title: Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model.
abstract: In neurodegenerative diseases like AD, tau forms neurofibrillary tangles, composed of tau protein. In the AD brain, activated caspases cleave tau at the 421th Asp, generating a caspase-cleaved form of tau, TauC3. Although TauC3 is known to assemble rapidly into filaments in vitro, a role of TauC3 in vivo remains unclear. Here, we generated a transgenic mouse expressing human TauC3 using a neuron-specific promoter. In this mouse, we found that human TauC3 was expressed in the hippocampus and cortex. Interestingly, TauC3 mice showed drastic learning and spatial memory deficits and reduced synaptic density at a young age (2-3months). Notably, tau oligomers as well as tau aggregates were found in TauC3 mice showing memory deficits. Further, i.p. or i.c.v. injection with methylene blue or Congo red, inhibitors of tau aggregation in vitro, and i.p. injection with rapamycin significantly reduced the amounts of tau oligomers in the hippocampus, rescued spine density, and attenuated memory impairment in TauC3 mice. Together, these results suggest that TauC3 facilitates early memory impairment in transgenic mice accompanied with tau oligomer formation, providing insight into the role of TauC3 in the AD pathogenesis associated with tau oligomers and a useful AD model to test drug candidates.
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: YoungDoo
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Hyunwoo
authors.initials: H
authors.lastname: Choi
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: WonJae
authors.initials: W
authors.lastname: Lee
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Hyejin
authors.initials: H
authors.lastname: Park
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Tae-In
authors.initials: TI
authors.lastname: Kam
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Nah
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Jung
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Bora
authors.initials: B
authors.lastname: Shin
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Huikyong
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Physiology, Seoul National University School of Dentistry, Seoul, Republic of Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Choi
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Hyosun
authors.initials: H
authors.lastname: Choo
authors.affiliation: Medical Research Center, Chonnam National University Medical School, Kwangju 501-190, Republic of Korea.
authors.forename: Kyung-Keun
authors.initials: KK
authors.lastname: Kim
authors.affiliation: Department of Physiology, Seoul National University School of Dentistry, Seoul, Republic of Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Departments of Neurology and Neuroscience & Cell Biology, University of Texas, Galveston, TX 77555-1045, USA.
authors.forename: Rakez
authors.initials: R
authors.lastname: Kayed
authors.affiliation: Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea. Electronic address: ykjung@snu.ac.kr.
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018697:Nootropic Agents / Q000494:pharmacology; D055503:Protein Multimerization / Q000187:drug effects / Q000502:physiology; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D018697:Nootropic Agents; D016875:tau Proteins; D020169:Caspases; D020123:Sirolimus
keywords: AD mice; Alzheimer's disease; Caspase-cleaved tau; Tau oligomers; Tauopathy