Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model
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...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996115301078 |
| _version_ | 1818336659118227456 |
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| author | YoungDoo Kim Hyunwoo Choi WonJae Lee Hyejin Park Tae-In Kam Se-hoon Hong Jihoon Nah Sunmin Jung Bora Shin Huikyong Lee Tae-Yong Choi Hyosun Choo Kyung-Keun Kim Se-Young Choi Rakez Kayed Yong-Keun Jung |
| author_facet | YoungDoo Kim Hyunwoo Choi WonJae Lee Hyejin Park Tae-In Kam Se-hoon Hong Jihoon Nah Sunmin Jung Bora Shin Huikyong Lee Tae-Yong Choi Hyosun Choo Kyung-Keun Kim Se-Young Choi Rakez Kayed Yong-Keun Jung |
| author_sort | YoungDoo Kim |
| collection | DOAJ |
| description | 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 (2–3 months). 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. |
| first_indexed | 2024-12-13T14:42:50Z |
| format | Article |
| id | doaj.art-3266bf39954941279563020c54c12ba7 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-13T14:42:50Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-3266bf39954941279563020c54c12ba72022-12-21T23:41:34ZengElsevierNeurobiology of Disease1095-953X2016-03-01871928Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse modelYoungDoo Kim0Hyunwoo Choi1WonJae Lee2Hyejin Park3Tae-In Kam4Se-hoon Hong5Jihoon Nah6Sunmin Jung7Bora Shin8Huikyong Lee9Tae-Yong Choi10Hyosun Choo11Kyung-Keun Kim12Se-Young Choi13Rakez Kayed14Yong-Keun Jung15Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaDepartment of Physiology, Seoul National University School of Dentistry, Seoul, Republic of KoreaGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of KoreaMedical Research Center, Chonnam National University Medical School, Kwangju 501-190, Republic of KoreaDepartment of Physiology, Seoul National University School of Dentistry, Seoul, Republic of KoreaDepartments of Neurology and Neuroscience & Cell Biology, University of Texas, Galveston, TX 77555-1045, USAGlobal Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea; Corresponding author at: School of Biological Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-747, Republic of Korea.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 (2–3 months). 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.http://www.sciencedirect.com/science/article/pii/S0969996115301078Caspase-cleaved tauTauopathyAlzheimer's diseaseTau oligomersAD mice |
| spellingShingle | YoungDoo Kim Hyunwoo Choi WonJae Lee Hyejin Park Tae-In Kam Se-hoon Hong Jihoon Nah Sunmin Jung Bora Shin Huikyong Lee Tae-Yong Choi Hyosun Choo Kyung-Keun Kim Se-Young Choi Rakez Kayed Yong-Keun Jung Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model Neurobiology of Disease Caspase-cleaved tau Tauopathy Alzheimer's disease Tau oligomers AD mice |
| title | Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model |
| title_full | Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model |
| title_fullStr | Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model |
| title_full_unstemmed | Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model |
| title_short | Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model |
| title_sort | caspase cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model |
| topic | Caspase-cleaved tau Tauopathy Alzheimer's disease Tau oligomers AD mice |
| url | http://www.sciencedirect.com/science/article/pii/S0969996115301078 |
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