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.
authors: Neuropsychopharmacology and Toxicology Program, Department of Pharmacy, College of Pharmacy, Kangwon National University, Chunchon, South Korea.
authors: Seok-Joo
authors: SJ
authors: Park
authors: Eun-Joo
authors: EJ
authors: Shin
authors: Sun Seek
authors: SS
authors: Min
authors: Jihua
authors: J
authors: An
authors: Zhengyi
authors: Z
authors: Li
authors: Yoon
authors: Y
authors: Hee Chung
authors: Ji
authors: J
authors: Hoon Jeong
authors: Jae-Hyung
authors: JH
authors: Bach
authors: Seung-Yeol
authors: SY
authors: Nah
authors: Won-Ki
authors: WK
authors: Kim
authors: Choon-Gon
authors: CG
authors: Jang
authors: Yong-Sun
authors: YS
authors: Kim
authors: Yo-Ichi
authors: Y
authors: Nabeshima
authors: Toshitaka
authors: T
authors: Nabeshima
authors: Hyoung-Chun
authors: HC
authors: Kim
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D015536:Down-Regulation / Q000502:physiology; D005966:Glucuronidase / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090265:Klotho Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D009924:Organ Culture Techniques; D043643:Receptor, Muscarinic M1 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D043643:Receptor, Muscarinic M1; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D005966:Glucuronidase; D000090265:Klotho Proteins
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