text:
\r\n\tThis book intends to provide readers with a comprehensive overview of the basic mechanisms of siRNA, progress in the development of safer delivery vehicles, current developments in siRNA-based therapeutics and state-of-the-art technology and platforms with evidence-based clinical applications of siRNA.",isbn:"978-1-78985-356-8",printIsbn:"978-1-78985-355-1",doi:null,price:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"c29da6fa3e8417ec0dde73b0cb79a7d0",bookSignature:"Dr. Muhammad Nawaz",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8132.jpg",keywords:"RNAi, siRNA, biogenesis, RISC, gene expression regulation,\r\nefficiency of encapsulation, exogenous loading, siRNA delivery methods and systems, Analytical methodology, Delivery efficiency, cytosolic release, targeted gene silencing,Therapeutic applications of siRNA",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 15th 2019",dateEndSecondStepPublish:"March 8th 2019",dateEndThirdStepPublish:"May 7th 2019",dateEndFourthStepPublish:"July 26th 2019",dateEndFifthStepPublish:"September 24th 2019",remainingDaysToSecondStep:"16 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,editors:[{id:"199581",title:"Dr.",name:"Muhammad",middleName:null,surname:"Nawaz",slug:"muhammad-nawaz",fullName:"Muhammad Nawaz",profilePictureURL:"https://mts.intechopen.com/storage/users/199581/images/system/199581.jpg",biography:"Dr. Nawaz is an academic researcher at the University of Gothenburg, Sweden, having expertise in the area of Biochemistry & Molecular Biology. Dr. Nawaz did his PhD from University of Sao Paulo, Ribeirao Preto Medical School (Brazil), where he worked on transcriptomic and microRNAs (miRNAs) profiling in the malignant progression of brain tumors (gliomas) with an aim to identify potential therapeutic targets and non-invasive biomarkers. During his PhD, Dr. Nawaz was granted with fellowship from FAPESP (the highest ranked funding body in Brazil), and was also awarded with Science without borders mobility award from Brazilian higher education agency (CAPES) to join the University of Gothenburg for one year PhD exchange, where he worked on mechanisms of packaging therapeutic RNAs into exosomes, which are now used as RNA delivery vehicles. Later, he continued his Postdoc at the University of Gothenburg. He has also served community services, and is the founder of Biochemists Association QUA Islamabad (BAQI), and is junior member of international society for extracellular vesicles (ISEV). Dr. Nawaz has won several awards, both from Brazil, and Sweden, has participated in several international conferences, and has published research papers in reputed peer reviewed international journals. He also serves as reviewer for different journals (https://publons.com/author/1268786/). \nCurrently, Dr. Nawaz is working on stem cell-derived exosomes in tissue repair and regenerative medicine and using exosomes as RNA delivery vehicles and Drug Delivery (siRNA, RNAi, and mRNA based therapy).",institutionString:"University of Gothenburg",position:"Researcher",outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Göteborg University",institutionURL:"http://www.gu.se/",country:{name:"Sweden"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"286446",firstName:"Sara",lastName:"Bacvarova",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"email@example.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6694",title:"New Trends in Ion Exchange Studies",subtitle:null,isOpenForSubmission:!1,hash:"3de8c8b090fd8faa7c11ec5b387c486a",slug:"new-trends-in-ion-exchange-studies",bookSignature:"Selcan Karakuş",coverURL:"https://cdn.intechopen.com/books/images_new/6694.jpg",editedByType:"Edited by",editors:[{id:"206110",title:"Dr.",name:"Selcan",surname:"Karakus",slug:"selcan-karakus",fullName:"Selcan Karakus"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6879",title:"Embryonic Stem Cells",subtitle:null,isOpenForSubmission:!1,hash:"20ac2d2d721a459fad5de55fff067784",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/6879.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6919",title:"Tumorigenesis",subtitle:null,isOpenForSubmission:!1,hash:"46d3363b21f482c9a22ba72cca9ec4c0",slug:null,bookSignature:"Dr. Nevim Aygun",coverURL:"https://cdn.intechopen.com/books/images_new/6919.jpg",editedByType:null,editors:[{id:"195365",title:"Dr.",name:"Nevim",surname:"Aygun",slug:"nevim-aygun",fullName:"Nevim Aygun"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6986",title:"Telomerase and non-Telomerase Mechanisms of Telomere Maintenance",subtitle:null,isOpenForSubmission:!1,hash:"79b7d4e97e1e0722f4ce1309a2088be3",slug:null,bookSignature:"Dr. Tammy A. Morrish",coverURL:"https://cdn.intechopen.com/books/images_new/6986.jpg",editedByType:null,editors:[{id:"275021",title:"Dr.",name:"Tammy A.",surname:"Morrish",slug:"tammy-a.-morrish",fullName:"Tammy A. Morrish"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7010",title:"Contemporary Methods in Protein Purification and Current Applications",subtitle:null,isOpenForSubmission:!1,hash:"a4788e440ba8605ccb2db109739add40",slug:null,bookSignature:"Prof. Yusuf Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/7010.jpg",editedByType:null,editors:[{id:"158492",title:"Prof.",name:"Yusuf",surname:"Tutar",slug:"yusuf-tutar",fullName:"Yusuf Tutar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7026",title:"Proteases in Biology and Disease",subtitle:null,isOpenForSubmission:!1,hash:"a23407678402198a2ae5a35e319c9bd5",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/7026.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9343",title:"Trace Elements",subtitle:null,isOpenForSubmission:!1,hash:"e10cc05ba08d4f801babb2e740a4151f",slug:null,bookSignature:"",coverURL:"//cdnintech.com/web/frontend/www/assets/cover.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9352",title:"Proteoforms",subtitle:null,isOpenForSubmission:!1,hash:"01de5eca191ce82b60e486a6b8fd2d32",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/9352.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8030",title:"Amino Acid",subtitle:null,isOpenForSubmission:!0,hash:"76cbf449d1ca4a4c4f7273824451d192",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/8030.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8038",title:"Pseudomonas aeruginosa - a Versatile Player",subtitle:null,isOpenForSubmission:!1,hash:"308d6be5ffbb4b2caa0a7c4146a7737d",slug:null,bookSignature:"Dr. Dinesh Sriramulu",coverURL:"https://cdn.intechopen.com/books/images_new/8038.jpg",editedByType:null,editors:[{id:"91317",title:"Dr.",name:"Dinesh",surname:"Sriramulu",slug:"dinesh-sriramulu",fullName:"Dinesh Sriramulu"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"28731",title:"Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic",doi:"10.5772/30311",slug:"universal-screening-for-thyroid-disorders-in-pregnancy-experience-of-the-czech-republic",body:null,keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/28731.pdf",chapterXML:null,downloadPdfUrl:"/chapter/pdf-download/28731",previewPdfUrl:"/chapter/pdf-preview/28731",totalDownloads:2221,totalViews:71,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"March 16th 2011",dateReviewed:"September 1st 2011",datePrePublished:null,datePublished:"February 17th 2012",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/28731",risUrl:"/chapter/ris/28731",book:{slug:"a-new-look-at-hypothyroidism"},signatures:"Eliska Potlukova, Jan Jiskra, Zdenek Telicka, Drahomira Springer and Zdenka Limanova",authors:[{id:"25847",title:"Dr.",name:"Drahomira",middleName:null,surname:"Springer",fullName:"Drahomira Springer",slug:"drahomira-springer",email:"firstname.lastname@example.com",position:null,institution:null},{id:"81897",title:"Dr.",name:"Eliska",middleName:null,surname:"Potlukova",fullName:"Eliska Potlukova",slug:"eliska-potlukova",email:"email@example.com",position:"teacher, researcher",institution:{name:"Charles University Prague",institutionURL:"http://www.cuni.cz/",country:{name:"Czech Republic"}}},{id:"144191",title:"Dr.",name:"Jan",middleName:null,surname:"Jiskra",fullName:"Jan Jiskra",slug:"jan-jiskra",email:"firstname.lastname@example.com",position:null,institution:null},{id:"144192",title:"Mr.",name:"Zdenek",middleName:null,surname:"Telicka",fullName:"Zdenek Telicka",slug:"zdenek-telicka",email:"email@example.com",position:null,institution:null},{id:"144194",title:"Dr.",name:"Zdenka",middleName:null,surname:"Limanova",fullName:"Zdenka Limanova",slug:"zdenka-limanova",email:"firstname.lastname@example.com",position:null,institution:null}],sections:null,chapterReferences:null,footnotes:null,contributors:null,corrections:null},book:{id:"706",title:"A New Look at Hypothyroidism",subtitle:null,fullTitle:"A New Look at Hypothyroidism",slug:"a-new-look-at-hypothyroidism",publishedDate:"February 17th 2012",bookSignature:"Drahomira Springer",coverURL:"https://cdn.intechopen.com/books/images_new/706.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"25847",title:"Dr.",name:"Drahomira",middleName:null,surname:"Springer",slug:"drahomira-springer",fullName:"Drahomira Springer"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"28724",title:"Hypothyroidism",slug:"hypothyroidism",totalDownloads:1869,totalCrossrefCites:0,signatures:"Osama M. Ahmed and R.G. Ahmed",authors:[{id:"81312",title:"Dr.",name:"Osama",middleName:"Mohamed",surname:"Ahmed",fullName:"Osama Ahmed",slug:"osama-ahmed"},{id:"138555",title:"Associate Prof.",name:"Ahmed",middleName:null,surname:"R. G.",fullName:"Ahmed R. G.",slug:"ahmed-r.-g."}]},{id:"28725",title:"Environmental Thyroid Disruptors and Human Endocrine Health",slug:"environmental-thyroid-disruptors-human-endocrine-health",totalDownloads:2914,totalCrossrefCites:0,signatures:"Francesco Massart, Pietro Ferrara and Giuseppe Saggese",authors:[{id:"87766",title:"Dr",name:"Francesco",middleName:null,surname:"Massart",fullName:"Francesco Massart",slug:"francesco-massart"}]},{id:"28726",title:"Hashimoto's Thyroiditis",slug:"hashimoto-s-disease",totalDownloads:15278,totalCrossrefCites:0,signatures:"Arvin Parvathaneni, Daniel Fischman and Pramil Cheriyath",authors:[{id:"53484",title:"Dr.",name:"Daniel",middleName:null,surname:"Fischman",fullName:"Daniel Fischman",slug:"daniel-fischman"},{id:"58704",title:"Dr.",name:"Pramil",middleName:null,surname:"Cheriyath",fullName:"Pramil Cheriyath",slug:"pramil-cheriyath"},{id:"77506",title:"Dr",name:"Arvin",middleName:null,surname:"Parvathaneni",fullName:"Arvin Parvathaneni",slug:"arvin-parvathaneni"}]},{id:"28727",title:"Hashimoto's Disease",slug:"hashimoto-s-disease-",totalDownloads:2400,totalCrossrefCites:0,signatures:"Noura Bougacha-Elleuch, Mouna Mnif-Feki, Nadia Charfi-Sellami, Mohamed Abid and Hammadi Ayadi",authors:[{id:"92450",title:"Prof.",name:"Hammadi",middleName:null,surname:"Ayadi",fullName:"Hammadi Ayadi",slug:"hammadi-ayadi"},{id:"92451",title:"Dr.",name:"Noura",middleName:null,surname:"Bougacha-Elleuch",fullName:"Noura Bougacha-Elleuch",slug:"noura-bougacha-elleuch"},{id:"141438",title:"Prof.",name:"Mouna",middleName:null,surname:"Mnif-Feki",fullName:"Mouna Mnif-Feki",slug:"mouna-mnif-feki"},{id:"141439",title:"Dr.",name:"Nadia",middleName:null,surname:"Charfi-Sellami",fullName:"Nadia Charfi-Sellami",slug:"nadia-charfi-sellami"},{id:"141440",title:"Prof.",name:"Mohamed",middleName:null,surname:"Abid",fullName:"Mohamed Abid",slug:"mohamed-abid"}]},{id:"28728",title:"Hashimoto's Disease - Involvement of Cytokine Network and Role of Oxidative Stress in the Severity of Hashimoto's Thyroiditis",slug:"hashimoto-s-disease-involvement-of-cytokine-network-and-role-of-oxidative-stress-in-the-severity-of-",totalDownloads:2712,totalCrossrefCites:2,signatures:"Julieta Gerenova, Irena Manolova and Veselina Gadjeva",authors:[{id:"84203",title:"PhD.",name:"Joulieta",middleName:"Borisova",surname:"Gerenova",fullName:"Joulieta Gerenova",slug:"joulieta-gerenova"},{id:"91539",title:"MSc.",name:"Irena",middleName:null,surname:"Manolova",fullName:"Irena Manolova",slug:"irena-manolova"},{id:"91541",title:"Prof.",name:"Veselina",middleName:null,surname:"Gadjeva",fullName:"Veselina Gadjeva",slug:"veselina-gadjeva"}]},{id:"28729",title:"Different Faces of Chronic Autoimmune Thyroiditis in Childhood and Adolescence",slug:"different-faces-of-chronic-autoimmune-thyroiditis-in-childhood-and-adolescence",totalDownloads:1342,totalCrossrefCites:0,signatures:"Ljiljana Saranac and Hristina Stamenkovic",authors:[{id:"61300",title:"Dr.",name:"Ljiljana",middleName:null,surname:"Saranac",fullName:"Ljiljana Saranac",slug:"ljiljana-saranac"},{id:"92399",title:"Prof.",name:"Hristina",middleName:null,surname:"Stamenkovic",fullName:"Hristina Stamenkovic",slug:"hristina-stamenkovic"}]},{id:"28730",title:"Treatment of Graves' Disease During Pregnancy",slug:"treatment-of-graves-disease-during-pregnancy",totalDownloads:3157,totalCrossrefCites:0,signatures:"Teresa M. Bailey",authors:[{id:"91453",title:"Prof.",name:"Teresa",middleName:null,surname:"Bailey",fullName:"Teresa Bailey",slug:"teresa-bailey"}]},{id:"28731",title:"Universal Screening for Thyroid Disorders in Pregnancy: Experience of the Czech Republic",slug:"universal-screening-for-thyroid-disorders-in-pregnancy-experience-of-the-czech-republic",totalDownloads:2221,totalCrossrefCites:0,signatures:"Eliska Potlukova, Jan Jiskra, Zdenek Telicka, Drahomira Springer and Zdenka Limanova",authors:[{id:"25847",title:"Dr.",name:"Drahomira",middleName:null,surname:"Springer",fullName:"Drahomira Springer",slug:"drahomira-springer"},{id:"81897",title:"Dr.",name:"Eliska",middleName:null,surname:"Potlukova",fullName:"Eliska Potlukova",slug:"eliska-potlukova"},{id:"144191",title:"Dr.",name:"Jan",middleName:null,surname:"Jiskra",fullName:"Jan Jiskra",slug:"jan-jiskra"},{id:"144192",title:"Mr.",name:"Zdenek",middleName:null,surname:"Telicka",fullName:"Zdenek Telicka",slug:"zdenek-telicka"},{id:"144194",title:"Dr.",name:"Zdenka",middleName:null,surname:"Limanova",fullName:"Zdenka Limanova",slug:"zdenka-limanova"}]},{id:"28732",title:"Thyroid Function Following Treatment of Childhood Acute Lymphoblastic Leukemia",slug:"thyroid-function-following-treatment-of-childhood-acute-lymphoblastic-leukemia",totalDownloads:2232,totalCrossrefCites:0,signatures:"Elpis Vlachopapadopoulou, Vassilios Papadakis, Georgia Avgerinou and Sophia Polychronopoulou",authors:[{id:"83171",title:"Dr.",name:"Elpis-Athina",middleName:null,surname:"Vlachopapadopoulou",fullName:"Elpis-Athina Vlachopapadopoulou",slug:"elpis-athina-vlachopapadopoulou"},{id:"96300",title:"Dr.",name:"Vassilios",middleName:null,surname:"Papadakis",fullName:"Vassilios Papadakis",slug:"vassilios-papadakis"},{id:"127329",title:"Dr.",name:"Georgia",middleName:null,surname:"Avgerinou",fullName:"Georgia Avgerinou",slug:"georgia-avgerinou"},{id:"127330",title:"Dr.",name:"Sophia",middleName:null,surname:"Polychronopoulou",fullName:"Sophia Polychronopoulou",slug:"sophia-polychronopoulou"}]},{id:"28733",title:"Congenital Hypothyroidism and Thyroid Cancer",slug:"congenital-hypothyroidism-and-thyroid-cancer",totalDownloads:1888,totalCrossrefCites:0,signatures:"Minjing Zou and Yufei Shi",authors:[{id:"84262",title:"Dr.",name:"Yufei",middleName:null,surname:"Shi",fullName:"Yufei Shi",slug:"yufei-shi"},{id:"84296",title:"Dr.",name:"Minjing",middleName:null,surname:"Zou",fullName:"Minjing Zou",slug:"minjing-zou"}]},{id:"28734",title:"Hypothyroidism and Thyroid Function Alterations During the Neonatal Period",slug:"hypothyroidism-and-thyroid-function-alterations-during-the-neonatal-period",totalDownloads:1966,totalCrossrefCites:0,signatures:"Susana Ares1, José Quero, Belén Sáenz-Rico de Santiago and Gabriela Morreale de Escobar",authors:[{id:"83882",title:"Dr.",name:"Susana",middleName:null,surname:"Ares",fullName:"Susana Ares",slug:"susana-ares"},{id:"83892",title:"Prof.",name:"Jose",middleName:null,surname:"Quero",fullName:"Jose Quero",slug:"jose-quero"},{id:"83893",title:"Prof.",name:"Gabriela",middleName:null,surname:"Morreale De Escobar",fullName:"Gabriela Morreale De Escobar",slug:"gabriela-morreale-de-escobar"}]},{id:"28735",title:"Neonatal-Prepubertal Hypothyroidism on Postnatal Testis Development",slug:"neonatal-prepubertal-hypothyroidism-and-postnatal-testis-development",totalDownloads:1632,totalCrossrefCites:0,signatures:"S.M.L. Chamindrani Mendis-Handagama",authors:[{id:"95387",title:"Prof.",name:"Lilitha",middleName:null,surname:"Mendis-Handagama",fullName:"Lilitha Mendis-Handagama",slug:"lilitha-mendis-handagama"}]},{id:"10310",title:"Analysis of Directive Sensor Influence on Array Beampatterns",slug:"analysis-of-directive-sensor-influence-on-array-beampatterns",totalDownloads:1160,totalCrossrefCites:3,signatures:"Lara del Val, Alberto Izquierdo, Maria I. Jimenez, Juan J. Villacorta and Mariano Raboso",authors:[{id:"3646",title:"Dr.",name:"Mariano",middleName:null,surname:"Raboso Mateos",fullName:"Mariano Raboso Mateos",slug:"mariano-raboso-mateos"},{id:"4377",title:"Dr.",name:"Lara",middleName:null,surname:"Del Val",fullName:"Lara Del Val",slug:"lara-del-val"},{id:"111759",title:"Dr.",name:"María Isabel",middleName:null,surname:"Jiménez",fullName:"María Isabel Jiménez",slug:"maria-isabel-jimenez"},{id:"111760",title:"Dr.",name:"Alberto",middleName:null,surname:"Izquierdo",fullName:"Alberto Izquierdo",slug:"alberto-izquierdo"},{id:"111761",title:"Dr.",name:"Juan José",middleName:null,surname:"Villacorta",fullName:"Juan José Villacorta",slug:"juan-jose-villacorta"}]},{id:"28736",title:"Congenital Hypothyroidism due to Thyroid Dysgenesis: From Epidemiology to Molecular Mechanisms",slug:"congenital-hypothyroidism-due-to-thyroid-dysgenesis-from-epidemiology-to-molecular-mechanisms",totalDownloads:3810,totalCrossrefCites:0,signatures:"Johnny Deladoey",authors:[{id:"85240",title:"Dr.",name:"Johnny",middleName:null,surname:"Deladoey",fullName:"Johnny Deladoey",slug:"johnny-deladoey"}]},{id:"28737",title:"Consideration of Congenital Hypothyroidism as the Possible Cause of Autism",slug:"consideration-of-congenital-hypothyroidism-as-the-possible-cause-of-autism-",totalDownloads:2033,totalCrossrefCites:0,signatures:"Xiaobin Xu, Hirohiko Kanai, Masanori Ookubo, Satoru Suzuki, Nobumasa Kato and Miyuki Sadamatsu",authors:[{id:"95062",title:"Dr.",name:"Miyuki",middleName:null,surname:"Sadamatsu",fullName:"Miyuki Sadamatsu",slug:"miyuki-sadamatsu"},{id:"126988",title:"Prof.",name:"Nobumasa",middleName:null,surname:"Kato",fullName:"Nobumasa Kato",slug:"nobumasa-kato"},{id:"127428",title:"Dr.",name:"Hirohiko",middleName:null,surname:"Kanai",fullName:"Hirohiko Kanai",slug:"hirohiko-kanai"},{id:"127540",title:"Dr.",name:"Masanori",middleName:null,surname:"Ookubo",fullName:"Masanori Ookubo",slug:"masanori-ookubo"},{id:"127723",title:"Dr.",name:"Xiaobin",middleName:null,surname:"Xu",fullName:"Xiaobin Xu",slug:"xiaobin-xu"}]}]},relatedBooks:[{type:"book",id:"2077",title:"Hypothyroidism",subtitle:"Influences and Treatments",isOpenForSubmission:!1,hash:"aa00ac07d4c368d46a101476e22a9538",slug:"hypothyroidism-influences-and-treatments",bookSignature:"Drahomira Springer",coverURL:"https://cdn.intechopen.com/books/images_new/2077.jpg",editedByType:"Edited by",editors:[{id:"25847",title:"Dr.",name:"Drahomira",surname:"Springer",slug:"drahomira-springer",fullName:"Drahomira Springer"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"},chapters:[{id:"27822",title:"Hypothyroidism on Lipid Metabolism",slug:"hypothyroidism-on-lipid-metabolism",signatures:"J. Coria Mariela, V. Carmona Yamila, B. Oliveros Liliana** and S. Giménez Maria",authors:[{id:"26171",title:"Prof.",name:"Maria",middleName:null,surname:"Gimenez",fullName:"Maria Gimenez",slug:"maria-gimenez"}]},{id:"27823",title:"Hypothyroidism After Hemithyroidectomy: Incidence, Risk Factors, Natural History and Management",slug:"hypothyroidism-after-thyroid-lobectomy-incidence-risk-factors-natural-history-and-management",signatures:"Jandee Lee and Woong Youn Chung",authors:[{id:"85649",title:"Prof.",name:"Jandee",middleName:null,surname:"Lee",fullName:"Jandee Lee",slug:"jandee-lee"},{id:"90364",title:"Prof.",name:"Woong Youn",middleName:null,surname:"Chung",fullName:"Woong Youn Chung",slug:"woong-youn-chung"}]},{id:"27824",title:"Hypothyroidism and Obstructive Sleep Apnea",slug:"hypothyroidism-and-obstructive-sleep-apnea",signatures:"Suhaila E. Al-Jawder and Ahmed S. BaHammam",authors:[{id:"92435",title:"Prof.",name:"Ahmed",middleName:"Salem",surname:"BaHammam",fullName:"Ahmed BaHammam",slug:"ahmed-bahammam"},{id:"125513",title:"Dr.",name:"Suhaila",middleName:null,surname:"Al-Jawder",fullName:"Suhaila Al-Jawder",slug:"suhaila-al-jawder"}]},{id:"27825",title:"Differential Adaptations of the Hypothalamus-Pituitary-Thyroid Axis Between Food Restriction and Anorexia",slug:"differential-adaptations-of-the-hypothalamus-pituitary-thyroid-axis-between-food-restriction-and-ano",signatures:"P. de Gortari, E. Alvarez-Salas, M. Morales-Mulia and V. Alcántara-Alonso",authors:[{id:"82895",title:"Dr.",name:"Patricia",middleName:null,surname:"De Gortari",fullName:"Patricia De Gortari",slug:"patricia-de-gortari"},{id:"92350",title:"Prof.",name:"Elena",middleName:null,surname:"Alvarez",fullName:"Elena Alvarez",slug:"elena-alvarez"},{id:"92353",title:"Dr.",name:"Marcela",middleName:null,surname:"Morales-Mulia",fullName:"Marcela Morales-Mulia",slug:"marcela-morales-mulia"}]},{id:"27826",title:"Hypothyroidism in Thalassemia",slug:"hypothyroidism-in-thalassemia",signatures:"Kallistheni Farmaki",authors:[{id:"94038",title:"Dr",name:"Kallistheni",middleName:null,surname:"Farmaki",fullName:"Kallistheni Farmaki",slug:"kallistheni-farmaki"}]},{id:"27827",title:"Thyroid Disorders and Brain Natriuretic Peptide",slug:"thyroid-disorders-and-brain-natriuretic-peptide",signatures:"Hamiyet Yılmaz, Barış Pamuk, Derun Taner Ertugrul and Erdem Yaşar",authors:[{id:"63566",title:"Dr.",name:"Baris",middleName:null,surname:"Pamuk",fullName:"Baris Pamuk",slug:"baris-pamuk"},{id:"68751",title:"Dr.",name:"Derun Taner",middleName:null,surname:"Ertugrul",fullName:"Derun Taner Ertugrul",slug:"derun-taner-ertugrul"},{id:"91171",title:"Dr.",name:"Hamiyet",middleName:null,surname:"Yilmaz",fullName:"Hamiyet Yilmaz",slug:"hamiyet-yilmaz"},{id:"127420",title:"Dr.",name:"Erdem",middleName:null,surname:"Yasar",fullName:"Erdem Yasar",slug:"erdem-yasar"}]},{id:"27828",title:"Hypothyroidism, Oxidative Stress and Reproduction",slug:"hypothyroidism-oxidative-stress-and-reproduction",signatures:"Antonio Mancini, Elena Giacchi, Sebastiano Raimondo, Chantal Di Segni, Andrea Silvestrini and Elisabetta Meucci",authors:[{id:"89423",title:"Dr.",name:"Antonio",middleName:null,surname:"Mancini",fullName:"Antonio Mancini",slug:"antonio-mancini"},{id:"91824",title:"Dr.",name:"Elena",middleName:null,surname:"Giacchi",fullName:"Elena Giacchi",slug:"elena-giacchi"},{id:"91827",title:"Dr.",name:"Sebastiano",middleName:null,surname:"Raimondo",fullName:"Sebastiano Raimondo",slug:"sebastiano-raimondo"},{id:"91831",title:"Dr",name:"Andrea",middleName:null,surname:"Silvestrini",fullName:"Andrea Silvestrini",slug:"andrea-silvestrini"},{id:"91833",title:"Prof.",name:"Elisabetta",middleName:null,surname:"Meucci",fullName:"Elisabetta Meucci",slug:"elisabetta-meucci"},{id:"91834",title:"Ms.",name:"Chantal",middleName:null,surname:"Di Segni",fullName:"Chantal Di Segni",slug:"chantal-di-segni"}]},{id:"27829",title:"Neurological Complications of Hypothyroidism",slug:"neurological-complications-of-hypothyroidism",signatures:"Hande Turker, Cuneyt Turker and Nilgun Cengiz",authors:[{id:"63331",title:"Prof.",name:"Dr.Hande",middleName:null,surname:"Turker",fullName:"Dr.Hande Turker",slug:"dr.hande-turker"},{id:"91386",title:"Dr.",name:"Nilgun",middleName:null,surname:"Cengiz",fullName:"Nilgun Cengiz",slug:"nilgun-cengiz"},{id:"91388",title:"Dr.",name:"Cuneyt",middleName:null,surname:"Turker",fullName:"Cuneyt Turker",slug:"cuneyt-turker"}]},{id:"27830",title:"Causes of Hypothyroidism",slug:"causes-of-hypothyroidism",signatures:"Irena Kostic and Francesco Curcio",authors:[{id:"91958",title:"Prof.",name:"Francesco",middleName:null,surname:"Curcio",fullName:"Francesco Curcio",slug:"francesco-curcio"},{id:"91962",title:"Dr.",name:"Irena",middleName:null,surname:"Kostic",fullName:"Irena Kostic",slug:"irena-kostic"}]},{id:"27831",title:"The Role of Real-Time Thyroid Ultrasonography in the Assessment and Management of Patients with Hashimoto's Thyroiditis",slug:"use-of-real-time-thyroid-ultrasonography-in-the-diagnosis-and-management-of-hashimoto-s-thyroiditis",signatures:"Jack R. Wall and Bernard Champion",authors:[{id:"84214",title:"Prof.",name:"Jack",middleName:null,surname:"Wall",fullName:"Jack Wall",slug:"jack-wall"},{id:"147310",title:"Dr.",name:"Bernard",middleName:null,surname:"Champion",fullName:"Bernard Champion",slug:"bernard-champion"}]},{id:"27832",title:"Options of Replacement Therapy in Hypothyroidism",slug:"options-of-replacement-therapy-in-hypothyroidism",signatures:"Valentine V. Fadeyev, Galina A. Melnichenko and Tatyana Morgunova",authors:[{id:"86129",title:"Dr.",name:"Tatyana",middleName:null,surname:"Morgunova",fullName:"Tatyana Morgunova",slug:"tatyana-morgunova"},{id:"91789",title:"Prof.",name:"Valentine",middleName:null,surname:"Fadeyev",fullName:"Valentine Fadeyev",slug:"valentine-fadeyev"},{id:"91790",title:"Prof.",name:"Galina A.",middleName:null,surname:"Melnichenko",fullName:"Galina A. Melnichenko",slug:"galina-a.-melnichenko"}]},{id:"27833",title:"Hypothyroidism and Radioiodine Therapy",slug:"hypothyroidism-and-radioiodine-therapy",signatures:"Otakar Kraft",authors:[{id:"91412",title:"Dr.",name:"Otakar",middleName:null,surname:"Kraft",fullName:"Otakar Kraft",slug:"otakar-kraft"}]},{id:"27834",title:"Treatment Related Hypothyroidism, a Viewpoint from Cancer Therapy and Hematopoietic Stem Cell Transplantation",slug:"treatment-related-hypothyroidism-a-viewpoint-from-hematopoietic-cell-transplantation",signatures:"Chao-Jung Tsao and Yin-Hsun Feng",authors:[{id:"91921",title:"Dr.",name:"Chao Jung",middleName:null,surname:"Tsao",fullName:"Chao Jung Tsao",slug:"chao-jung-tsao"},{id:"91968",title:"Dr.",name:"Yin-Hsun",middleName:null,surname:"Feng",fullName:"Yin-Hsun Feng",slug:"yin-hsun-feng"}]},{id:"27835",title:"A 3,3'-Diiodothyronine Sulfate Cross-Reactive Material (Compound W), a Potential Marker for Fetal Hypothyroidism",slug:"a-3-3-diiodothyronine-sulfate-cross-reactive-material-compound-w-a-potential-marker-for-fetal-hypoth",signatures:"Sing-Yung Wu and William L. Green",authors:[{id:"84551",title:"Prof.",name:"Sing-Yung",middleName:null,surname:"Wu",fullName:"Sing-Yung Wu",slug:"sing-yung-wu"},{id:"95130",title:"Dr.",name:"William L.",middleName:null,surname:"Green",fullName:"William L. Green",slug:"william-l.-green"}]},{id:"27836",title:"Thyroid-Stimulating Hormone Regulation and Transcription in Hypothyroidism",slug:"thyroid-stimulating-hormone-regulation-and-transcription-in-hypothyroidism",signatures:"Koreaki Sugimoto and Kouki Mori",authors:[{id:"89710",title:"Prof.",name:"Koreaki",middleName:null,surname:"Sugimoto",fullName:"Koreaki Sugimoto",slug:"koreaki-sugimoto"},{id:"91207",title:"Dr.",name:"Kouki",middleName:null,surname:"Mori",fullName:"Kouki Mori",slug:"kouki-mori"}]},{id:"27837",title:"Thyroid Hormones and Motoneurons Development",slug:"thyroid-hormones-and-motoneurons-development",signatures:"Farzaneh Ganji",authors:[{id:"81783",title:"Dr.",name:"Farzaneh",middleName:null,surname:"Ganji",fullName:"Farzaneh Ganji",slug:"farzaneh-ganji"}]},{id:"27838",title:"The Clinical Spectrum of Thyrotropin Receptor Gene (TSHR) Mutations",slug:"the-clinical-spectrum-of-tsh-receptor-tshr-mutations",signatures:"Yardena Tenenbaum-Rakover",authors:[{id:"85817",title:"Dr.",name:"Yardena",middleName:null,surname:"Tenenbaum-Rakover",fullName:"Yardena Tenenbaum-Rakover",slug:"yardena-tenenbaum-rakover"}]},{id:"27839",title:"Structure and Function of the Circulatory System in Hypothyroid Patients",slug:"structure-and-function-of-the-circulatory-system-in-hypothyroid-patients-pathobiochemistry-and-patho",signatures:"Jacek Drobnik",authors:[{id:"91757",title:"Dr.",name:"Jacek",middleName:null,surname:"Drobnik",fullName:"Jacek Drobnik",slug:"jacek-drobnik"}]},{id:"27840",title:"Spirometry in Patients with Clinical and Subclinical Hypothyroidism",slug:"spirometry-in-patients-with-clinical-and-subclinical-hypothyroidism",signatures:"Gulfidan Cakmak",authors:[{id:"86825",title:"Dr.",name:"Gulfidan",middleName:null,surname:"Cakmak",fullName:"Gulfidan Cakmak",slug:"gulfidan-cakmak"}]},{id:"27841",title:"Cognitive Function in Elderly with Subclinical Hypothyroidism",slug:"cognitive-function-in-elderly-with-subclinical-hypothyroidism",signatures:"Lilia Cárdenas-Ibarra, Jesús Zacarías Villarreal-Pérez and Abraham Antonio Vázquez-García",authors:[{id:"83533",title:"Dr.",name:"Lilia",middleName:null,surname:"Cardenas-Ibarra",fullName:"Lilia Cardenas-Ibarra",slug:"lilia-cardenas-ibarra"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"58932",title:"Tauopathy",doi:"10.5772/intechopen.73198",slug:"tauopathy",body:'\n
Tauopathy is used to summarize all the diseases that the pathogenesis processes are related to tau protein. Tau is one of the most common proteins involved in neurodegenerative diseases. In many tauopathy cases, tau protein seeds and forms intracellular fibrillary tangles on itself, one of the pathological hallmarks of Alzheimer diseases [1]. The tangles formations are believed mostly due to altered posttranslational modifications of tau protein, which detaches from microtubules and binds each other forming aggregates. In several parkinsonism-associated movement disorders, including frontotemporal dementia with parkinsonism-17 (FTDP-17), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), mutations in tau have been identified, and those altered tau are prone to tangles formation [2]. The common involvement of tau protein in a range of neurological disorders makes it one of the most studied proteins. However, despite it has been studied for approximately 30 years since tau is coined as the major component of fibrillary tangles, concrete evidence that detail tauopathy in molecular and cellular levels is still limited [3], and most of the pathological data are obtained from studies using postmortem brain. Therefore, how tau protein and its dynamic changes affect the pathogenesis of various neurodegenerative diseases is still a mystery. Many outstanding questions are being stressed, including which posttranslational modifications are critical for it to gain toxicity, does other neurodegenerative diseases involved proteins interact with tau protein, which brain regions or cell types are most susceptive to the toxicity of tau and how the aggregates cause cellular dysfunction, and which forms of tau during the tangle formation process are toxic. In this process, some widely accepted concepts are being challenged. For example, traditionally, it is believed that hyperphosphorylation of tau induces it to detach from microtubule and increases its toxicity, but recent findings suggest some phosphorylations are protective instead [4, 5]. These findings will be emphasized in the following sections. Apparently, more efforts are needed before we can reach a definitive answer for these questions. Some exciting technological advances promise further exploration of some exist questions and more unexplored fields involving tau protein.\n
Tau pathology, namely fibrillary tangles, was observed way before the protein was identified. In fact, it was Alois Alzheimer who first described the heavy burdens of this never reported feature in his demented patient back to 1906 [6]. Seventy years later, tau protein was isolated as a factor that is critical for the re-polymerization of some depolymerized tubulins to form microtubules in vitro [7]. After another 10 years, a series studies confirmed that the tangles observed in AD brain are composed of tau [3, 8, 9, 10]. Since then, tau received significant attention in AD research. Nevertheless, as researchers soon realized tau pathology in a panel of neurological dysfunction, solving the underlying mechanism of tauopathy has been regarded as a unique field of neurobiology.\n
The expression of tau protein varies in different tissues, but the brain has the most abundant level. In brains, tau is predominately expressed in neurons but can also be detected in glial cells, especially in oligodendrocytes [11]. In neurons, tau proteins are mainly localized in axons, but they are not excluded from dendrites [12]. Functional analyses in vitro demonstrated that tau plays critical roles in both microtubules assembly and maintaining the structural stabilization [7, 13]. But not until recently, researchers are starting to understand the interactions between tau and microtubule in real-time by adopting different newly developed techniques. By fusing a Halo-tag, a dehalogenase modified to bind certain fluorescent ligand; tau could be labeled and monitored in live imaging [14]. With tubulins being labeled with photoactivatable green fluorescent protein (PAGFP), the interactions between tau and tubulins are viewed under total internal reflection fluorescence microscope (TIRF). With such high resolution and relatively short time frame, the live imaging revealed that tau moves on microtubule quickly without direction. In authors' words, it could "hops on and off" to another microtubule in milliseconds and moves along a microtubule with little dwindle time [14, 15]. In another study, under transmission electron microscope (TEM), it was found that tau could promote the microtubule assemble by laterally crosslinking protofilaments [13]. Moreover, tau showed a preference to bind GDP-tubulin over GTP-tubulin, but the reason behind it is not understood [13].\n
Tau is encoded by the gene MAPT (microtubule-associated protein tau), which is located on chromosome 17q21. MAPT has 15 exons, and the alternative splicing of the mRNA resulted in six different isoforms. The longest one among these has 441 amino acids, which is often referred as full-length tau. In late 1980s, the basic protein structure of tau was defined [16, 17], and it was realized that the C-terminus of tau protein contains repeated domains responsible for the binding of microtubules [17]. The basic structure and functions of each functional region of it are summarized as follow:\n
On the N terminal side (1–150), it has two N-terminal domains. Each has 29 amino acids, one from 45 to 74 and another from 75 to 103. The physiological functions of N terminal domain are largely unknown, and speculations on that including it could play roles in signal transduction as tau could co-immunoprecipitated with phospholipase C gamma through the binding sites within N terminus [18].\n
The N terminal side is followed by two proline-rich domains, one from 151 to 198 followed by another from 199 to 243. Studies showed that this region interacts with src kinase family members, such as fyn serving for signal transductions [19, 20]. Furthermore, it was shown that tau could interact with beta and gamma actins, which are the subtypes of actins commonly seen in neurons [21]. A panel of different truncated and or mutated tau was generated to test the interactions of it with actins, and it was found that the proline-rich regions were responsible for this interaction [21].\n
The proline-rich region is followed by microtubule binding region (244–370), which is composed of four repeated domains and each one of them contains 18 highly conserved amino acids. The microtubule binding region directly binds to tubulin, which plays the most critical role in microtubule interaction [22]. Because the N terminal side does not bind to microtubule and was thought to interact with other proteins, the N terminal side plus the first proline-rich domain is often referred as projection domain of tau. The rest residues, including the second proline-rich domain and microtubule binding domains as well as the C terminal tail, are often referred as microtubule assembly domain [23].\n
Because the full-length tau has all these N terminal regions (2 N) and C terminal repeats (4R), it is also referred as "2N4R" tau. The rest of other tau isoforms found in brain are the combinations of either lacks one (the second N terminal domain; 1 N) or two N terminal domains (0 N) or does not contain the second microtubule-binding domain (3R). Therefore, isoforms "1N4R", "0N4R", "2N3R", "1N3R," and "0N3R" are simply denoting the major functional domains of tau [22, 23]. The dominate forms found in human brain are 2N4R and 2N3R. Under physiological conditions, the ratio of isoforms with 4R and 3R is around 1 [24]. While in pathological conditions, the expression of tau isoforms could favor one form, especially 2N4R for most tauopathies. Researchers have long noticed the ratio alterations in disease conditions, but the exact meaning and the reason behind this change are still unknown [25].\n
Under physiological condition, tau exists in an unfolded state, and 80% of the proteins interact with microtubule in neurons [22, 26]. When tau is not interacting with other proteins, it may curl on its own, and this random curled state is believed important for preventing interactions with other tau proteins by masking the possible interacting sites [27, 28]. The protein itself is bipolar; the N-terminal side is highly negatively charged in normal physiology, while the proline-rich domain and C-terminal end are positively charged, allowing it to interact with the negatively charged C-terminal of tubulins [22, 29]. Various posttranslational modifications could alter its charge. Paired helical filaments (PHFs) are relatively acidic compared to normal full-length tau, which is believed due to the phosphorylation of the amino acid residues [30, 31]. Tau is also very hydrophilic, containing only a small portion of hydrophobic residues [27]. Both the net charge changes and a possible shift from being hydrophilic to hydrophobic are speculated of contributing to its aggregation behavior under pathological conditions [28, 31]. Also, normal tau proteins only exhibit transient secondary structures [27]. Phosphorylation of certain residues may prompt tau to form secondary structures, which is revealed by pseudophosphorylation of all the residues that could be recognized by phospho-tau specific antibodies AT8, AT100, and PHF1 and are shown by the structural changes in nuclear magnetic resonance spectroscopy [32]. But how normal tau proteins are transformed to form aggregates remains a mystery.\n
Given that tau may exist in various forms and structures, one shall be mindful not to overstate the possible role of tau based on data derived from truncated/engineered tau, which may only have the N terminal side or the C terminal side [18, 33, 34, 35]. Nevertheless, we have gained more understanding of tau and its function from previous works, but better manipulations are needed before we can be comfortable about applying those bench-side results to tauopathies treatment.\n
Tauopathies feature a variety of pathological brain defects, such as neurites dystrophy, cell loss of certain brain regions, and brain shrinkage. The patients show associated symptoms like the decline of cognitive function, memory loss, and defects of the visual system. In the postmortem brains of most affected patients, tau aggregations are commonly found.\n
The fibrillar tangle is the hallmark of tauopathy. The formation process of this aberrant salient could generally be categorized into several stages described as follow:
Step 1. Conformational change of tau: Certain sites phosphorylation and other posttranslational modifications or genetic mutation of MAPT rendering tau bind to tubulins with reduced affinity and detaches from microtubules no longer support the microtubule assemble, increasing the free tau protein pool [22, 36].
Step 2. Oligomer formation: The detached tau proteins form globular oligomers, which are composed of 40 monomers in vitro in the presence of heparin [37]. The mainstream opinion speculates that the detached/modified tau proteins, especially the hyperphosphorylated types, are prone to interact with each other. The phosphorylation on the residues of C-terminal and proline-rich domains neutralizes the charges of the region and reduces the net charge of the protein by which it may contribute to losing the natively unfolded property and prohibit the intramolecular interactions of tau protein [22, 38, 39]. On the other hand, it was reported that the two cysteine residues on tau, cysteine-291 and cysteine-322, play a pivotal role in the tau dimerization [40] because oxidation of the residues may lead to the disulfide bond formation between tau monomers, which potentially seeds for the oligomerization process. This theory is supported by the frequent observation of oxidative stress in tauopathies [41]. Moreover, a recent study showed a compound which could effectively inhibit heparin-induced tau oligomerization was through its interaction with the cysteine residues [37]. However, tau can also form cysteine-independent oligomers [40]. Another recent study adopted tau fragment (aa. 297–391), which is the core of PHF, to study the role of cysteine in the polymerization of tau in the absence of heparin [42]. The results showed that replacement of the cysteine residue or in the presence of reducing agents, the polymerization process was accelerated rather than decelerated [42].
It is noteworthy that most of these studies used anionic agents like heparin to induce the oligomerization of different recombinant tau isoforms or fragments to test the intrinsic properties and the effects of the modifications in vitro. But to what extent could this artificially induced tau oligomerization reflects the real pathological process is questionable. A recent study showed that heparin-induced recombinant tau tangles have little seeding ability in the wild-type mouse. In contrast, tau tangles isolated from patients have a strong seeding ability, and the pathology could spread quickly to different brain regions, shedding lights on the difference between in vitro generated tau tangles and in situ harvested tau tangles [43].
Step 3. PHF formation: Tau oligomers may further develop into more complex structures like PHF or straight filaments (SF) [44]. It has been shown that in different tauopathies, the ratio of PHF/SF and their sizes may vary [45, 46]. For example, in Alzheimer's disease, PHF is more commonly observed than SF [45]. On the other hand, in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and pick's disease (PiD), SF is predominately found [46]. In certain cell types beyond neurons, tau inclusions may exhibit different morphologies and have been given different names to describe their shapes [47]. With the help of Cryo-Electron Microscopy (Cryo-EM), we are now able to identify the structures with high resolutions [48]. It becomes clear that the cores of the filaments are composed of eight β-sheets which requires some hydrophobic interactions between individual peptides; the difference between PHF and SF is due to the lateral interactions between the sheets. However, disulfide bonds formed in the structures remain to be determined [48]. The β-sheets formed in tau oligomers and PHF could be detected with thioflavin T or S staining [28].
As mentioned above, tau inclusions are found in different types of cells in different tauopathies. In Alzheimer's disease (AD), tau inclusions are found in neurons as neurofibrillary tangles (NFT). While in many other tauopathies, the inclusions are found both in neurons and glia cells. Also, the compositions of the inclusions are different. In many tauopathies, the inclusions are mainly composed by 4R tau, while in PiD, 3R tau is the dominant form in the inclusions. In AD, the ratio of 3R/4R is close to 1 albeit the expression favors 2N4R [46]. How the different tau tangles are constructed and what the chemical and physical factors attributing the assembled pattern are still an enigma. Moreover, the locations where the aggregates are first found are also different, following different transmission pathways [46]. Together these indicate that although tau aggregate is the hallmark for all tauopathies, the properties of the inclusions are different and the factors that trigger various pathological changes may also be different [43, 46].\n
Normally, the lifetime of tau is short. It was tested in cultured cells that the lifetime of tau is within 24 hours [49, 50]. It is presumed that tau proteolysis is mainly controlled by proteasomes degradation and in vitro studies also support this notion [51]. Since many endogenous proteolytic enzymes can cleave tau proteins, it is likely there is some coordination which may exist among them and also with the proteasomes [51]. Nevertheless, in tau pathology, the turnover time for tau significantly increased. It has been reported that tau phosphorylation inhibits the protein degradation [52], which could explain its pathogenic link. Recently, studies showed autophagy is involved in the digestion of tau, especially for those bulky inclusions that are probably hard to be digested by the proteasome [53]. It was found hyperphosphorylated tau co-localized with LC3 positive vesicles, a critical autophagy adaptor protein, in postmortem brains of different tauopathies [54]. More importantly, many evidence directly shows that both proteasome and autophagy systems are impaired in tauopathies, likely resulting from the assault of tau aggregation [55, 56].\n
For proteasome-mediated degradation of tau, different studies have shown that proteasome activities are decreased in tauopathies. Both in a tauopathy animal model or AD brains, isolated tau of sarkosyl-insoluble fraction was co-immunoprecipitated with proteasome subunits [57, 58]. Furthermore, incubating proteasome with fibrillar tau or tau oligomers decreased the activities of the proteasome, whereas when it was incubated with monomer tau, the activities were not affected, demonstrating that pathological tau might cause proteasome dysfunction [57]. It was observed that the ubiquitinated protein levels are increased in a tauopathy model, and PHF tau was also ubiquitinated in both animal models and AD brains [57, 59, 60]. While these results demonstrate a nice correlation between proteasome function and tau degradation, whether the turnover of normal or pathological tau depends on proteasome or not is still unclear [61].\n
For autophagy, it was observed that the dystrophic neuritis of postmortem AD brains contains huge amounts of autophagic-like vacuoles, which are presumably to be autophagosome or autolysosomes. These observations imply a significant upregulation of autophagy activities preceded by certain stimuli like cytoskeletal dysregulation or oxidative stress, likely causing the neurons to initiate apoptosis and contribute to neurites dystrophy [55, 56, 62]. Dense lysosome proteases staining results in AD brains also indicate defective degradation of major intracellular protein aggregates. Moreover, in the familial AD, presenilin 1 mutation is one of the most common mutations causing the disease. Traditionally, it is believed the pathogenic mechanism is that the expression of presenilin 1 mutations results in the generation of Amyloid-beta, as this molecule constitutes the active domain of γ-Secretase. However, presenilin 1 also plays a critical role in autophagy that functions as an ER chaperon transporting enzyme subunit critical for lysosome protease activation. Deletion of presenilin 1 could abolish autophagy [56]. All these results support the notion that tau aggregation may cause upregulation of autophagy activity.\n
There are two forms of tauopathy, familial and sporadic. Familial tauopathy is linked with genetic mutations of tau, and sporadic tauopathy is often associated with altered posttranslational modifications. Since the pathogenesis of the two forms is different, so they are discussed separately in the sections below.\n
Genetic mutations of tau can cause familial tauopathies, which are commonly found in frontal temporal dementia (FTD), including a range of clinical conditions like Pick's disease, corticobasal dementia, and progressive supranuclear palsy [63, 64]. Mutations of tau were first discovered in the late 1990s in inherited FTD families [65], and it was the first known monogenic mutations that could cause FTD [63, 64]. Epidemiological surveys showed MAPT mutations are responsible for 5–20% FTD cases [63]. Since MAPT is localized to chromosome 17 and the subject showed FTD with parkinsonism syndrome, it was named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) to refer tau mutations-associated FTD [66]. More than a hundred tau mutations have been identified, and not all of them are pathogenic. A detailed mutations list and their associated impacts can be found online at
Pathogenic tau mutations typically result in either RNA splicing variation causing the ratio change of 3R/4R or a structure change, which will further affect its binding affinity with microtubule and other proteins or promote its self-assembly [66, 67, 69]. The mutation sites cover the whole protein and could also be in the introns affecting the RNA splicing [67]. Some much more common mutations have been selected in generating transgenic models for studying tauopathies [70]. To date, 28 tauopathy mouse models have been reported according to
Transgenic expression of normal human tau in mouse models with either 3R or 4R forms were unable to induce significant pathological changes [75]. While with strong pan-neuronal promoters could induce more pathological features, this approach also raises a concern of overwhelmed tau expression, which may lead to possible artificial effects by causing heavy burdens on protein degradation systems, which obviously deviated from the progressive pathogenesis that is responsible for the sporadic tauopathy [75, 76, 77]. Notably, a recent study created transgenic mice expressing an N-terminal truncated tau under the control of human tau promoter so to mimic the normal expression level and by which recapitulated some major pathological features of tauopathies [76]. The authors claimed that a similarly truncated tau could be found in postmortem progressive supranuclear palsy brains, which makes this finding quite interesting.\n
In comparison, expressing disease-linked mutant tau can induce more pronounced pathological effects, and some of the models are widely used in basic or pre-clinical research settings if not in combined with other tauopathy-related protein expression [67, 70, 75, 77]. The most commonly adopted tau mutations in transgenic animal models are P301L, P301S, R406W, and V337 M [59, 77]. All these mutants were found in FTD patients, and their expression showed reduced binding affinity to the microtubule. Importantly, all of them could efficiently induce tau filaments formations in mouse models, although the composition of the filaments may be different for different tau mutations [66, 70]. Among them, three mouse models stand out in terms of their wide usage in basic research, as well as in the pre-clinical tests of drug development. These are P301L, PS19, and rTg4510 (r for regulatable), all of which were developed in the mid-2000s [78, 79, 80]. P301L mice overexpress 2N4R tau with P301L mutation under the pan-neuronal driver Thy1 [78]. PS19 mice overexpress 1N4R tau with P301S mutation driven by mouse prion protein promoter [79], and rTg4510 adopts the tet-off system to overexpress 0N4R tau bearing P301L mutation only in the absence of tetracycline that controlled by Ca2+/calmodulin-dependent protein kinase II (CAMKII) promoter [80]. In general, rTg4510 and PS19 mice show more massive pathology burdens in comparison with to P301L. Although overt tau aggregations were observed in all three types of mice and showed cognitive defects, only rTg4510 and PS19 were reported to induce significant neuronal loss [79, 80]. PS19 mice showed severe hippocampus shrinkage at the age of 9 months, while rTg4510 mice showed gross forebrain atrophy at the age of 10 months [79, 80]. It is noteworthy that human tau expression levels were several times higher than the endogenous mouse tau levels for all three models [78, 79, 80].\n
These data collectively show that while significant tau aggregates can be induced by expressing mutant tau, the models are different from sporadic tauopathy, especially in terms of studying the pathogenesis and treatment methods for tauopathy with a mouse. Another major concern is related to the modulation of endogenous enzymes at the time of human tau expression, which is an issue difficult to control. Some key features related to general pathogenesis process were missed from the transgenic mice models, including robust tau propagation and significant cell apoptosis [48, 81]. In one study, by injecting insoluble tau to mouse hippocampus, it was found that the seeding and propagation ability of the synthesized insoluble tau are much weaker than the insoluble fraction of isolated tau from the AD in vivo [48]. Together, it shows there is still a long way to go before using these animal models to find a strategy for detour tauopathy.\n
Recent advances in human stem cell research may provide a solution for tauopathy and related research. By grafting human stem cell-derived neuron to express amyloid-beta in mouse brain, a study revealed that the human neurons are more susceptible to the toxicity of amyloid-beta than mouse neurons [81]. This observation proved the discrepancy of cells from the two organisms. Therefore, if the quality of the grafted cells and the surrounding microenvironment represent the physiological conditions in the human brain, shall we also expect human neurons are more susceptible to the toxicity of tau?\n
Most patients who suffer from tauopathies carry wild-type MAPT. Therefore, posttranslational modifications of tau are believed to be the key of tau pathogenesis and have been the major area of tauopathy research for years. Understanding the posttranslational modifications of tau not only helps us to pin down the pathogenic mechanism but also offers a viable path for drug screen by targeting certain enzymes that modifying tau. As mentioned in the above sections, altered posttranslational modifications of tau could render the protein to lose its native unfolded structure and by which to promote aggregate formation. In this process, the modifications also changed the interactions between tau and other proteins in addition to tubulins. So far, 10 types of tau posttranslational modifications have been documented [82], among which phosphorylation and truncation are most found, representing the majority of the modifications, while other modifications (ubiquitylation, oxidation, glycosylation, glycation, nitration, acetylation, and sumoylation) are either not often discussed in this setting or just recently founded. In total, over 100 sites on a tau protein have been proposed that could be modified if not considering the truncation [83].\n
In one of the pioneer studies aimed to prove that neurofibrillary tangles are made of tau, the researchers found treating the tissue section with phosphatase could dramatically increase the antibody labeling of tau on the tangles [9], and the researchers coined the staining as "atypical phosphorylated" tau. Since then, the "hyperphosphorylated" tau under pathological conditions received a great deal of attention. Many protein kinases have been proposed to play roles in tau phosphorylation, and some of them have been confirmed by in vivo studies [9, 84]. Recent developments have proposed to try out some kinase inhibitors as potential tauopathy therapeutics [85]. For a 2N4R tau protein, it consists of 45 serine residues, 35 threonine residues, 12 histidine residues, and 5 tyrosine residues. Current postulated phosphorylation sites have essentially covered most of the available sites, and indeed many of these residues are found being phosphorylated under physiological conditions. Therefore, the widespread, and likely dynamic, tau phosphorylation appears to serve for certain uncovered functions. Nevertheless, it also indicates that the differences in general phosphorylation and changes of phosphorylation state in certain residues may play a critical role in tauopathies [83, 84]. Moreover, hyperphosphorylated tau could also be detected in other pathological conditions aside from tauopathy. It was found that phosphorylated tau proteins are co-aggregated with alpha-synuclein in Parkinson disease and Lewy bodies dementia [86]. In some reports, phosphorylated tau aggregation can be found in Huntington disease and amyotrophic lateral sclerosis brains [87, 88]. In traumatic brain injury patients, the levels of phosphorylated tau, but not total tau, are significantly increased [89]. Recently, it is also suspected that tau phosphorylation may play a role in type 2 diabetes, rendering the patients incline to have cognitive defects [90]. These data collectively indicate hyperphosphorylation of tau has a strong correlation with a variety of brain pathologies, not just tauopathies.\n
However, the scenario of pathogenesis in tau hyperphosphorylation is more than merely the activation of some kinases or down-regulation of some phosphatase. As a matter of fact, different kinases are interacting, regulating, and even competing with each other for acting or interfering on same sites [91, 92], it is conceivable that the dynamics of transferring/removing phosphate groups on tau protein could be complex. Besides, kinases have multiple substrates, and some of them have important roles in normal cell functions [91]. The activities change of a kinase could lead to a domino effect toward the change of cellular activities. Last but not least, not all phosphorylations are toxic as some of them are required for normal tau functions, and certain sites phosphorylation may even serve as a protective effect in tauopathies [4, 5]. Therefore, a systemic dissection of disease-prone tau phosphorylations and their regulation is a pre-requisite before aiming such complex regulation for a therapeutic exploration.\n
To study the phosphorylations, many antibodies recognizing specific phosphorylated residues on tau have been generated, and a list can be found on
It is well acknowledged that glycogen synthase kinase 3 beta (GSK3β) plays a pivotal role in tau hyperphosphorylation [96, 97]. An early study showed that recombinant tau and microtubule-associated GSK3β that were harvested from bacterial lysates could be co-eluted in immunochromatography with anti-GSK3β and co-immunoprecipitated [98]. A subsequent study found active GSK3β co-localized with tau inclusions in tauopathy brain tissues, and the amount of active GSK3β was significantly increased in the patients [99]. Moreover, in vitro study found active GSK3β could efficiently facilitate tau tangles formation after tau are initially polymerized in the presence of arachidonic acid [100]. It should be noticed that effects of GSK3β in tau-mediated toxicity are unsettled; a report found that overexpression of GSK3β in tauopathy models may not necessarily lead to shortened lifespan or accelerate pathological burden in the animal model [101]. In contrast, results from some studies hinted that activation of GSK3β is critical for exacerbating tauopathy [102, 103]. These observations should be interpreted carefully as the tau models used or compared are not in the same background.\n
GSK3β is a constitutively active protein that can autophosphorylate its tyrosine residues like Tyr 216 to increase the enzyme stability [104]. The activity of GSK3β is mainly regulated by insulin and Wnt signaling pathways [105]. When insulin pathway is activated, protein kinase B/Akt will be activated, which in turns phosphorylate serine 9 on GSK3β and causes its inactivation. In the case of activated Wnt signaling pathway, the inhibition of GSK3β activity would alleviate the degradation of β-catenin, whose nuclear translocation is responsible for the downstream genes activation of the pathway, but the precise mechanism regarding tauopathy modulation is still unknown [106, 107]. Nevertheless, a report showed both pathways are being downregulated in AD [96].\n
It was postulated that the phosphorylation by GSK3β requires the priming of adjacent proline residue as GSK3β is a member of proline-directed kinase family [84]. So far, more than 40 sites in tau, either serine or threonine, have been reported could be phosphorylated by GSK3β, and some of them are exclusively found in pathological conditions [84]. Among these sites, in vitro study first identified tau could be phosphorylated by GSK3β at the sites S202, S396, and S404 [108]. Since then, different studies reported many different phosphorylation sites with the availability of the corresponded phospho- site-specific antibodies. Some in vitro/in vivo studies later confirmed that frequent phosphorylation sites include S262, S396, and S404 [101, 109]. The phosphorylation of some residues may play important roles in affecting the binding affinity between tau and tubulins or regulating synaptic plasticity [4, 110, 111]. However, it is still unknown which residues are most frequently phosphorylated by GSK3β under different pathological states in contrast to normal condition, and if there is any protective effect by GSK3β phosphorylation against tau from forming the aggregates. Probing these questions is a major challenge but will help our understanding of the role of GSK3β in tau-associated disease conditions.\n
Besides GSK3β, other kinases such as p38, cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinase (JNK), extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A), casein kinase (CK), protein kinase A (PKA), and Ca2+ /calmodulin-dependent protein kinase II (CAMKII) have been reported to involve in directing tau phosphorylation [4, 84, 112, 113, 114]. Although the possible phosphorylation sites mediated by these kinases, especially in tauopathy conditions, may be less than GSK3β, it is fair to say that their roles in modulating tau toxicity are less well studied, thus whether the modulations by these kinases are less critical than GSK3β in tauopathy remain to be addressed. Indeed, a recent study found P38γ overexpression could ameliorate excitotoxicity induced by amyloid-beta in a tau-dependent manner. Further experiments showed that the effect was mediated by the phosphorylation of tau S205 through the action of P38γ, and the phosphorylation of this residue could abolish the interaction between tau and Fyn and PSD95, which otherwise could form a complex interacting with NMDA receptor to induce excitotoxicity [4]. This result strongly suggests different kinases may have different roles in tauopathy, and not every up-regulated tau phosphorylations under pathological conditions are for enhancing the toxicity. Given such complex modifications, more studies shall emphasize the difference of activity among these kinases under physiological and pathological conditions, as another recent study showed that ERK1/2 does not phosphorylate tau under physiological condition [115]. Furthermore, since the pathology development in tauopathy usually takes years, whether there is any sequential activation of the kinases appears to be another intriguing issue. Indeed, a recent study examining tau-staining in the postmortem AD brains of different stages showed that N-terminal side of tau is preferentially phosphorylated at early stages [116].\n
Proteases including calpain and caspases are involved in tauopathy pathogenesis [117, 118]. They are activated in tauopathies, either directly cleave tau or indirectly cleaving its associated kinases, affecting the structure/function of tau [118, 119, 120, 121]. While less commonly reported, other proteases are suspected to play roles in tauopathy-related protein truncations [122].\n
Two truncated tau proteins have caught attention in tauopathy, as they are abundant in the postmortem AD brains [123]. In fact, truncated tau could also found in other tauopathies beyond AD. Importantly, researchers used live multiphoton imaging combined with thioflavin S administration and a dye for activated caspases and observed that the tangle formation was preceded by caspases activation in a classic P301L tauopathy mice (tg4510) [124], indicating a close tight between tau cleavage and toxicity. Currently, two truncation sites, E391 and D421, have been characterized and both are on the C-terminus. We also learned that the truncation on D421 is mediated by caspases, mainly by Caspase-3. D421-truncated tau is associated with lysosome in AD brain, indicating that the truncated tau may be favored to be degraded through autophagy or maybe impairing the autophagy system [124]. However, it is still unclear what kind of proteases are responsible for the cleavage at E391, albeit the site was the first-identified cleavage site in tau, and its C-terminal cleavage product appears in PHF core [118, 123, 125, 126, 127, 128]. While various reports have suggested that caspase and calpain are capable of cleaving tau and both present as an early event in pathogenesis and could aggravate tau toxicity [124, 129, 130], an important issue should be solved in studying tau truncation that is whether the aberrant increase of tau truncation is a consequence of tau aggregation or actually the cause that induces tau aggregate formation [124].\n
Calpains are cytosolic calcium-dependent cysteine proteases. In an analysis of a postmortem brain lysates, calpain 1 was found to activate at early stages of AD, close to the stage when GSK-3β and CDK5 were activated [130]. The human genome has two identified calpain family members, calpain 1 and calpain 2. Calpain 1 is mainly expressed by neurons and thus received most attention by researchers concerning neurodegeneration, and calpain 2, on the other hand, is mostly expressed by glial cells. Studies have shown that calpain 1 can cleave p35 to generate p25, which could further induce prolonged activation of CDK5 [120]. Calpain can also cleave GSK3β to generate a C-terminal truncated form, which makes its inhibitory site less likely to be phosphorylated and thus produces a dominant-active GSK3β [121, 131]. Also, calpain can directly process tau and generate small fragments. However, the physiological or pathological impacts of those cleaved calpain products in regarding tauopathy are unclear, and the calpain-mediated tau cleavage site(s) remains elusive [120, 127, 132].\n
Among the caspases, executive caspases, especially caspase-3, play a critical role in the direct processing of tau at the site D421. As mentioned above, D421-truncated tau can be found in AD brains, and this cleaved form is suspected to facilitate tau aggregate formation and thus enhancing the toxicity [124, 129, 133, 134]. Phosphorylation at S422 could prevent the truncation, which could be mediated by JNK and TTBK-1 [114, 135, 136]. Nevertheless, JNK and TTBK-1 could also phosphorylate tau at the sites other than S422, which complexes the protective scenario [114, 136]. Caspase 3 can also regulate the phosphorylation of tau through cleaving and activates protein kinase B and thereby activates GSK3β [119].\n
Besides caspase-3, other caspases may involve in tauopathy as well. A recent study showed that caspase-2 could cleave tau at the site D314. This truncated tau could not participate in tau aggregation but is existing in the brains of P301L mice by a significant amount. Pseudophoshorylation of this site prevented caspase-2 cleavage and consequently caused memory and cognitive defects of the mice [137].\n
Tau lysine residues could be acetylated by certain endogenous acetyltransferase, and such modulations were first demonstrated by p300 and Creb-binding protein (CBP) [138, 139]. Importantly, the insoluble tau protein fraction isolated from postmortem brains of the AD patients could be recognized by an anti-acetylated tau antibody [138]. Since then, tau acetylation studies start to emerge, and up to date, four tau acetylation sites, K174, K274, K280, and K281, have been confirmed in pathological conditions [140]. Acetylation of K280 and K281 reduced tau binding affinity to microtubules in vivo and facilitated tau aggregation in vitro [140, 141]. Moreover, acetylation of K280 exacerbated tau toxicity in a Drosophila model, and acetylation of K174 worsened neurodegeneration and behavior defects in PS19 mice [142, 143]. An overall tau acetylation effect is likely to aggravate tau toxicity. A study showed the administration of salsalate, a drug that could inhibit p300, ameliorated the tau pathology and memory defects in PS19 mice [143]. Interestingly, a recent study reported acetylation of K321 could impede S324 phosphorylation, a frequent modification in postmortem AD brains. This observation leads to an intriguing prospect that some switches from acetylation to phosphorylation might affect disease progression [144]. Altogether, these studies bring up questions including to what extent tau acetylation could affect tau toxicity and whether there are interactions between tau acetylation and other posttranslational modifications.\n
So far, our understanding of other tau modifications is still limited [82]. Take glycosylation as an example, glycosylation of tau was only found under pathological conditions but not physiological conditions [145], indicating that this type of posttranslational modification has a significant impact toward cell function. However, probed glycosylation sites of tau are limited, and some of the proposed sites might overlap with the known phosphorylation sites, suggesting a potential competition between glycosyltransferase and phosphorylation kinases [145]. The role of glycosylation in tauopathy is unknown [82]. A recent study using Drosophila showed that different gene locus of glycosyltransferases might have a different impact on tauopathy [146].\n
To date, no drug targeting tauopathies has entered the market [147]. Over the past two decades, a dozen representative drugs have been pursued in the clinical trials [148], and these drugs represented the major therapeutic approaches in tauopathy treatment, including tau aggregation inhibitors, tau phosphorylation-related kinase inhibitors, microtubule stabilizers, and immunotherapy against tau. However, since these strategies have yet to show significant benefit, new approaches are being probed, among which a scheme to enhancing protein homeostasis is an intriguing approach [147, 149]. Other alternative approaches including using traditional Chinese medicine are also being pursued [150].\n
Five treatment approaches mentioned above have been scrutinized in clinical trials, and only microtubule stabilization and immunotherapy against tau are still active tau aggregation inhibitors, and phosphorylation kinase inhibitors, including GSK3β inhibitors and CDK5 inhibitors, were once favored, but they showed little efficacy in clinical trials [151].\n
The direct inhibition of tau aggregation was the major therapeutic strategy being developed and had entered the clinical trials [151]. The development of tau aggregation inhibitor was initiated in the mid-1990s. The first platform to screen the drugs was reported in 1996 with the discovery of phenothiazine, a relatively potent tau aggregation inhibitor in vitro [152]. In this platform, recombinant PHF core tau fragment was incubated in wells, by reciprocal treating the wells with recombinant full-length tau, the protease-resistant tau aggregation could form [152]. By incubating the wells with compounds, the goal was to identify inhibitors that could effectively disrupt tau aggregation through the high-throughput assay, and phenothiazine showed a strong potency [152]. Unfortunately, phenothiazine was found no efficacy in clinical trials, and it was blamed for its poor absorption and was difficult to be transported into the brain [153]. Years later, a renewed platform was designed [153]. In this platform, fibroblasts overexpressing a cocktail of different tau isoforms were incubated in wells. This setting could yield tau aggregations inside the cells, and compounds were tested to compare the labeled tau immunofluorescence as the readout [153]. Although this platform was a lower throughput, it overcame the shortages of the first platform in which cytotoxicity was unknown [153, 154]. With this platform, TRx0237 was later selected to be the lead candidate and went into clinical trials [151]. Unfortunately, the drug did not work in phase 3 as it failed to slow cognitive decline in AD patients [155].\n
Biochemically, the inhibitors could be categorized into two types, covalently and no-covalently tau aggregation inhibitors [156]. However, although they are called "tau" inhibitors, these chemicals are most likely inhibitors to other protein aggregations, and their selectivity is highly questionable [151]. Therefore, a highly selective with high-affinity tau inhibitor is still waiting to be discovered [151, 156].\n
The aim of immunotherapy is to clear pathological tau through the immune system [157]. It could be achieved either by applying antibodies that could recognize pathological tau or by vaccination to elicit activation of antigen presenting cells and subsequently the B cells and T cells to clear up pathological tau [157, 158]. Ten years have passed since the publication of the first study on tau immunotherapy [159]. In the study, the researchers showed that inoculation of a tau peptide aa R379-L408, which covers two critical phosphorylation sites S396 and S404 that being phosphorylated in P301L tau mice, could successfully elicit endogenous immune system to generate antibodies against tau, and the animal showed ameliorated symptoms of tauopathy-related behavior and decreased tau aggregation [160]. Multiple different antibodies or vaccines aiming at different tau epitopes have been developed since then, and some have entered the early phases of clinical trials [157].\n
Molecular chaperones play important roles in protein homeostasis. It was reported that inhibiting heat shock protein 90 (Hsp90) could inhibit tau toxicity in tauopathy model [160]. The mechanism behind could involve Hsp90 stabilize p35, the activator of CDK5, GSK3β, and tau, inhibiting their degradation [160, 161]. On the other hand, Hsp70 could facilitate protein ubiquitination and degradation by the proteasome [162]. Overexpression of Hsp70 in cells could decrease tau aggregation in vitro [163]. Recently, it is also suggested that targeting co-chaperones of Hsp90 could offer another approach to ameliorate tauopathy [164].\n
Several traditional Chinese medicines have been suggested that might be useful for treating tauopathies [150, 165]. Huannao Yicong Decotion was shown to improve learning and memory in rat AD model. Immunolabeling showed the expression levels of GSK3β, CDK5, and TTBK1 in CA1 region of the hippocampus are downregulated in the drug treatment groups [150]. Interestingly, it was also suggested that some traditional Chinese medicines, including Huperzine A and Tianma, could induce upregulation of ubiquitin ligases, indicating that they might facilitate protein degradation through ubiquitin-proteasome pathway [166].\n
In this chapter, we discussed major basic aspects of tauopathy, from tau normal functions to pathology formation process and from tau genetic mutations to posttranslational modifications. Finally, we discussed currently proposed tauopathy treatment methods. With the findings showing tau proteins are involved in many brain pathology conditions beyond tauopathy and more evidences showing the roles of tau in Alzheimer's disease are critical, it is expected to receive more basic research attentions in the future [167, 168]. Better animal models tailored for different tauopathy are of pursuit, which will benefit both basic research and clinical drug developments.\n
IntechOpen celebrates Open Access academic research of women scientists: Call Opens on February 11, 2018 and closes on March 8th, 2018.",metaTitle:'Call for Applications: "IntechOpen Women in Science 2018" Book Collection',metaDescription:"IntechOpen celebrates Open Access academic research of women scientists: Call Opens on February 11, 2018 and closes on March 8th, 2018.",metaKeywords:null,canonicalURL:"/page/women-in-science-book-collection-2018/",contentRaw:'[{"type":"htmlEditorComponent","content":"
On February 9th, 2018, which marks the official celebration of UNESCO's International Day of Women and Girls in Science, we have announced we are seeking contributors for the upcoming "IntechOpen Women in Science 2018" Book Collection. The program aims to support women scientists worldwide whose academic needs include quality assurance, peer-review, fast publishing, collaboration among complementary authors, immediate exposure, and post-publishing citations reporting.\\n\\n
APPLYING FOR THE "INTECHOPEN WOMEN IN SCIENCE 2018" OPEN ACCESS BOOK COLLECTION\\n\\n
Women scientists can apply for one book topic, either as an editor or with co-editors, for a publication of an OA book in any of the scientific categories that will be evaluated by The Women in Science Book Collection Committee, led by IntechOpen's Editorial Board. Submitted proposals will be sent to designated members of the IntechOpen Editorial Advisory Board who will evaluate proposals based on the following parameters: the proposal's originality, the topic's relation to recent trends in the corresponding scientific field, and significance to the scientific community.\\n\\n
The submissions are now closed. All applicants will be notified on the results in due time. Thank you for participating!\\n"}]'},components:[{type:"htmlEditorComponent",content:"
On February 9th, 2018, which marks the official celebration of UNESCO's International Day of Women and Girls in Science, we have announced we are seeking contributors for the upcoming "IntechOpen Women in Science 2018" Book Collection. The program aims to support women scientists worldwide whose academic needs include quality assurance, peer-review, fast publishing, collaboration among complementary authors, immediate exposure, and post-publishing citations reporting.\n\n
APPLYING FOR THE "INTECHOPEN WOMEN IN SCIENCE 2018" OPEN ACCESS BOOK COLLECTION\n\n
Women scientists can apply for one book topic, either as an editor or with co-editors, for a publication of an OA book in any of the scientific categories that will be evaluated by The Women in Science Book Collection Committee, led by IntechOpen's Editorial Board. Submitted proposals will be sent to designated members of the IntechOpen Editorial Advisory Board who will evaluate proposals based on the following parameters: the proposal's originality, the topic's relation to recent trends in the corresponding scientific field, and significance to the scientific community.\n\n
The submissions are now closed. All applicants will be notified on the results in due time. Thank you for participating!\n"}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[],filtersByRegion:[],offset:0,limit:12,total:null},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{},books:[],filtersByTopic:[],offset:0,limit:12,total:null},popularBooks:{featuredBooks:[],offset:0,limit:12,total:null},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[],latestBooks:[]},subject:{topic:{id:"889",title:"Recycling",slug:"recycling",parent:{title:"Waste Management",slug:"environmental-sciences-waste-management"},numberOfBooks:1,numberOfAuthorsAndEditors:24,numberOfWosCitations:11,numberOfCrossrefCitations:9,numberOfDimensionsCitations:30},booksByTopicFilter:{topicSlug:"recycling",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"7557",title:"Recovery and Utilization of Metallurgical Solid Waste",subtitle:null,isOpenForSubmission:!1,hash:"e9d20f98cdcbb7b5d0c35f53e06c74be",slug:"recovery-and-utilization-of-metallurgical-solid-waste",bookSignature:"Yingyi Zhang",coverURL:"https://cdn.intechopen.com/books/images_new/7557.jpg",editedByType:"Edited by",editors:[{id:"221673",title:"Prof.",name:"Yingyi",middleName:null,surname:"Zhang",slug:"yingyi-zhang",fullName:"Yingyi Zhang"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2254",title:"Post-Consumer Waste Recycling and Optimal Production",subtitle:null,isOpenForSubmission:!1,hash:"aecfc52fb19d9de94ca93473cbe7fd74",slug:"post-consumer-waste-recycling-and-optimal-production",bookSignature:"Enri Damanhuri",coverURL:"https://cdn.intechopen.com/books/images_new/2254.jpg",editedByType:"Edited by",editors:[{id:"96952",title:"Prof.",name:"Enri",middleName:null,surname:"Damanhuri",slug:"enri-damanhuri",fullName:"Enri Damanhuri"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:2,mostCitedChapters:[{id:"37110",doi:"10.5772/31530",title:"Electronics Waste: Recycling of Mobile Phones",slug:"electronics-waste-recycling-of-mobile-phones",totalDownloads:6169,totalCrossrefCites:2,totalDimensionsCites:12,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Pia Tanskanen",authors:[{id:"87626",title:"Dr.",name:"Pia",middleName:null,surname:"Tanskanen",slug:"pia-tanskanen",fullName:"Pia Tanskanen"}]},{id:"37113",doi:"10.5772/34054",title:"Modelling of Recycling in LCA",slug:"modelling-of-recycling-in-lca",totalDownloads:6743,totalCrossrefCites:0,totalDimensionsCites:6,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Tom N. Ligthart and Toon (A.)M.M. Ansems",authors:[{id:"98477",title:"Dr.",name:"Tom",middleName:null,surname:"Ligthart",slug:"tom-ligthart",fullName:"Tom Ligthart"}]},{id:"37105",doi:"10.5772/33760",title:"The Role of Informal Collectors of Recyclable Waste and Used Goods in Indonesia",slug:"the-role-of-informal-collectors-of-recyclable-waste-and-used-goods-in-indonesia",totalDownloads:2177,totalCrossrefCites:4,totalDimensionsCites:4,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Enri Damanhuri and Tri Padmi",authors:[{id:"96952",title:"Prof.",name:"Enri",middleName:null,surname:"Damanhuri",slug:"enri-damanhuri",fullName:"Enri Damanhuri"}]}],mostDownloadedChaptersLast30Days:[{id:"37110",title:"Electronics Waste: Recycling of Mobile Phones",slug:"electronics-waste-recycling-of-mobile-phones",totalDownloads:6172,totalCrossrefCites:2,totalDimensionsCites:12,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Pia Tanskanen",authors:[{id:"87626",title:"Dr.",name:"Pia",middleName:null,surname:"Tanskanen",slug:"pia-tanskanen",fullName:"Pia Tanskanen"}]},{id:"63272",title:"Treatments and Recycling of Metallurgical Slags",slug:"treatments-and-recycling-of-metallurgical-slags",totalDownloads:70,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"recovery-and-utilization-of-metallurgical-solid-waste",title:"Recovery and Utilization of Metallurgical Solid Waste",fullTitle:"Recovery and Utilization of Metallurgical Solid Waste"},signatures:"Elena Brandaleze, Edgardo Benavidez and Leandro Santini",authors:null},{id:"37113",title:"Modelling of Recycling in LCA",slug:"modelling-of-recycling-in-lca",totalDownloads:6750,totalCrossrefCites:0,totalDimensionsCites:6,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Tom N. Ligthart and Toon (A.)M.M. Ansems",authors:[{id:"98477",title:"Dr.",name:"Tom",middleName:null,surname:"Ligthart",slug:"tom-ligthart",fullName:"Tom Ligthart"}]},{id:"37105",title:"The Role of Informal Collectors of Recyclable Waste and Used Goods in Indonesia",slug:"the-role-of-informal-collectors-of-recyclable-waste-and-used-goods-in-indonesia",totalDownloads:2180,totalCrossrefCites:4,totalDimensionsCites:4,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Enri Damanhuri and Tri Padmi",authors:[{id:"96952",title:"Prof.",name:"Enri",middleName:null,surname:"Damanhuri",slug:"enri-damanhuri",fullName:"Enri Damanhuri"}]},{id:"63982",title:"The Comprehensive Utilization of Steel Slag in Agricultural Soils",slug:"the-comprehensive-utilization-of-steel-slag-in-agricultural-soils",totalDownloads:32,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"recovery-and-utilization-of-metallurgical-solid-waste",title:"Recovery and Utilization of Metallurgical Solid Waste",fullTitle:"Recovery and Utilization of Metallurgical Solid Waste"},signatures:"Angélica Cristina Fernandes Deus, Rosemary Marques de Almeida Bertani,\nGuilherme Constantino Meirelles, Anelisa de Aquino Vidal Lacerda Soares,\nLais Lorena Queiroz Moreira, Leonardo Theodoro Büll and\nDirceu Maximino Fernandes",authors:null},{id:"37111",title:"Design for E-Waste Recycling Deposit System and Expense Mechanism in China",slug:"design-for-e-waste-recycling-deposit-system-and-expense-mechanism-in-china",totalDownloads:3280,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Hua Zhong",authors:[{id:"90255",title:"Associate Prof.",name:"Hua",middleName:null,surname:"Zhong",slug:"hua-zhong",fullName:"Hua Zhong"}]},{id:"65036",title:"Introductory Chapter: Metallurgical Solid Waste",slug:"introductory-chapter-metallurgical-solid-waste",totalDownloads:50,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"recovery-and-utilization-of-metallurgical-solid-waste",title:"Recovery and Utilization of Metallurgical Solid Waste",fullTitle:"Recovery and Utilization of Metallurgical Solid Waste"},signatures:"Yingyi Zhang",authors:[{id:"221673",title:"Prof.",name:"Yingyi",middleName:null,surname:"Zhang",slug:"yingyi-zhang",fullName:"Yingyi Zhang"}]},{id:"37109",title:"The Economic Aspects of Recycling",slug:"the-economic-aspects-of-recycling",totalDownloads:7186,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Beatriz Ferreira, Javier Monedero, Juan Luís Martí, César Aliaga, Mercedes Hortal and Antonio Dobón López",authors:[{id:"98867",title:"MSc.",name:"Beatriz",middleName:null,surname:"Ferreira Pozo",slug:"beatriz-ferreira-pozo",fullName:"Beatriz Ferreira Pozo"},{id:"134225",title:"MSc.",name:"Javier",middleName:null,surname:"Monedero Tortola",slug:"javier-monedero-tortola",fullName:"Javier Monedero Tortola"},{id:"134226",title:"MSc.",name:"Juan Luis",middleName:null,surname:"Martí Arbona",slug:"juan-luis-marti-arbona",fullName:"Juan Luis Martí Arbona"},{id:"134227",title:"MSc.",name:"César",middleName:null,surname:"Aliaga Baquero",slug:"cesar-aliaga-baquero",fullName:"César Aliaga Baquero"},{id:"134228",title:"BSc.",name:"Antonio",middleName:null,surname:"Dobón López",slug:"antonio-dobon-lopez",fullName:"Antonio Dobón López"},{id:"134229",title:"Dr.",name:"Mercedes",middleName:null,surname:"Hortal Ramos",slug:"mercedes-hortal-ramos",fullName:"Mercedes Hortal Ramos"}]},{id:"37117",title:"Evaluation of the Energy Consumption of Recycling Process",slug:"evaluation-of-the-energy-consumption-of-recycling-process",totalDownloads:1494,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Toshiharu Goto",authors:[{id:"87515",title:"MSc.",name:"Toshiharu",middleName:null,surname:"Goto",slug:"toshiharu-goto",fullName:"Toshiharu Goto"}]},{id:"37112",title:"PET Containers in Brazil: A Logistics Model for Post-Consumer Waste Recycling",slug:"pet-containers-in-brazil-a-reverse-logistics-model-post-consumer",totalDownloads:2450,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"post-consumer-waste-recycling-and-optimal-production",title:"Post-Consumer Waste Recycling and Optimal Production",fullTitle:"Post-Consumer Waste Recycling and Optimal Production"},signatures:"Tatiene Martins Coelho, Rosani de Castro and José Alcides Gobbo Junior",authors:[{id:"102842",title:"MSc.",name:"Tatiene",middleName:null,surname:"Coelho",slug:"tatiene-coelho",fullName:"Tatiene Coelho"},{id:"102846",title:"Dr.",name:"Rosani",middleName:null,surname:"Castro",slug:"rosani-castro",fullName:"Rosani Castro"},{id:"102847",title:"Dr.",name:"José Alcides",middleName:null,surname:"Gobbo Junior",slug:"jose-alcides-gobbo-junior",fullName:"José Alcides Gobbo Junior"}]}],onlineFirstChaptersFilter:{topicSlug:"recycling",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},privacyPolicy:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},humansInSpaceProgram:{},route:{name:"chapter.detail",path:"/books/a-new-look-at-hypothyroidism/universal-screening-for-thyroid-disorders-in-pregnancy-experience-of-the-czech-republic",hash:"",query:{},params:{book:"a-new-look-at-hypothyroidism",chapter:"universal-screening-for-thyroid-disorders-in-pregnancy-experience-of-the-czech-republic"},fullPath:"/books/a-new-look-at-hypothyroidism/universal-screening-for-thyroid-disorders-in-pregnancy-experience-of-the-czech-republic",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()


text:
Remember your video choices. Released on November 4, by Paradise. Jabu Hlongwane – Izithembiso. Make my profile public at. Music for your Website. Music playback has been interrupted because your Qobuz account is currently being used on another device [?
|Date Added:
|19 July 2012
|File Size:
|30.50 Mb
|Operating Systems:
|Windows NT/2000/XP/2003/2003/7/8/10 MacOS 10/X
|Free* [*Free Regsitration Required]
The sub-genre Jazz in the magazine Dandy Man Jbu Ferry is the ultimate dandy, the singer that never gets old and who does as he pleases.
Edit Profile View as Public Logout. Want to watch more videos hlonngwane this song? To watch videos non-fullscreen: Automatically share your activity on Facebook. Watch artist interviews here. Log in to watch more. To live, to listen, to learn. Log in with Facebook. Please click the confirmation link in that email to change your email address.
Listen & view Jabu Hlongwane – Izethembiso Zenkosi lyrics & tabs
Click this button to skip to the next video. Jabu Hlongwane – Izithembiso. Jabu Hlongwane Crosspower Experience 2. An unexpected error has been encountered. Always play videos fullscreen. Make my profile public at. We have emailed you a change of email request.
Seems like you're using an old browser 🙁
This action cannot be undone! We've received your report and will correct the listing shortly.
See all tracks 14 Export playlist to the new widget. About Album description 1 disk – 14 tracks – Total length: Bryan Ferry is the ultimate dandy, the singer that never gets hlongdane and who does as he pleases. Read the article A Night of Nat InGregory Porter released a tribute album – or rather a love letter, to the man he considers his ultimate hero: Display track details Album: Music for your Website.
Music playback hlogwane been interrupted because your Qobuz account is currently being used on another device [? Please activate your account by clicking the link in the welcome email we've just sent you.
Winnie Mashaba O Mohau Messiah. Please select a valid image file.
Izethembiso – Jabu Hlongwane | Shazam
Let us know your feedback so we can evolve and improve. Are you certain you want to delete this board? InGregory Porter released a tribute album – ajbu rather a love letter, to the man he considers his ultimate hero: Show my social media links facebook.
For some years now, Barbara Hendricks has had the blues. Jabu Hlongwane habu Izithembiso Leave us feedback. You've reached the daily limit of 10 videos.

subset: commoncrawl


text:
Baskin Robbins, East 2100 South, Salt Lake City, UT, United States Food Poisoning
1Total sick persons:
"i orderd a medium sized shake it was the pistacio almond flavor. my friends told me that there ice cream tasted funny and mine did to. but not bad enouhg to eat it didnt taste spoiled but just a little sweeter."
Baskin Robbins
Salt Lake City
United States
CommentsNo comments. Be the first to comment.
Baskin Robbins recent reports
Jul 17 2018 8:04pm
Baskin-Robbins, Vancouver, WA, USA
Symptoms: Diarrhea, Nausea
Report Type: Food Poisoning
Sunday afternoon July 15 , 3 different kinds of shakes, 4 people got sick
Symptoms: diarrhea stomach ache, headache, pain, nausea, lightheaded
May 15 2018 9:16pm
Baskin-Robbins, Farm to Market 1960 Road West, Houston, TX, USA
Symptoms: Vomiting
Report Type: Food Poisoning
3 year old son and mom had vanilla ice cream. Within 1 hour son started saying his stomach was hurting and all of the sudden he started vomiting. Just got off the phone with my mom and she started getting sharp stomach pains and vomited as well.
Nov 16 2017 3:51am
Baskin-Robbins, East Main Street, Tustin, CA, United States
Symptoms: Diarrhea
Report Type: Food Poisoning
I daughter and I both have felt sick all night after eating ice cream..and we had different flavors
May 25 2017 2:02am
Baskin-Robbins, North Mountain Avenue, Ontario, CA, United States
Symptoms: Diarrhea, Fever, Nausea, Vomiting
Report Type: Food Poisoning
3 Scoop ice cream my whole family sick , I am actually on home health care and thank god I have a picc line , iv fluids and iv Zofran . My 6 year old and my husband I can't say the same ! We took our daughter to BB as a kid 31 flavors was where my parents took me when I graduated Pre K and Kidagarden ! Well my daughter was hit with nausea stomach pain and the runs I just thought she ate to much ! Then came the runs and screaming bloody murder ! Then my husband had the runs and the worst gas !... See More