Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Kang Woo Lee; Joo Young Im; Jin Sook Song; Si Hyoung Lee; Ho Jeong Lee; Hye Yeong Ha; Jae Young Koh; Byoung Joo Gwag; Sung Don Yang; Sang Gi Paik; Pyung Lim Han

doi:10.1016/j.nbd.2005.09.011

Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Kang Woo Lee, Joo Young Im, Jin Sook Song, Si Hyoung Lee, Ho Jeong Lee, Hye Yeong Ha, Jae Young Koh, Byoung Joo Gwag, Sung Don Yang, Sang Gi Paik, Pyung Lim Han

Divison of Brain & Cognitive Sciences

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

The β-secretase cleaved Aβ-bearing carboxy-terminal fragments (βCTFs) of amyloid precursor protein (APP) in neural cells have been suggested to be cytotoxic. However, the functional significance of βCTFs in vivo remains elusive. We created a transgenic mouse line Tg-βCTF99/B6 expressing the human βCTF99 in the brain of inbred C57BL/6 strain. Tg-βCTF99/B6 mouse brain at 12-16 months showed severely down-regulated calbindin, phospho-CREB, and Bcl-x_L expression and up-regulated phospho-JNK, Bcl-2, and Bax expression. Neuronal cell density in the Tg-βCTF99/B6 cerebral cortex at 16-18 months was lower than that of the non-transgenic control, but not at 5 months. At 11-14 months, Tg-βCTF99/B6 mice displayed cognitive impairments and increased anxiety, which were not observed at 5 months. These results suggest that increased βCTF99 expression is highly detrimental to the aging brain and that it produces a progressive and age-dependent AD-like pathogenesis.

Original language	English
Pages (from-to)	10-24
Number of pages	15
Journal	Neurobiology of Disease
Volume	22
Issue number	1
DOIs	https://doi.org/10.1016/j.nbd.2005.09.011
State	Published - Apr 2006

Bibliographical note

Funding Information:
This work was supported by a grant (M103KV010020 03K2201 02020) from Brain Research Center, The 21st Century Frontier Research Program of the Ministry of Science and Technology, Republic of Korea.

Keywords

AD model
CTF
Cognitive deficits
Neuronal loss
Transgenic animal

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10.1016/j.nbd.2005.09.011

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Lee, K. W., Im, J. Y., Song, J. S., Lee, S. H., Lee, H. J., Ha, H. Y., Koh, J. Y., Gwag, B. J., Yang, S. D., Paik, S. G., & Han, P. L. (2006). Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein. Neurobiology of Disease, 22(1), 10-24. https://doi.org/10.1016/j.nbd.2005.09.011

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title = "Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein",

abstract = "The β-secretase cleaved Aβ-bearing carboxy-terminal fragments (βCTFs) of amyloid precursor protein (APP) in neural cells have been suggested to be cytotoxic. However, the functional significance of βCTFs in vivo remains elusive. We created a transgenic mouse line Tg-βCTF99/B6 expressing the human βCTF99 in the brain of inbred C57BL/6 strain. Tg-βCTF99/B6 mouse brain at 12-16 months showed severely down-regulated calbindin, phospho-CREB, and Bcl-xL expression and up-regulated phospho-JNK, Bcl-2, and Bax expression. Neuronal cell density in the Tg-βCTF99/B6 cerebral cortex at 16-18 months was lower than that of the non-transgenic control, but not at 5 months. At 11-14 months, Tg-βCTF99/B6 mice displayed cognitive impairments and increased anxiety, which were not observed at 5 months. These results suggest that increased βCTF99 expression is highly detrimental to the aging brain and that it produces a progressive and age-dependent AD-like pathogenesis.",

keywords = "AD model, CTF, Cognitive deficits, Neuronal loss, Transgenic animal",

author = "Lee, \{Kang Woo\} and Im, \{Joo Young\} and Song, \{Jin Sook\} and Lee, \{Si Hyoung\} and Lee, \{Ho Jeong\} and Ha, \{Hye Yeong\} and Koh, \{Jae Young\} and Gwag, \{Byoung Joo\} and Yang, \{Sung Don\} and Paik, \{Sang Gi\} and Han, \{Pyung Lim\}",

note = "Funding Information: This work was supported by a grant (M103KV010020 03K2201 02020) from Brain Research Center, The 21st Century Frontier Research Program of the Ministry of Science and Technology, Republic of Korea. ",

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AU - Song, Jin Sook

AU - Lee, Si Hyoung

AU - Lee, Ho Jeong

AU - Ha, Hye Yeong

AU - Koh, Jae Young

AU - Gwag, Byoung Joo

AU - Yang, Sung Don

AU - Paik, Sang Gi

AU - Han, Pyung Lim

N1 - Funding Information: This work was supported by a grant (M103KV010020 03K2201 02020) from Brain Research Center, The 21st Century Frontier Research Program of the Ministry of Science and Technology, Republic of Korea.

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N2 - The β-secretase cleaved Aβ-bearing carboxy-terminal fragments (βCTFs) of amyloid precursor protein (APP) in neural cells have been suggested to be cytotoxic. However, the functional significance of βCTFs in vivo remains elusive. We created a transgenic mouse line Tg-βCTF99/B6 expressing the human βCTF99 in the brain of inbred C57BL/6 strain. Tg-βCTF99/B6 mouse brain at 12-16 months showed severely down-regulated calbindin, phospho-CREB, and Bcl-xL expression and up-regulated phospho-JNK, Bcl-2, and Bax expression. Neuronal cell density in the Tg-βCTF99/B6 cerebral cortex at 16-18 months was lower than that of the non-transgenic control, but not at 5 months. At 11-14 months, Tg-βCTF99/B6 mice displayed cognitive impairments and increased anxiety, which were not observed at 5 months. These results suggest that increased βCTF99 expression is highly detrimental to the aging brain and that it produces a progressive and age-dependent AD-like pathogenesis.

AB - The β-secretase cleaved Aβ-bearing carboxy-terminal fragments (βCTFs) of amyloid precursor protein (APP) in neural cells have been suggested to be cytotoxic. However, the functional significance of βCTFs in vivo remains elusive. We created a transgenic mouse line Tg-βCTF99/B6 expressing the human βCTF99 in the brain of inbred C57BL/6 strain. Tg-βCTF99/B6 mouse brain at 12-16 months showed severely down-regulated calbindin, phospho-CREB, and Bcl-xL expression and up-regulated phospho-JNK, Bcl-2, and Bax expression. Neuronal cell density in the Tg-βCTF99/B6 cerebral cortex at 16-18 months was lower than that of the non-transgenic control, but not at 5 months. At 11-14 months, Tg-βCTF99/B6 mice displayed cognitive impairments and increased anxiety, which were not observed at 5 months. These results suggest that increased βCTF99 expression is highly detrimental to the aging brain and that it produces a progressive and age-dependent AD-like pathogenesis.

KW - AD model

KW - CTF

KW - Cognitive deficits

KW - Neuronal loss

KW - Transgenic animal

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Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein

Abstract

Bibliographical note

Keywords

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