Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging

Seok Joo Park; Eun Joo Shin; Sun Seek Min; Jihua An; Zhengyi Li; Yoon Hee Chung; Ji Hoon Jeong; Jae Hyung Bach; Seung Yeol Nah; Won Ki Kim; Choon Gon Jang; Yong Sun Kim; Yo Ichi Nabeshima; Toshitaka Nabeshima; Hyoung Chun Kim

doi:10.1038/npp.2013.39

Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging

Seok Joo Park, Eun Joo Shin, Sun Seek Min, Jihua An, Zhengyi Li, Yoon Hee Chung, Ji Hoon Jeong, Jae Hyung Bach, Seung Yeol Nah, Won Ki Kim, Choon Gon Jang, Yong Sun Kim, Yo Ichi Nabeshima, Toshitaka Nabeshima, Hyoung Chun Kim

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Abstract

We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.

Original language	English
Pages (from-to)	1426-1437
Number of pages	12
Journal	Neuropsychopharmacology
Volume	38
Issue number	8
DOIs	https://doi.org/10.1038/npp.2013.39
Publication status	Published - 2013 Jul

Bibliographical note

Funding Information:
This study was supported by a grant from the Brain Research Center from 21st Century Frontier Research Program (2012K001115) funded by the Ministry of Science and Technology, Republic of Korea. This work was, in part, supported by a Grant (#20120006020) from the Bio & Medical Technology Development Program through the National Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea; by a Grant (#E00025) of the Korea–Japan Joint Research Program, National Research Foundation of Korea, Republic of Korea; and by grants from Ministry of Health Labour and Welfare (MHLW): Research on Risk of Chemical Substances, and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project. Zhengyi Li and Jae-Hyung Bach were supported by BK 21 program. The English in this manuscript has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck. com/certificate/x6dfJe

Keywords

JAK2/STAT3
M1 mAChR
PKC/ERK/CREB/BDNF
cognitive impairment
klotho gene
long-term potentiation

ASJC Scopus subject areas

Pharmacology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/npp.2013.39

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Park, S. J., Shin, E. J., Min, S. S., An, J., Li, Z., Hee Chung, Y., Hoon Jeong, J., Bach, J. H., Nah, S. Y., Kim, W. K., Jang, C. G., Kim, Y. S., Nabeshima, Y. I., Nabeshima, T., & Kim, H. C. (2013). Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging. Neuropsychopharmacology, 38(8), 1426-1437. https://doi.org/10.1038/npp.2013.39

Park, SJ, Shin, EJ, Min, SS, An, J, Li, Z, Hee Chung, Y, Hoon Jeong, J, Bach, JH, Nah, SY, Kim, WK, Jang, CG, Kim, YS, Nabeshima, YI, Nabeshima, T & Kim, HC 2013, 'Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging', Neuropsychopharmacology, vol. 38, no. 8, pp. 1426-1437. https://doi.org/10.1038/npp.2013.39

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title = "Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging",

abstract = "We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.",

keywords = "JAK2/STAT3, M1 mAChR, PKC/ERK/CREB/BDNF, cognitive impairment, klotho gene, long-term potentiation",

author = "Park, {Seok Joo} and Shin, {Eun Joo} and Min, {Sun Seek} and Jihua An and Zhengyi Li and {Hee Chung}, Yoon and {Hoon Jeong}, Ji and Bach, {Jae Hyung} and Nah, {Seung Yeol} and Kim, {Won Ki} and Jang, {Choon Gon} and Kim, {Yong Sun} and Nabeshima, {Yo Ichi} and Toshitaka Nabeshima and Kim, {Hyoung Chun}",

note = "Funding Information: This study was supported by a grant from the Brain Research Center from 21st Century Frontier Research Program (2012K001115) funded by the Ministry of Science and Technology, Republic of Korea. This work was, in part, supported by a Grant (#20120006020) from the Bio & Medical Technology Development Program through the National Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea; by a Grant (#E00025) of the Korea–Japan Joint Research Program, National Research Foundation of Korea, Republic of Korea; and by grants from Ministry of Health Labour and Welfare (MHLW): Research on Risk of Chemical Substances, and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project. Zhengyi Li and Jae-Hyung Bach were supported by BK 21 program. The English in this manuscript has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck. com/certificate/x6dfJe",

year = "2013",

month = jul,

doi = "10.1038/npp.2013.39",

language = "English",

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T1 - Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging

AU - Park, Seok Joo

AU - Shin, Eun Joo

AU - Min, Sun Seek

AU - An, Jihua

AU - Li, Zhengyi

AU - Hee Chung, Yoon

AU - Hoon Jeong, Ji

AU - Bach, Jae Hyung

AU - Nah, Seung Yeol

AU - Kim, Won Ki

AU - Jang, Choon Gon

AU - Kim, Yong Sun

AU - Nabeshima, Yo Ichi

AU - Nabeshima, Toshitaka

AU - Kim, Hyoung Chun

N1 - Funding Information: This study was supported by a grant from the Brain Research Center from 21st Century Frontier Research Program (2012K001115) funded by the Ministry of Science and Technology, Republic of Korea. This work was, in part, supported by a Grant (#20120006020) from the Bio & Medical Technology Development Program through the National Research Foundation funded by the Ministry of Education, Science and Technology, Republic of Korea; by a Grant (#E00025) of the Korea–Japan Joint Research Program, National Research Foundation of Korea, Republic of Korea; and by grants from Ministry of Health Labour and Welfare (MHLW): Research on Risk of Chemical Substances, and Ministry of Education, Culture, Sports, Science and Technology (MEST): Academic Frontier Project. Zhengyi Li and Jae-Hyung Bach were supported by BK 21 program. The English in this manuscript has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: http://www.textcheck. com/certificate/x6dfJe

PY - 2013/7

Y1 - 2013/7

N2 - We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.

AB - We previously reported cognitive dysfunction in klotho mutant mice. In the present study, we further examined novel mechanisms involved in cognitive impairment in these mice. Significantly decreased janus kinase 2 (JAK2) and signal transducer and activator of transcription3 (STAT3) phosphorylation were observed in the hippocampus of klotho mutant mice. A selective decrease in protein expression and binding density of the M1 muscarinic cholinergic receptor (M1 mAChR) was observed in these mice. Cholinergic parameters (ie, acetylcholine (ACh), choline acetyltransferase (ChAT), and acetylcholinesterase (AChE)) and NMDAR-dependent long-term potentiation (LTP) were significantly impaired in klotho mutant mice. McN-A-343 (McN), an M1 mAChR agonist, significantly attenuated these impairments. AG490 (AG), a JAK2 inhibitor, counteracted the attenuating effects of McN, although AG did not significantly alter the McN-induced effect on AChE. Furthermore, AG significantly inhibited the attenuating effects of McN on decreased NMDAR-dependent LTP, protein kinase C βII, p-ERK, p-CREB, BDNF, and p-JAK2/p-STAT3-expression in klotho mutant mice. In addition, k252a, a BDNF receptor tyrosine kinase B (TrkB) inhibitor, significantly counteracted McN effects on decreased ChAT, ACh, and M1 mAChR and p-JAK2/p-STAT3 expression. McN-induced effects on cognitive impairment in klotho mutant mice were consistently counteracted by either AG or k252a. Our results suggest that inactivation of the JAK2/STAT3 signaling axis and M1 mAChR downregulation play a critical role in cognitive impairment observed in klotho mutant mice.

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KW - M1 mAChR

KW - PKC/ERK/CREB/BDNF

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KW - klotho gene

KW - long-term potentiation

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Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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