title: Tau silencing by siRNA in the P301S mouse model of tauopathy.
abstract: Suppression of tau protein expression has been shown to improve behavioral deficits in mouse models of tauopathies, offering an attractive therapeutic approach. Experimentally this had been achieved by switching off the promoters controlling the transgenic human tau gene (MAPT), which is not possible in human patients. The aim of the present study was therefore to evaluate the effectiveness of small interfering RNAs (siRNAs) and their cerebral delivery to suppress human tau expression in vivo, which might be a therapeutic option for human tauopathies. We used primary cortical neurons of transgenic mice expressing P301S-mutated human tau and Lund human mesencephalic (LUHMES) cells to validate the suppressive effect of siRNA in vitro. For measuring the effect in vivo, we stereotactically injected siRNA into the brains of P301S mice to reveal the suppression of tau by immunochemistry (AT180, MC1, and CP13 antibodies). We found that the Accell™ SMART pool siRNA against MAPT can effectively suppress tau expression in vitro and in vivo without a specific delivery agent. The siRNA showed a moderate distribution in the hippocampus of mice after single injection. NeuN, GFAP, Iba-1, MHC II immunoreactivities and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed neither signs of neurotoxicity or neuroinflammation nor apoptosis when MAPT siRNA is present in the hippocampus. Our data suggest that siRNA against MAPT can serve as a potential tool for gene therapy in tauopathies.
authors: Hong
authors: H
authors: Xu
authors: Thomas W
authors: TW
authors: Rösler
authors: Thomas
authors: T
authors: Carlsson
authors: Anderson
authors: A
authors: de Andrade
authors: Ondrej
authors: O
authors: Fiala
authors: Matthias
authors: M
authors: Hollerhage
authors: Wolfgang H
authors: WH
authors: Oertel
authors: Michel
authors: M
authors: Goedert
authors: Achim
authors: A
authors: Aigner
authors: Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Max-Lebsche-Platz 30, 81377 Munich, Germany. guenter.hoeglinger@dzne.de.
authors: Gunter U
authors: GU
authors: Höglinger
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016875:tau Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016875:tau Proteins