, Wenjie; Guo, Xu-Guang; Gust, Andrea A; Gustafsson, Asa B; Gutierrez, Elaine; Gutierrez, Maximiliano G; Gwak, Ho-Shin; Haas, Albert; Haber, James E; Hadano, Shinji; Hagedorn, Monica; Hahn, David R; Halayko, Andrew J; Hamacher-Brady, Anne; Hamada, Kozo; Hamai, Ahmed; Hamann, Andrea; Hamasaki, Maho; Hamer, Isabelle; Hamid, Qutayba; Hammond, Ester M; Han, Feng; Han, Weidong; Handa, James T; Hanover, John A; Hansen, Malene; Harada, Masaru; Harhaji-Trajkovic, Ljubica; Harper, J Wade; Harrath, Abdel Halim; Harris, Adrian L; Harris, James; Hasler, Udo; Hasselblatt, Peter; Hasui, Kazuhisa; Hawley, Robert G; Hawley, Teresa S; He, Congcong; He, Cynthia Y; He, Fengtian; He, Gu; He, Rong-Rong; He, Xian-Hui; He, You-Wen; He, Yu-Ying; Heath, Joan K; Hebert, Marie-Josee; Heinzen, Robert A; Helgason, Gudmundur Vignir; Hensel, Michael; Henske, Elizabeth P; Her, Chengtao; Herman, Paul K; Hernandez, Agustin; Hernandez, Carlos; Hernandez-Tiedra, Sonia; Hetz, Claudio; Hiesinger, P Robin; Higaki, Katsumi; Hilfiker, Sabine; Hill, Bradford G; Hill, Joseph A; Hill, William D; Hino, Keisuke; Hofius, Daniel; Hofman, Paul; Hoglinger, Gunter U; Hohfeld, Jorg; Holz, Marina K; Hong, Yonggeun; Hood, David A; Hoozemans, Jeroen Jm; Hoppe, Thorsten; Hsu, Chin; Hsu, Chin-Yuan; Hsu, Li-Chung; Hu, Dong; Hu, Guochang; Hu, Hong-Ming; Hu, Hongbo; Hu, Ming Chang; Hu, Yu-Chen; Hu, Zhuo-Wei; Hua, Fang; Hua, Ya; Huang, Canhua; Huang, Huey-Lan; Huang, Kuo-How; Huang, Kuo-Yang; Huang, Shile; Huang, Shiqian; Huang, Wei-Pang; Huang, Yi-Ran; Huang, Yong; Huang, Yunfei; Huber, Tobias B; Huebbe, Patricia; Huh, Won-Ki; Hulmi, Juha J; Hur, Gang Min; Hurley, James H; Husak, Zvenyslava; Hussain, Sabah Na; Hussain, Salik; Hwang, Jung Jin; Hwang, Seungmin; Hwang, Thomas Is; Ichihara, Atsuhiro; Imai, Yuzuru; Imbriano, Carol; Inomata, Megumi; Into, Takeshi; Iovane, Valentina; Iovanna, Juan L; Iozzo, Renato V; Ip, Nancy Y; Irazoqui, Javier E; Iribarren, Pablo; Isaka, Yoshitaka; Isakovic, Aleksandra J; Ischiropoulos, Harry; Isenberg, Jeffrey S; Ishaq, Mohammad; Ishida, Hiroyuki; Ishii, Isao; Ishmael, Jane E; Isidoro, Ciro; Isobe, Ken-Ichi; Isono, Erika; Issazadeh-Navikas, Shohreh; Itahana, Koji; Itakura, Eisuke; Ivanov, Andrei I; Iyer, Anand Krishnan V; Izquierdo, Jose M; Izumi, Yotaro; Izzo, Valentina; Jaattela, Marja; Jaber, Nadia; Jackson, Daniel John; Jackson, William T; Jacob, Tony George; Jacques, Thomas S; Jagannath, Chinnaswamy; Jain, Ashish; Jana, Nihar Ranjan; Jang, Byoung Kuk; Jani, Alkesh; Janji, Bassam; Jannig, Paulo Roberto; Jansson, Patric J; Jean, Steve; Jendrach, Marina; Jeon, Ju-Hong; Jessen, Niels; Jeung, Eui-Bae; Jia, Kailiang; Jia, Lijun; Jiang, Hong; Jiang, Hongchi; Jiang, Liwen; Jiang, Teng; Jiang, Xiaoyan; Jiang, Xuejun; Jiang, Xuejun; Jiang, Ying; Jiang, Yongjun; Jimenez, Alberto; Jin, Cheng; Jin, Hongchuan; Jin, Lei; Jin, Meiyan; Jin, Shengkan; Jinwal, Umesh Kumar; Jo, Eun-Kyeong; Johansen, Terje; Johnson, Daniel E; Johnson, Gail Vw; Johnson, James D; Jonasch, Eric; Jones, Chris; Joosten, Leo Ab; Jordan, Joaquin; Joseph, Anna-Maria; Joseph, Bertrand; Joubert, Annie M; Ju, Dianwen; Ju, Jingfang; Juan, Hsueh-Fen; Juenemann, Katrin; Juhasz, Gabor; Jung, Hye Seung; Jung, Jae U; Jung, Yong-Keun; Jungbluth, Heinz; Justice, Matthew J; Jutten, Barry; Kaakoush, Nadeem O; Kaarniranta, Kai; Kaasik, Allen; Kabuta, Tomohiro; Kaeffer, Bertrand; Kagedal, Katarina; Kahana, Alon; Kajimura, Shingo; Kakhlon, Or; Kalia, Manjula; Kalvakolanu, Dhan V; Kamada, Yoshiaki; Kambas, Konstantinos; Kaminskyy, Vitaliy O; Kampinga, Harm H; Kandouz, Mustapha; Kang, Chanhee; Kang, Rui; Kang, Tae-Cheon; Kanki, Tomotake; Kanneganti, Thirumala-Devi; Kanno, Haruo; Kanthasamy, Anumantha G; Kantorow, Marc; Kaparakis-Liaskos, Maria; Kapuy, Orsolya; Karantza, Vassiliki; Karim, Md Razaul; Karmakar, Parimal; Kaser, Arthur; Kaushik, Susmita; Kawula, Thomas; Kaynar, A Murat; Ke, Po-Yuan; Ke, Zun-Ji; Kehrl, John H; Keller, Kate E; Kemper, Jongsook Kim; Kenworthy, Anne K; Kepp, Oliver; Kern, Andreas; Kesari, Santosh; Kessel, David; Ketteler, Robin; Kettelhut, Isis do Carmo; Khambu, Bilon; Khan, Muzamil Majid; Khandelwal, Vinoth Km; Khare, Sangeeta; Kiang, Juliann G; Kiger, Amy A; Kihara, Akio; Kim, Arianna L; Kim, Cheol Hyeon; Kim, Deok Ryong; Kim, Do-Hyung; Kim, Eung Kweon; Kim, Hye Young; Kim, Hyung-Ryong; Kim, Jae-Sung; Kim, Jeong Hun; Kim, Jin Cheon; Kim, Jin Hyoung; Kim, Kwang Woon; Kim, Michael D; Kim, Moon-Moo; Kim, Peter K; Kim, Seong Who; Kim, Soo-Youl; Kim, Yong-Sun; Kim, Yonghyun; Kimchi, Adi; Kimmelman, Alec C; Kimura, Tomonori; King, Jason S; Kirkegaard, Karla; Kirkin, Vladimir; Kirshenbaum, Lorrie A; Kishi, Shuji; Kitajima, Yasuo; Kitamoto, Katsuhiko; Kitaoka, Yasushi; Kitazato, Kaio; Kley, Rudolf A; Klimecki, Walter T; Klinkenberg, Michael; Klucken, Jochen; Knaevelsrud, Helene; Knecht, Erwin; Knuppertz, Laura; Ko, Jiunn-Liang; Kobayashi, Satoru; Koch, Jan C; Koechlin-Ramonatxo, Christelle; Koenig, Ulrich; Koh, Young Ho; Kohler, Katja; Kohlwein, Sepp D; Koike, Masato; Komatsu, Masaaki; Kominami, Eiki; Kong, Dexin; Kong, Hee Jeong; Konstantakou, Eumorphia G; Kopp, Benjamin T; Korcsmaros, Tamas; Korhonen, Laura; Korolchuk, Viktor I; Koshkina, Nadya V; Kou, Yanjun; Koukourakis, Michael I; Koumenis, Constantinos; Kovacs, Attila L; Kovacs, Tibor; Kovacs, Werner J; Koya, Daisuke; Kraft, Claudine; Krainc, Dimitri; Kramer, Helmut; Kravic-Stevovic, Tamara; Krek, Wilhelm; Kretz-Remy, Carole; Krick, Roswitha; Krishnamurthy, Malathi; Kriston-Vizi, Janos; Kroemer, Guido; Kruer, Michael C; Kruger, Rejko; Ktistakis, Nicholas T; Kuchitsu, Kazuyuki; Kuhn, Christian; Kumar, Addanki Pratap; Kumar, Anuj; Kumar, Ashok; Kumar, Deepak; Kumar, Dhiraj; Kumar, Rakesh; Kumar, Sharad; Kundu, Mondira; Kung, Hsing-Jien; Kuno, Atsushi; Kuo, Sheng-Han; Kuret, Jeff; Kurz, Tino; Kwok, Terry; Kwon, Taeg Kyu; Kwon, Yong Tae; Kyrmizi, Irene; La Spada, Albert R; Lafont, Frank; Lahm, Tim; Lakkaraju, Aparna; Lam, Truong; Lamark, Trond; Lancel, Steve; Landowski, Terry H; Lane, Darius Jr; Lane, Jon D; Lanzi, Cinzia; Lapaquette, Pierre; Lapierre, Louis R; Laporte, Jocelyn; Laukkarinen, Johanna; Laurie, Gordon W; Lavandero, Sergio; Lavie, Lena; LaVoie, Matthew J; Law, Betty Yuen Kwan; Law, Helen Ka-Wai; Law, Kelsey B; Layfield, Robert; Lazo, Pedro A; Le Cam, Laurent; Le Roch, Karine G; Le Stunff, Herve; Leardkamolkarn, Vijittra; Lecuit, Marc; Lee, Byung-Hoon; Lee, Che-Hsin; Lee, Erinna F; Lee, Gyun Min; Lee, He-Jin; Lee, Hsinyu; Lee, Jae Keun; Lee, Jongdae; Lee, Ju-Hyun; Lee, Jun Hee; Lee, Michael; Lee, Myung-Shik; Lee, Patty J; Lee, Sam W; Lee, Seung-Jae; Lee, Shiow-Ju; Lee, Stella Y; Lee, Sug Hyung; Lee, Sung Sik; Lee, Sung-Joon; Lee, Sunhee; Lee, Ying-Ray; Lee, Yong J; Lee, Young H; Leeuwenburgh, Christiaan; Lefort, Sylvain; Legouis, Renaud; Lei, Jinzhi; Lei, Qun-Ying; Leib, David A; Leibowitz, Gil; Lekli, Istvan; Lemaire, Stephane D; Lemasters, John J; Lemberg, Marius K; Lemoine, Antoinette; Leng, Shuilong; Lenz, Guido; Lenzi, Paola; Lerman, Lilach O; Lettieri Barbato, Daniele; Leu, Julia I-Ju; Leung, Hing Y; Levine, Beth; Lewis, Patrick A; Lezoualc'h, Frank; Li, Chi; Li, Faqiang; Li, Feng-Jun; Li, Jun; Li, Ke; Li, Lian; Li, Min; Li, Min; Li, Qiang; Li, Rui; Li, Sheng; Li, Wei; Li, Wei; Li, Xiaotao; Li, Yumin; Lian, Jiqin; Liang, Chengyu; Liang, Qiangrong; Liao, Yulin; Liberal, Joana; Liberski, Pawel P; Lie, Pearl; Lieberman, Andrew P; Lim, Hyunjung Jade; Lim, Kah-Leong; Lim, Kyu; Lima, Raquel T; Lin, Chang-Shen; Lin, Chiou-Feng; Lin, Fang; Lin, Fangming; Lin, Fu-Cheng; Lin, Kui; Lin, Kwang-Huei; Lin, Pei-Hui; Lin, Tianwei; Lin, Wan-Wan; Lin, Yee-Shin; Lin, Yong; Linden, Rafael; Lindholm, Dan; Lindqvist, Lisa M; Lingor, Paul; Linkermann, Andreas; Liotta, Lance A; Lipinski, Marta M; Lira, Vitor A; Lisanti, Michael P; Liton, Paloma B; Liu, Bo; Liu, Chong; Liu, Chun-Feng; Liu, Fei; Liu, Hung-Jen; Liu, Jianxun; Liu, Jing-Jing; Liu, Jing-Lan; Liu, Ke; Liu, Leyuan; Liu, Liang; Liu, Quentin; Liu, Rong-Yu; Liu, Shiming; Liu, Shuwen; Liu, Wei; Liu, Xian-De; Liu, Xiangguo; Liu, Xiao-Hong; Liu, Xinfeng; Liu, Xu; Liu, Xueqin; Liu, Yang; Liu, Yule; Liu, Zexian; Liu, Zhe; Liuzzi, Juan P; Lizard, Gerard; Ljujic, Mila; Lodhi, Irfan J; Logue, Susan E; Lokeshwar, Bal L; Long, Yun Chau; Lonial, Sagar; Loos, Benjamin; Lopez-Otin, Carlos; Lopez-Vicario, Cristina; Lorente, Mar; Lorenzi, Philip L; Lorincz, Peter; Los, Marek; Lotze, Michael T; Lovat, Penny E; Lu, Binfeng; Lu, Bo; Lu, Jiahong; Lu, Qing; Lu, She-Min; Lu, Shuyan; Lu, Yingying; Luciano, Frederic; Luckhart, Shirley; Lucocq, John Milton; Ludovico, Paula; Lugea, Aurelia; Lukacs, Nicholas W; Lum, Julian J; Lund, Anders H; Luo, Honglin; Luo, Jia; Luo, Shouqing; Luparello, Claudio; Lyons, Timothy; Ma, Jianjie; Ma, Yi; Ma, Yong; Ma, Zhenyi; Machado, Juliano; Machado-Santelli, Glaucia M; Macian, Fernando; MacIntosh, Gustavo C; MacKeigan, Jeffrey P; Macleod, Kay F; MacMicking, John D; MacMillan-Crow, Lee Ann; Madeo, Frank; Madesh, Muniswamy; Madrigal-Matute, Julio; Maeda, Akiko; Maeda, Tatsuya; Maegawa, Gustavo; Maellaro, Emilia; Maes, Hannelore; Magarinos, Marta; Maiese, Kenneth; Maiti, Tapas K; Maiuri, Luigi; Maiuri, Maria Chiara; Maki, Carl G; Malli, Roland; Malorni, Walter; Maloyan, Alina; Mami-Chouaib, Fathia; Man, Na; Mancias, Joseph D; Mandelkow, Eva-Maria; Mandell, Michael A; Manfredi, Angelo A; Manie, Serge N; Manzoni, Claudia; Mao, Kai; Mao, Zixu; Mao, Zong-Wan; Marambaud, Philippe; Marconi, Anna Maria; Marelja, Zvonimir; Marfe, Gabriella; Margeta, Marta; Margittai, Eva; Mari, Muriel; Mariani, Francesca V; Marin, Concepcio; Marinelli, Sara; Marino, Guillermo; Markovic, Ivanka; Marquez, Rebecca; Martelli, Alberto M; Martens, Sascha; Martin, Katie R; Martin, Seamus J; Martin, Shaun; Martin-Acebes, Miguel A; Martin-Sanz, Paloma; Martinand-Mari, Camille; Martinet, Wim; Martinez, Jennifer; Martinez-Lopez, Nuria; Martinez-Outschoorn, Ubaldo; Martinez-Velazquez, Moises; Martinez-Vicente, Marta; Martins, Waleska Kerllen; Mashima, Hirosato; Mastrianni, James A; Matarese, Giuseppe; Matarrese, Paola; Mateo, Roberto; Matoba, Satoaki; Matsumoto, Naomichi; Matsushita, Takehiko; Matsuura, Akira; Matsuzawa, Takeshi; Mattson, Mark P; Matus, Soledad; Maugeri, Norma; Mauvezin, Caroline; Mayer, Andreas; Maysinger, Dusica; Mazzolini, Guillermo D; McBrayer, Mary Kate; McCall, Kimberly; McCormick, Craig; McInerney, Gerald M; McIver, Skye C; McKenna, Sharon; McMahon, John J; McNeish, Iain A; 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Mizushima, Noboru; Mnich, Katarzyna; Mograbi, Baharia; Mohseni, Simin; Moita, Luis Ferreira; Molinari, Marco; Molinari, Maurizio; Moller, Andreas Buch; Mollereau, Bertrand; Mollinedo, Faustino; Mongillo, Marco; Monick, Martha M; Montagnaro, Serena; Montell, Craig; Moore, Darren J; Moore, Michael N; Mora-Rodriguez, Rodrigo; Moreira, Paula I; Morel, Etienne; Morelli, Maria Beatrice; Moreno, Sandra; Morgan, Michael J; Moris, Arnaud; Moriyasu, Yuji; Morrison, Janna L; Morrison, Lynda A; Morselli, Eugenia; Moscat, Jorge; Moseley, Pope L; Mostowy, Serge; Motori, Elisa; Mottet, Denis; Mottram, Jeremy C; Moussa, Charbel E-H; Mpakou, Vassiliki E; Mukhtar, Hasan; Mulcahy Levy, Jean M; Muller, Sylviane; Munoz-Moreno, Raquel; Munoz-Pinedo, Cristina; Munz, Christian; Murphy, Maureen E; Murray, James T; Murthy, Aditya; Mysorekar, Indira U; Nabi, Ivan R; Nabissi, Massimo; Nader, Gustavo A; Nagahara, Yukitoshi; Nagai, Yoshitaka; Nagata, Kazuhiro; Nagelkerke, Anika; Nagy, Peter; Naidu, Samisubbu R; Nair, Sreejayan; Nakano, Hiroyasu; Nakatogawa, Hitoshi; Nanjundan, Meera; Napolitano, Gennaro; Naqvi, Naweed I; Nardacci, Roberta; Narendra, Derek P; Narita, Masashi; Nascimbeni, Anna Chiara; Natarajan, Ramesh; Navegantes, Luiz C; Nawrocki, Steffan T; Nazarko, Taras Y; Nazarko, Volodymyr Y; Neill, Thomas; Neri, Luca M; Netea, Mihai G; Netea-Maier, Romana T; Neves, Bruno M; Ney, Paul A; Nezis, Ioannis P; Nguyen, Hang Tt; Nguyen, Huu Phuc; Nicot, Anne-Sophie; Nilsen, Hilde; Nilsson, Per; Nishimura, Mikio; Nishino, Ichizo; Niso-Santano, Mireia; Niu, Hua; Nixon, Ralph A; Njar, Vincent Co; Noda, Takeshi; Noegel, Angelika A; Nolte, Elsie Magdalena; Norberg, Erik; Norga, Koenraad K; Noureini, Sakineh Kazemi; Notomi, Shoji; Notterpek, Lucia; Nowikovsky, Karin; Nukina, Nobuyuki; Nurnberger, Thorsten; O'Donnell, Valerie B; O'Donovan, Tracey; O'Dwyer, Peter J; Oehme, Ina; Oeste, Clara L; Ogawa, Michinaga; Ogretmen, Besim; Ogura, Yuji; Oh, Young J; Ohmuraya, Masaki; Ohshima, Takayuki; Ojha, Rani; Okamoto, Koji; Okazaki, Toshiro; Oliver, F Javier; Ollinger, Karin; Olsson, Stefan; Orban, Daniel P; Ordonez, Paulina; Orhon, Idil; Orosz, Laszlo; O'Rourke, Eyleen J; Orozco, Helena; Ortega, Angel L; Ortona, Elena; Osellame, Laura D; Oshima, Junko; Oshima, Shigeru; Osiewacz, Heinz D; Otomo, Takanobu; Otsu, Kinya; Ou, Jing-Hsiung James; Outeiro, Tiago F; Ouyang, Dong-Yun; Ouyang, Hongjiao; Overholtzer, Michael; Ozbun, Michelle A; Ozdinler, P Hande; Ozpolat, Bulent; Pacelli, Consiglia; Paganetti, Paolo; Page, Guylene; Pages, Gilles; Pagnini, Ugo; Pajak, Beata; Pak, Stephen C; Pakos-Zebrucka, Karolina; Pakpour, Nazzy; Palkova, Zdena; Palladino, Francesca; Pallauf, Kathrin; Pallet, Nicolas; Palmieri, Marta; Paludan, Soren R; Palumbo, Camilla; Palumbo, Silvia; Pampliega, Olatz; Pan, Hongming; Pan, Wei; Panaretakis, Theocharis; Pandey, Aseem; Pantazopoulou, Areti; Papackova, Zuzana; Papademetrio, Daniela L; Papassideri, Issidora; Papini, Alessio; Parajuli, Nirmala; Pardo, Julian; Parekh, Vrajesh V; Parenti, Giancarlo; Park, Jong-In; Park, Junsoo; Park, Ohkmae K; Parker, Roy; Parlato, Rosanna; Parys, Jan B; Parzych, Katherine R; Pasquet, Jean-Max; Pasquier, Benoit; Pasumarthi, Kishore Bs; Patschan, Daniel; Patterson, Cam; Pattingre, Sophie; Pattison, Scott; Pause, Arnim; Pavenstadt, Hermann; Pavone, Flaminia; Pedrozo, Zully; Pena, Fernando J; Penalva, Miguel A; Pende, Mario; Peng, Jianxin; Penna, Fabio; Penninger, Josef M; Pensalfini, Anna; Pepe, Salvatore; Pereira, Gustavo Js; Pereira, Paulo C; Perez-de la Cruz, Veronica; Perez-Perez, Maria Esther; Perez-Rodriguez, Diego; Perez-Sala, Dolores; Perier, Celine; Perl, Andras; Perlmutter, David H; Perrotta, Ida; Pervaiz, Shazib; Pesonen, Maija; Pessin, Jeffrey E; Peters, Godefridus J; Petersen, Morten; Petrache, Irina; Petrof, Basil J; Petrovski, Goran; Phang, James M; Piacentini, Mauro; Pierdominici, Marina; Pierre, Philippe; Pierrefite-Carle, Valerie; Pietrocola, Federico; Pimentel-Muinos, Felipe X; Pinar, Mario; Pineda, Benjamin; Pinkas-Kramarski, Ronit; Pinti, Marcello; Pinton, Paolo; Piperdi, Bilal; Piret, James M; Platanias, Leonidas C; Platta, Harald W; Plowey, Edward D; Poggeler, Stefanie; Poirot, Marc; Polcic, Peter; Poletti, Angelo; Poon, Audrey H; Popelka, Hana; Popova, Blagovesta; Poprawa, Izabela; Poulose, Shibu M; Poulton, Joanna; Powers, Scott K; Powers, Ted; Pozuelo-Rubio, Mercedes; Prak, Krisna; Prange, Reinhild; Prescott, Mark; Priault, Muriel; Prince, Sharon; Proia, Richard L; Proikas-Cezanne, Tassula; Prokisch, Holger; Promponas, Vasilis J; Przyklenk, Karin; Puertollano, Rosa; Pugazhenthi, Subbiah; Puglielli, Luigi; Pujol, Aurora; Puyal, Julien; Pyeon, Dohun; Qi, Xin; Qian, Wen-Bin; Qin, Zheng-Hong; Qiu, Yu; Qu, Ziwei; Quadrilatero, Joe; Quinn, Frederick; Raben, Nina; Rabinowich, Hannah; Radogna, Flavia; Ragusa, Michael J; Rahmani, Mohamed; Raina, Komal; Ramanadham, Sasanka; Ramesh, Rajagopal; Rami, Abdelhaq; Randall-Demllo, Sarron; Randow, Felix; Rao, Hai; Rao, V Ashutosh; Rasmussen, Blake B; Rasse, Tobias M; Ratovitski, Edward A; Rautou, Pierre-Emmanuel; Ray, Swapan K; Razani, Babak; Reed, Bruce H; Reggiori, Fulvio; Rehm, Markus; Reichert, Andreas S; Rein, Theo; Reiner, David J; Reits, Eric; Ren, Jun; Ren, Xingcong; Renna, Maurizio; Reusch, Jane Eb; Revuelta, Jose L; Reyes, Leticia; Rezaie, Alireza R; Richards, Robert I; Richardson, Des R; Richetta, Clemence; Riehle, Michael A; Rihn, Bertrand H; Rikihisa, Yasuko; Riley, Brigit E; Rimbach, Gerald; Rippo, Maria Rita; Ritis, Konstantinos; Rizzi, Federica; Rizzo, Elizete; Roach, Peter J; Robbins, Jeffrey; Roberge, Michel; Roca, Gabriela; Roccheri, Maria Carmela; Rocha, Sonia; Rodrigues, Cecilia Mp; Rodriguez, Clara I; de Cordoba, Santiago Rodriguez; Rodriguez-Muela, Natalia; Roelofs, Jeroen; Rogov, Vladimir V; Rohn, Troy T; Rohrer, Barbel; Romanelli, Davide; Romani, Luigina; Romano, Patricia Silvia; Roncero, M Isabel G; Rosa, Jose Luis; Rosello, Alicia; Rosen, Kirill V; Rosenstiel, Philip; Rost-Roszkowska, Magdalena; Roth, Kevin A; Roue, Gael; Rouis, Mustapha; Rouschop, Kasper M; Ruan, Daniel T; Ruano, Diego; Rubinsztein, David C; Rucker, Edmund B 3rd; Rudich, Assaf; Rudolf, Emil; Rudolf, Ruediger; Ruegg, Markus A; Ruiz-Roldan, Carmen; Ruparelia, Avnika Ashok; Rusmini, Paola; Russ, David W; Russo, Gian Luigi; Russo, Giuseppe; Russo, Rossella; Rusten, Tor Erik; Ryabovol, Victoria; Ryan, Kevin M; Ryter, Stefan W; Sabatini, David M; Sacher, Michael; Sachse, Carsten; Sack, Michael N; Sadoshima, Junichi; Saftig, Paul; Sagi-Eisenberg, Ronit; Sahni, Sumit; Saikumar, Pothana; Saito, Tsunenori; Saitoh, Tatsuya; Sakakura, Koichi; Sakoh-Nakatogawa, Machiko; Sakuraba, Yasuhito; Salazar-Roa, Maria; Salomoni, Paolo; Saluja, Ashok K; Salvaterra, Paul M; Salvioli, Rosa; Samali, Afshin; Sanchez, Anthony Mj; Sanchez-Alcazar, Jose A; Sanchez-Prieto, Ricardo; Sandri, Marco; Sanjuan, Miguel A; Santaguida, Stefano; Santambrogio, Laura; Santoni, Giorgio; Dos Santos, Claudia Nunes; Saran, Shweta; Sardiello, Marco; Sargent, Graeme; Sarkar, Pallabi; Sarkar, Sovan; Sarrias, Maria Rosa; Sarwal, Minnie M; Sasakawa, Chihiro; Sasaki, Motoko; Sass, Miklos; Sato, Ken; Sato, Miyuki; Satriano, Joseph; Savaraj, Niramol; Saveljeva, Svetlana; Schaefer, Liliana; Schaible, Ulrich E; Scharl, Michael; Schatzl, Hermann M; Schekman, Randy; Scheper, Wiep; Schiavi, Alfonso; Schipper, Hyman M; Schmeisser, Hana; Schmidt, Jens; Schmitz, Ingo; Schneider, Bianca E; Schneider, E Marion; Schneider, Jaime L; Schon, Eric A; Schonenberger, Miriam J; Schonthal, Axel H; Schorderet, Daniel F; Schroder, Bernd; Schuck, Sebastian; Schulze, Ryan J; Schwarten, Melanie; Schwarz, Thomas L; Sciarretta, Sebastiano; Scotto, Kathleen; Scovassi, A Ivana; Screaton, Robert A; Screen, Mark; Seca, Hugo; Sedej, Simon; Segatori, Laura; Segev, Nava; Seglen, Per O; Segui-Simarro, Jose M; Segura-Aguilar, Juan; Seki, Ekihiro; Sell, Christian; Selliez, Iban; Semenkovich, Clay F; Semenza, Gregg L; Sen, Utpal; Serra, Andreas L; Serrano-Puebla, Ana; Sesaki, Hiromi; Setoguchi, Takao; Settembre, Carmine; Shacka, John J; Shajahan-Haq, Ayesha N; Shapiro, Irving M; Sharma, Shweta; She, Hua; Shen, C-K James; Shen, Chiung-Chyi; Shen, Han-Ming; Shen, Sanbing; Shen, Weili; Sheng, Rui; Sheng, Xianyong; Sheng, Zu-Hang; Shepherd, Trevor G; Shi, Junyan; Shi, Qiang; Shi, Qinghua; Shi, Yuguang; Shibutani, Shusaku; Shibuya, Kenichi; Shidoji, Yoshihiro; Shieh, Jeng-Jer; Shih, Chwen-Ming; Shimada, Yohta; Shimizu, Shigeomi; Shin, Dong Wook; Shinohara, Mari L; Shintani, Michiko; Shintani, Takahiro; Shioi, Tetsuo; Shirabe, Ken; Shiri-Sverdlov, Ronit; Shirihai, Orian; Shore, Gordon C; Shu, Chih-Wen; Shukla, Deepak; Sibirny, Andriy A; Sica, Valentina; Sigurdson, Christina J; Sigurdsson, Einar M; Sijwali, Puran Singh; Sikorska, Beata; Silveira, Wilian A; Silvente-Poirot, Sandrine; Silverman, Gary A; Simak, Jan; Simmet, Thomas; Simon, Anna Katharina; Simon, Hans-Uwe; Simone, Cristiano; Simons, Matias; Simonsen, Anne; Singh, Rajat; Singh, Shivendra V; Singh, Shrawan K; Sinha, Debasish; Sinha, Sangita; Sinicrope, Frank A; Sirko, Agnieszka; Sirohi, Kapil; Sishi, Balindiwe Jn; Sittler, Annie; Siu, Parco M; Sivridis, Efthimios; Skwarska, Anna; Slack, Ruth; Slaninova, Iva; Slavov, Nikolai; Smaili, Soraya S; Smalley, Keiran Sm; Smith, Duncan R; Soenen, Stefaan J; Soleimanpour, Scott A; Solhaug, Anita; Somasundaram, Kumaravel; Son, Jin H; Sonawane, Avinash; Song, Chunjuan; Song, Fuyong; Song, Hyun Kyu; Song, Ju-Xian; Song, Wei; Soo, Kai Y; Sood, Anil K; Soong, Tuck Wah; Soontornniyomkij, Virawudh; Sorice, Maurizio; Sotgia, Federica; Soto-Pantoja, David R; Sotthibundhu, Areechun; Sousa, Maria Joao; Spaink, Herman P; Span, Paul N; Spang, Anne; Sparks, Janet D; Speck, Peter G; Spector, Stephen A; Spies, Claudia D; Springer, Wolfdieter; Clair, Daret St; Stacchiotti, Alessandra; Staels, Bart; Stang, Michael T; Starczynowski, Daniel T; Starokadomskyy, Petro; Steegborn, Clemens; Steele, John W; Stefanis, Leonidas; Steffan, Joan; Stellrecht, Christine M; Stenmark, Harald; Stepkowski, Tomasz M; Stern, Stephan T; Stevens, Craig; Stockwell, Brent R; Stoka, Veronika; Storchova, Zuzana; Stork, Bjorn; Stratoulias, Vassilis; Stravopodis, Dimitrios J; Strnad, Pavel; Strohecker, Anne Marie; Strom, Anna-Lena; Stromhaug, Per; Stulik, Jiri; Su, Yu-Xiong; Su, Zhaoliang; Subauste, Carlos S; Subramaniam, Srinivasa; Sue, Carolyn M; Suh, Sang Won; Sui, Xinbing; Sukseree, Supawadee; Sulzer, David; Sun, Fang-Lin; Sun, Jiaren; Sun, Jun; Sun, Shi-Yong; Sun, Yang; Sun, Yi; Sun, Yingjie; Sundaramoorthy, Vinod; Sung, Joseph; Suzuki, Hidekazu; Suzuki, Kuninori; Suzuki, Naoki; Suzuki, Tadashi; Suzuki, Yuichiro J; Swanson, Michele S; Swanton, Charles; Sward, Karl; Swarup, Ghanshyam; Sweeney, Sean T; Sylvester, Paul W; Szatmari, Zsuzsanna; Szegezdi, Eva; Szlosarek, Peter W; Taegtmeyer, Heinrich; Tafani, Marco; Taillebourg, Emmanuel; Tait, Stephen Wg; Takacs-Vellai, Krisztina; Takahashi, Yoshinori; Takats, Szabolcs; Takemura, Genzou; Takigawa, Nagio; Talbot, Nicholas J; Tamagno, Elena; Tamburini, Jerome; Tan, Cai-Ping; Tan, Lan; Tan, Mei Lan; Tan, Ming; Tan, Yee-Joo; Tanaka, Keiji; Tanaka, Masaki; Tang, Daolin; Tang, Dingzhong; Tang, Guomei; Tanida, Isei; Tanji, Kunikazu; Tannous, Bakhos A; Tapia, Jose A; Tasset-Cuevas, Inmaculada; Tatar, Marc; Tavassoly, Iman; Tavernarakis, Nektarios; Taylor, Allen; Taylor, Graham S; Taylor, Gregory A; Taylor, J Paul; Taylor, Mark J; Tchetina, Elena V; Tee, Andrew R; Teixeira-Clerc, Fatima; Telang, Sucheta; Tencomnao, Tewin; Teng, Ba-Bie; Teng, Ru-Jeng; Terro, Faraj; Tettamanti, Gianluca; Theiss, Arianne L; Theron, Anne E; Thomas, Kelly Jean; Thome, Marcos P; Thomes, Paul G; Thorburn, Andrew; Thorner, Jeremy; Thum, Thomas; Thumm, Michael; Thurston, Teresa Lm; Tian, Ling; Till, Andreas; Ting, Jenny Pan-Yun; Titorenko, Vladimir I; Toker, Lilach; Toldo, Stefano; Tooze, Sharon A; Topisirovic, Ivan; Torgersen, Maria Lyngaas; Torosantucci, Liliana; Torriglia, Alicia; Torrisi, Maria Rosaria; Tournier, Cathy; Towns, Roberto; Trajkovic, Vladimir; Travassos, Leonardo H; Triola, Gemma; Tripathi, Durga Nand; Trisciuoglio, Daniela; Troncoso, Rodrigo; Trougakos, Ioannis P; Truttmann, Anita C; Tsai, Kuen-Jer; Tschan, Mario P; Tseng, Yi-Hsin; Tsukuba, Takayuki; Tsung, Allan; Tsvetkov, Andrey S; Tu, Shuiping; Tuan, Hsing-Yu; Tucci, Marco; Tumbarello, David A; Turk, Boris; Turk, Vito; Turner, Robin Fb; Tveita, Anders A; Tyagi, Suresh C; Ubukata, Makoto; Uchiyama, Yasuo; Udelnow, Andrej; Ueno, Takashi; Umekawa, Midori; Umemiya-Shirafuji, Rika; Underwood, Benjamin R; Ungermann, Christian; Ureshino, Rodrigo P; Ushioda, Ryo; Uversky, Vladimir N; Uzcategui, Nestor L; Vaccari, Thomas; Vaccaro, Maria I; Vachova, Libuse; Vakifahmetoglu-Norberg, Helin; Valdor, Rut; Valente, Enza Maria; Vallette, Francois; Valverde, Angela M; Van den Berghe, Greet; Van Den Bosch, Ludo; van den Brink, Gijs R; van der Goot, F Gisou; van der Klei, Ida J; van der Laan, Luc Jw; van Doorn, Wouter G; van Egmond, Marjolein; van Golen, Kenneth L; Van Kaer, Luc; van Lookeren Campagne, Menno; Vandenabeele, Peter; Vandenberghe, Wim; Vanhorebeek, Ilse; Varela-Nieto, Isabel; Vasconcelos, M Helena; Vasko, Radovan; Vavvas, Demetrios G; Vega-Naredo, Ignacio; Velasco, Guillermo; Velentzas, Athanassios D; Velentzas, Panagiotis D; Vellai, Tibor; Vellenga, Edo; Vendelbo, Mikkel Holm; Venkatachalam, Kartik; Ventura, Natascia; Ventura, Salvador; Veras, Patricia St; Verdier, Mireille; Vertessy, Beata G; Viale, Andrea; Vidal, Michel; Vieira, Helena LA; Vierstra, Richard D; Vigneswaran, Nadarajah; Vij, Neeraj; Vila, Miquel; Villar, Margarita; Villar, Victor H; Villarroya, Joan; Vindis, Cecile; Viola, Giampietro; Viscomi, Maria Teresa; Vitale, Giovanni; Vogl, Dan T; Voitsekhovskaja, Olga V; von Haefen, Clarissa; von Schwarzenberg, Karin; Voth, Daniel E; Vouret-Craviari, Valerie; Vuori, Kristina; Vyas, Jatin M; Waeber, Christian; Walker, Cheryl Lyn; Walker, Mark J; Walter, Jochen; Wan, Lei; Wan, Xiangbo; Wang, Bo; Wang, Caihong; Wang, Chao-Yung; Wang, Chengshu; Wang, Chenran; Wang, Chuangui; Wang, Dong; Wang, Fen; Wang, Fuxin; Wang, Guanghui; Wang, Hai-Jie; Wang, Haichao; Wang, Hong-Gang; Wang, Hongmin; Wang, Horng-Dar; Wang, Jing; Wang, Junjun; Wang, Mei; Wang, Mei-Qing; Wang, Pei-Yu; Wang, Peng; Wang, Richard C; Wang, Shuo; Wang, Ting-Fang; Wang, Xian; Wang, Xiao-Jia; Wang, Xiao-Wei; Wang, Xin; Wang, Xuejun; Wang, Yan; Wang, Yanming; Wang, Ying; Wang, Ying-Jan; Wang, Yipeng; Wang, Yu; Wang, Yu Tian; Wang, Yuqing; Wang, Zhi-Nong; Wappner, Pablo; Ward, Carl; Ward, Diane McVey; Warnes, Gary; Watada, Hirotaka; Watanabe, Yoshihisa; Watase, Kei; Weaver, Timothy E; Weekes, Colin D; Wei, Jiwu; Weide, Thomas; Weihl, Conrad C; Weindl, Gunther; Weis, Simone Nardin; Wen, Longping; Wen, Xin; Wen, Yunfei; Westermann, Benedikt; Weyand, Cornelia M; White, Anthony R; White, Eileen; Whitton, J Lindsay; Whitworth, Alexander J; Wiels, Joelle; Wild, Franziska; Wildenberg, Manon E; Wileman, Tom; Wilkinson, Deepti Srinivas; Wilkinson, Simon; Willbold, Dieter; Williams, Chris; Williams, Katherine; Williamson, Peter R; Winklhofer, Konstanze F; Witkin, Steven S; Wohlgemuth, Stephanie E; Wollert, Thomas; Wolvetang, Ernst J; Wong, Esther; Wong, G William; Wong, Richard W; Wong, Vincent Kam Wai; Woodcock, Elizabeth A; Wright, Karen L; Wu, Chunlai; Wu, Defeng; Wu, Gen Sheng; Wu, Jian; Wu, Junfang; Wu, Mian; Wu, Min; Wu, Shengzhou; Wu, William Kk; Wu, Yaohua; Wu, Zhenlong; Xavier, Cristina Pr; Xavier, Ramnik J; Xia, Gui-Xian; Xia, Tian; Xia, Weiliang; Xia, Yong; Xiao, Hengyi; Xiao, Jian; Xiao, Shi; Xiao, Wuhan; Xie, Chuan-Ming; Xie, Zhiping; Xie, Zhonglin; Xilouri, Maria; Xiong, Yuyan; Xu, Chuanshan; Xu, Congfeng; Xu, Feng; Xu, Haoxing; Xu, Hongwei; Xu, Jian; Xu, Jianzhen; Xu, Jinxian; Xu, Liang; Xu, Xiaolei; Xu, Yangqing; Xu, Ye; Xu, Zhi-Xiang; Xu, Ziheng; Xue, Yu; Yamada, Takahiro; Yamamoto, Ai; Yamanaka, Koji; Yamashina, Shunhei; Yamashiro, Shigeko; Yan, Bing; Yan, Bo; Yan, Xianghua; Yan, Zhen; Yanagi, Yasuo; Yang, Dun-Sheng; Yang, Jin-Ming; Yang, Liu; Yang, Minghua; Yang, Pei-Ming; Yang, Peixin; Yang, Qian; Yang, Wannian; Yang, Wei Yuan; Yang, Xuesong; Yang, Yi; Yang, Ying; Yang, Zhifen; Yang, Zhihong; Yao, Meng-Chao; Yao, Pamela J; Yao, Xiaofeng; Yao, Zhenyu; Yao, Zhiyuan; Yasui, Linda S; Ye, Mingxiang; Yedvobnick, Barry; Yeganeh, Behzad; Yeh, Elizabeth S; Yeyati, Patricia L; Yi, Fan; Yi, Long; Yin, Xiao-Ming; Yip, Calvin K; Yoo, Yeong-Min; Yoo, Young Hyun; Yoon, Seung-Yong; Yoshida, Ken-Ichi; Yoshimori, Tamotsu; Young, Ken H; Yu, Huixin; Yu, Jane J; Yu, Jin-Tai; Yu, Jun; Yu, Li; Yu, W Haung; Yu, Xiao-Fang; Yu, Zhengping; Yuan, Junying; Yuan, Zhi-Min; Yue, Beatrice Yjt; Yue, Jianbo; Yue, Zhenyu; Zacks, David N; Zacksenhaus, Eldad; Zaffaroni, Nadia; Zaglia, Tania; Zakeri, Zahra; Zecchini, Vincent; Zeng, Jinsheng; Zeng, Min; Zeng, Qi; Zervos, Antonis S; Zhang, Donna D; Zhang, Fan; Zhang, Guo; Zhang, Guo-Chang; Zhang, Hao; Zhang, Hong; Zhang, Hong; Zhang, Hongbing; Zhang, Jian; Zhang, Jian; Zhang, Jiangwei; Zhang, Jianhua; Zhang, Jing-Pu; Zhang, Li; Zhang, Lin; Zhang, Lin; Zhang, Long; Zhang, Ming-Yong; Zhang, Xiangnan; Zhang, Xu Dong; Zhang, Yan; Zhang, Yang; Zhang, Yanjin; Zhang, Yingmei; Zhang, Yunjiao; Zhao, Mei; Zhao, Wei-Li; Zhao, Xiaonan; Zhao, Yan G; Zhao, Ying; Zhao, Yongchao; Zhao, Yu-Xia; Zhao, Zhendong; Zhao, Zhizhuang J; Zheng, Dexian; Zheng, Xi-Long; Zheng, Xiaoxiang; Zhivotovsky, Boris; Zhong, Qing; Zhou, Guang-Zhou; Zhou, Guofei; Zhou, Huiping; Zhou, Shu-Feng; Zhou, Xu-Jie; Zhu, Hongxin; Zhu, Hua; Zhu, Wei-Guo; Zhu, Wenhua; Zhu, Xiao-Feng; Zhu, Yuhua; Zhuang, Shi-Mei; Zhuang, Xiaohong; Ziparo, Elio; Zois, Christos E; Zoladek, Teresa; Zong, Wei-Xing; Zorzano, Antonio; Zughaier, Susu M
PMCID:4835977
PMID: 26799652
ISSN: 1554-8635
CID: 1922322

Tau Immunotherapy

Sigurdsson, Einar M
In recent years, tau immunotherapy has advanced from proof-of-concept studies [Sigurdsson EM, NIH R01AG020197, 2001; Asuni AA, et al: J Neurosci 2007;27:9115-9129], which have now been confirmed and extended by us and others. Phase I clinical trials on active and passive tau immunizations are being conducted, with several additional passive tau antibody trials likely to be initiated in the near future for Alzheimer's disease and other tauopathies. Because tau pathology correlates better with the degree of dementia than amyloid-beta (Abeta) pathology, greater clinical efficacy may be achieved by clearing tau than Abeta aggregates in the later stages of the disease, when cognitive impairments become evident. Substantial insight has now been obtained regarding which epitopes to target, mechanism of action and potential toxicity, but much remains to be clarified. All of these factors likely depend on the model/disease or stage of pathology and the immunogen/antibody. Interestingly, tau antibodies interact with the protein both extra- and intracellularly, but the importance of each site for tau clearance is not well defined. Some antibodies are readily taken up into neurons, whereas others are not. It can be argued that extracellular clearance may be safer but less efficacious than intraneuronal clearance and/or sequestration to prevent secretion and further spread of tau pathology. Development of therapeutic tau antibodies has led to antibody-derived imaging probes, which are more specific than the dye-based compounds that are already in clinical trials. Such specificity may give valuable information on the pathological tau epitope profile, which could then guide the selection of therapeutic antibodies for maximal efficacy and safety. Hopefully, tau immunotherapy will be effective in clinical trials, and further advanced by mechanistic clarification in experimental models with insights from biomarkers and postmortem analyses of clinical subjects.
PMCID:4777344
PMID: 26551002
ISSN: 1660-2862
CID: 1834672

Tau immunotherapy for Alzheimer's disease

Pedersen, Jan Torleif; Sigurdsson, Einar M
Targeting pathological tau protein in Alzheimer's disease (AD) and related tauopathies has shown great potential in animal models. Given that tau lesions correlate better with the degree of dementia than do amyloid-beta (Abeta) plaques, their clearance may be clinically more efficacious than removing Abeta when cognitive deficits become evident in AD. Several complementary mechanisms of antibody-mediated removal of tau aggregates are likely to act in concert and the importance of each one may depend on antibody properties, the disease, and its stage. Clinical trials of tau immunotherapy are already underway and several more are likely to be initiated in the near future.
PMID: 25846560
ISSN: 1471-499x
CID: 1644542

Specific Amyloid beta Clearance by a Catalytic Antibody Construct

Planque, Stephanie A; Nishiyama, Yasuhiro; Sonoda, Sari; Lin, Yan; Taguchi, Hiroaki; Hara, Mariko; Kolodziej, Steven; Mitsuda, Yukie; Gonzalez, Veronica; Sait, Hameetha B R; Fukuchi, Ken-Ichiro; Massey, Richard J; Friedland, Robert P; O'Nuallain, Brian; Sigurdsson, Einar M; Paul, Sudhir
Classical immunization methods do not generate catalytic antibodies (catabodies), but recent findings suggest that the innate antibody repertoire is a rich catabody source. We describe the specificity and amyloid beta (Abeta)-clearing effect of a catabody construct engineered from innate immunity principles. The catabody recognized the Abeta C terminus noncovalently and hydrolyzed Abeta rapidly, with no reactivity to the Abeta precursor protein, transthyretin amyloid aggregates, or irrelevant proteins containing the catabody-sensitive Abeta dipeptide unit. The catabody dissolved preformed Abeta aggregates and inhibited Abeta aggregation more potently than an Abeta-binding IgG. Intravenous catabody treatment reduced brain Abeta deposits in a mouse Alzheimer disease model without inducing microgliosis or microhemorrhages. Specific Abeta hydrolysis appears to be an innate immune function that could be applied for therapeutic Abeta removal.
PMCID:4400338
PMID: 25724648
ISSN: 1083-351x
CID: 1544012

Antibody-derived in vivo imaging of tau pathology

Krishnaswamy, Senthilkumar; Lin, Yan; Rajamohamedsait, Wajitha J; Rajamohamedsait, Hameetha B; Krishnamurthy, Pavan; Sigurdsson, Einar M
Antibodies or their derivatives as imaging probes for pathological tau protein have great potential, but have not been well studied. In particular, smaller, single-chain-variable antibody fragments (scFv's) are attractive for detecting tau lesions in live subjects. Here, we generated libraries of scFv's and identified numerous phospho-tau-selective scFv's. Peripheral injection of one of these scFv's consistently resulted in a strong in vivo brain signal in transgenic tauopathy mice, but not in wild-type or amyloid-beta plaque mice. The parent tau antibody provided similar results, albeit with a weaker signal intensity. The imaging signal correlated very well with colocalization of the probe with intraneuronal tau aggregates. Both were associated with markers of endosomes, autophagosomes, and lysosomes, suggesting their interaction in these degradation pathways. Such specific antibody-derived imaging probes have great potential as diagnostic markers for Alzheimer's disease and related tauopathies.
PMCID:4261104
PMID: 25505335
ISSN: 0270-6474
CID: 1424802

Harnessing the immune system for treatment and detection of tau pathology

Congdon, Erin E; Krishnaswamy, Senthilkumar; Sigurdsson, Einar M
The tau protein is an attractive target for therapy and diagnosis. We started a tau immunotherapy program about 13 years ago and have since demonstrated that active and passive immunotherapies diminish tau pathology and improve function, including cognition, in different mouse models. These findings have been confirmed and extended by several groups. We routinely detect neuronal, and to a lesser extent microglial, antibody uptake correlating with tau pathology. Antibodies bind tau aggregates in the endosomal/lysosomal system, enhancing clearance presumably by promoting their disassembly. Extracellular clearance has recently been shown by others, using antibodies that apparently are not internalized. As most pathological tau is neuronal, intracellular targeting may be more efficacious. However, extracellular tau may be more accessible to antibodies, with tau-antibody complexes a target for microglial phagocytosis. The extent of involvement of each pathway may depend on numerous factors including antibody properties, degree of pathology, and experimental model. On the imaging front, multiple tau ligands derived from beta-sheet dyes have been developed by several groups, some with promising results in clinical PET tests. Postmortem analysis should clarify their tau specificity, as in theory and based on histological staining, those are likely to have some affinity for various amyloids. We are developing antibody-derived tau probes that should be more specific, and have in mouse models shown in vivo detection and binding to pathological tau after peripheral injection. These are exciting times for research on tau therapies and diagnostic agents that hopefully can be applied to humans in the near future.
PMCID:4075177
PMID: 24603943
ISSN: 1387-2877
CID: 1032252

Tau Immunotherapy and Imaging

Sigurdsson, Einar M
Disappointing findings from recent phase III trials on amyloid-beta (Abeta) immunotherapy for Alzheimer's disease (AD) have shifted the focus of such treatments to the tau protein. As tau pathology correlates better with the degree of dementia than Abeta plaque burden, it is a more attractive target once cognitive impairments are evident, while Abeta therapies may be better suited for the presymptomatic phase of the disease. Over 12 years ago, we initiated a tau immunotherapy program, seeking to alleviate the functional impairments associated with tau lesions in tauopathies. We have reported that various active and passive tau immunizations diminish tau pathology and improve function, including cognition, in different mouse models. Both extra- and intracellular pathways are likely involved. The antibodies may block the spread of tau pathology via microglial phagocytosis of the antibody-tau complex and facilitate lysosomal tau clearance in neurons after endosomal uptake. We have observed such antibody internalization following intracarotid injection in mice and in various culture models. These include brain slices and primary neurons from tangle mice as well as human neuroblastoma cell lines. Antibody targeting of different intracellular protein aggregates, including alpha-synuclein, Abeta and superoxide dismutase has been reported by others. Now, several laboratories have confirmed and extended our findings using various active and passive tau immunizations in different models, thereby clearly establishing the feasibility of this approach for clinical trials. We are also working on imaging approaches to monitor tau pathology, its consequences and the efficacy of treatments. Dire need exists for such diagnostic methods for tauopathies. Overall, therapies and diagnostic tools targeting tau pathology have a great potential for AD and other tauopathies. (c) 2013 S. Karger AG, Basel.
PMCID:3946316
PMID: 24029727
ISSN: 1660-2854
CID: 712672

Antibody Uptake into Neurons Occurs Primarily via Clathrin-dependent Fcgamma Receptor Endocytosis and Is a Prerequisite for Acute Tau Protein Clearance

Congdon, Erin E; Gu, Jiaping; Sait, Hameetha B R; Sigurdsson, Einar M
Tau immunotherapy is effective in transgenic mice, but the mechanisms of Tau clearance are not well known. To this end, Tau antibody uptake was analyzed in brain slice cultures and primary neurons. Internalization was rapid (<1 h), saturable, and substantial compared with control mouse IgG. Furthermore, temperature reduction to 4 degrees C, an excess of unlabeled mouse IgG, or an excess of Tau antibodies reduced uptake in slices by 63, 41, and 62%, respectively (p = 0.002, 0.04, and 0.005). Uptake strongly correlated with total and insoluble Tau levels (r(2) = 0.77 and 0.87 and p = 0.002 and 0.0002), suggesting that Tau aggregates influence antibody internalization and/or retention within neurons. Inhibiting phagocytosis did not reduce uptake in slices or neuronal cultures, indicating limited microglial involvement. In contrast, clathrin-specific inhibitors reduced uptake in neurons (
PMCID:3853292
PMID: 24163366
ISSN: 0021-9258
CID: 712662

Two novel Tau antibodies targeting the 396/404 region are primarily taken up by neurons and reduce Tau protein pathology

Gu, Jiaping; Congdon, Erin E; Sigurdsson, Einar M
Aggregated Tau proteins are hallmarks of Alzheimer disease and other tauopathies. Recent studies from our group and others have demonstrated that both active and passive immunizations reduce Tau pathology and prevent cognitive decline in transgenic mice. To determine the efficacy and safety of targeting the prominent 396/404 region, we developed two novel monoclonal antibodies (mAbs) with distinct binding profiles for phospho and non-phospho epitopes. The two mAbs significantly reduced hyperphosphorylated soluble Tau in long term brain slice cultures without apparent toxicity, suggesting the therapeutic importance of targeting the 396/404 region. In mechanistic studies, we found that neurons were the primary cell type that internalized the mAbs, whereas a small amount of mAbs was taken up by microglia cells. Within neurons, the two mAbs were highly colocalized with distinct pathological Tau markers, indicating their affinity toward different stages or forms of pathological Tau. Moreover, the mAbs were largely co-localized with endosomal/lysosomal markers, and partially co-localized with autophagy pathway markers. Additionally, the Fab fragments of the mAbs were able to enter neurons, but unlike the whole antibodies, the fragments were not specifically localized in pathological neurons. In summary, our Tau mAbs were safe and efficient to clear pathological Tau in a brain slice model. Fc-receptor-mediated endocytosis and the endosome/autophagosome/lysosome system are likely to have a critical role in antibody-mediated clearance of Tau pathology.
PMCID:3829157
PMID: 24089520
ISSN: 0021-9258
CID: 712162