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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

Authors
Park, Seok-JooShin, Eun-JooMin, Sun SeekAn, JihuaLi, ZhengyiChung, Yoon HeeJeong, Ji HoonBach, Jae-HyungNah, Seung-YeolKim, Won-KiJang, Choon-GonKim, Yong-SunNabeshima, Yo-ichiNabeshima, ToshitakaKim, Hyoung-Chun
Issue Date
7월-2013
Publisher
NATURE PUBLISHING GROUP
Keywords
cognitive impairment; JAK2/STAT3; klotho gene; long-term potentiation; M1 mAChR; PKC/ERK/CREB/BDNF
Citation
NEUROPSYCHOPHARMACOLOGY, v.38, no.8, pp.1426 - 1437
Indexed
SCIE
SCOPUS
Journal Title
NEUROPSYCHOPHARMACOLOGY
Volume
38
Number
8
Start Page
1426
End Page
1437
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/102877
DOI
10.1038/npp.2013.39
ISSN
0893-133X
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 beta II, 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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