Activation of the 5′-AMP-Activated Protein Kinase in the Cerebral Cortex of Young Senescence-Accelerated P8 Mice and Association with GSK3β- and PP2A-Dependent Inhibition of p-tau₃₉₆ Expression

Article type: Research Article

Authors: Kim, Hak-Su^{a; b} | Moon, Sohee^{a; b} | Paik, Jin-Hwe^c | Shin, Dong Wun^d | Kim, Lindsay S.^{e; 1} | Park, Chang-Shin^{a; b} | Ha, Joohun^f | Kang, Ju-Hee^{a; b; *}

Affiliations: [a] Department of Pharmacology and Medicinal Toxicology Research Center, Inha University, Incheon, Republic of Korea | [b] Hypoxia-related Diseases Research Center, College of Medicine, Inha University, Incheon, Republic of Korea | [c] Department of Emergency Medicine, Inha University Hospital, Incheon, Republic of Korea | [d] Department of Emergency Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-Do, Republic of Korea | [e] College of Arts and Science, Boston College, Boston, MA, USA | [f] Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul, Republic of Korea

Correspondence: [1] Current position: Undergraduate student, Boston College, Boston, MA, USA.

Correspondence: [*] Correspondence to: Ju-Hee Kang, Department of Pharmacology and Medicinal Toxicology Research Center, Hypoxia-related Diseases Research Center, College of Medicine, Inha University, Jungseok Building, 3rd Street, Shinheungdong, Jung-Gu, Incheon 400-712, Republic of Korea. Tel.: +82 32 890 0963; Fax: +82 32 887 7488; [email protected]

Abstract: The 5′-AMP-activated protein kinase (AMPK), which is a sensor of cellular energy, regulates neuronal survival and energy homeostasis. However, the roles of AMPK in the pathogenesis of Alzheimer's disease (AD) are unclear. The senescence-accelerated mouse prone 8 (SAMP8) strain is characterized by deficits in learning and memory, exhibits pathological characteristics of AD as early as 5 months of age, and is being increasingly recognized as a model of AD. Here, we investigated the relationship between AMPK activation and phosphorylation of the tau protein in the brain of young (2-month-old) SAMP8 animals and in differentiated SH-SY5Y cells. Upregulation of p-AMPK, p-ACC, and p-GSK3βS9 and downregulation of p-tau396 and sirtuin 1 (Sirt1) were observed in the cerebral cortex of young SAMP8 mice compared with that of age-matched SAMR1 animals. The hippocampal levels of p-AMPK and p-tau396 in SAMP8 animals were not significantly different from those of SAMR1, whereas upregulation of p-GSK3βS9 and downregulation of sirt1 was observed in the hippocampus of SAMP8 mice. Consistent with in vivo findings in the cortex, AMPK activation in SH-SY5Y cells upregulated p-GSK3βS9 but downregulated p-tau396, whereas it had no significant effect on p-tau262 expression. In addition, the AMPK-mediated inhibition of p-tau396 expression was attenuated by okadaic acid, a protein phosphatase 2A (PP2A) inhibitor. Taken together, our data showed that AMPK activation inhibits p-tau396 expression in a GSK3β- and PP2A-dependent manner, and suggest that differential regulation of tau phosphorylation in young SAMP8 mice by AMPK plays a compensatory role against accelerated senescence in this AD animal model.

Keywords: 5′-AMP-activated protein kinase, GSK3β, p-tau, protein phosphatase 2A, senescence-accelerated mice, sirtuin 1, tau protein

DOI: 10.3233/JAD-150035

Journal: Journal of Alzheimer's Disease, vol. 46, no. 1, pp. 249-259, 2015