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

Research output: Contribution to journalArticle

42 Citations (Scopus)

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 languageEnglish
Pages (from-to)1426-1437
Number of pages12
JournalNeuropsychopharmacology
Volume38
Issue number8
DOIs
Publication statusPublished - 2013 Jul 1

Fingerprint

Janus Kinase 2
Genetic Models
Transducers
Down-Regulation
Cholinergic Receptors
Muscarinic Receptors
Choline O-Acetyltransferase
Long-Term Potentiation
Acetylcholinesterase
Acetylcholine
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
trkB Receptor
Muscarinic Agonists
Cognitive Dysfunction
Brain-Derived Neurotrophic Factor
Protein Binding
Protein-Tyrosine Kinases
Protein Kinase C
Cholinergic Agents
Hippocampus

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging. / Park, Seok Joo; Shin, Eun Joo; Min, Sun Seek; An, Jihua; Li, Zhengyi; Hee Chung, Yoon; Hoon Jeong, Ji; Bach, Jae Hyung; Nah, Seung Yeol; Kim, Won-Ki; Jang, Choon Gon; Kim, Yong Sun; Nabeshima, Yo Ichi; Nabeshima, Toshitaka; Kim, Hyoung Chun.

In: Neuropsychopharmacology, Vol. 38, No. 8, 01.07.2013, p. 1426-1437.

Research output: Contribution to journalArticle

Park, SJ, Shin, EJ, Min, SS, An, J, Li, Z, Hee Chung, Y, Hoon Jeong, J, Bach, JH, Nah, SY, Kim, W-K, 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
Park, Seok Joo ; Shin, Eun Joo ; Min, Sun Seek ; An, Jihua ; Li, Zhengyi ; Hee Chung, Yoon ; Hoon Jeong, Ji ; Bach, Jae Hyung ; Nah, Seung Yeol ; Kim, Won-Ki ; Jang, Choon Gon ; Kim, Yong Sun ; Nabeshima, Yo Ichi ; Nabeshima, Toshitaka ; Kim, Hyoung Chun. / Inactivation of JAK2/STAT3 signaling axis and downregulation of m1 mAChR cause cognitive impairment in klotho mutant mice, a genetic model of aging. In: Neuropsychopharmacology. 2013 ; Vol. 38, No. 8. pp. 1426-1437.
@article{f2631192525049368d29f671895aab48,
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 = "cognitive impairment, JAK2/STAT3, klotho gene, long-term potentiation, M1 mAChR, PKC/ERK/CREB/BDNF",
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 Won-Ki Kim and Jang, {Choon Gon} and Kim, {Yong Sun} and Nabeshima, {Yo Ichi} and Toshitaka Nabeshima and Kim, {Hyoung Chun}",
year = "2013",
month = "7",
day = "1",
doi = "10.1038/npp.2013.39",
language = "English",
volume = "38",
pages = "1426--1437",
journal = "Neuropsychopharmacology",
issn = "0893-133X",
publisher = "Nature Publishing Group",
number = "8",

}

TY - JOUR

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

PY - 2013/7/1

Y1 - 2013/7/1

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.

KW - cognitive impairment

KW - JAK2/STAT3

KW - klotho gene

KW - long-term potentiation

KW - M1 mAChR

KW - PKC/ERK/CREB/BDNF

UR - http://www.scopus.com/inward/record.url?scp=84879415127&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879415127&partnerID=8YFLogxK

U2 - 10.1038/npp.2013.39

DO - 10.1038/npp.2013.39

M3 - Article

VL - 38

SP - 1426

EP - 1437

JO - Neuropsychopharmacology

JF - Neuropsychopharmacology

SN - 0893-133X

IS - 8

ER -