Kim Hak-Su, Moon Sohee, Kim Sujin, Lee Min-Jae, Suk Min Hwa, Park Dong-Ho, Shin Dong Wun, Park Chang-Shin, Kang Ju-Hee
Department of Pharmacology and Medicinal Toxicology Research Center, Inha University School of Medicine, Inha University, Incheon 22212, Republic of Korea.
Department of Kinesiology, College of Arts and Sports, Inha University, Incheon 22212, Republic of Korea.
Mol Med Rep. 2017 May;15(5):3301-3309. doi: 10.3892/mmr.2017.6361. Epub 2017 Mar 23.
Senescence-accelerated mouse prone 8 (SAMP8), a non‑transgenic animal model used for researching sporadic Alzheimer's disease (AD), presents AD pathologies and overall dysregulation in brain energy metabolism, which is one of the early pathogenic characteristics of AD. In the present study, the authors examined chronological changes in the expression patterns of phosphorylated tau and of proteins related to energy metabolism to evaluate the association of tau phosphorylation and metabolism, using young‑ (2‑months‑old), middle‑ (5‑months‑old) and old‑aged (10‑months‑old) SAMP8. The levels of phosphorylated 5'‑AMP activated protein kinase at Thr172 (p‑AMPK) and phosphorylated glycogen synthase kinase 3β (p‑GSK3βS9) in the cortex of SAMP8 at 2 months were significantly higher than those in senescence‑accelerated mouse resistant 1 (SAMR1). The differences were not detected at 5 and 10 months of age, which were concurrent with the changes in levels of phosphorylated tau at Ser396 (p‑tauS396), but not with p‑tauS262. The level of p‑tauS262 was considerably higher in the cortex of middle‑aged SAMP8 when compared with that of SAMR1 and sustained in old‑aged SAMP8, but not in the young cortex. The levels of cortical sirtuin1 (Sirt1) and insulin receptor substrate 1 (IRS‑1) expression of young SAMP8 were significantly lower, when compared with those in SAMR1. However, in the hippocampus of SAMP8, the patterns of chronological changes and levels of p‑tau, p‑AMPK, Sirt1 and IRS‑1 relative to SAMR1 were different from those in the cortex. Taken together, the results suggested that regulation of tau phosphorylation via the AMPK‑GSK3β pathway concurrent with dysregulation of energy metabolism may precede the pathological tau hyperphosphorylation in the cortex of SAMP8, and that the regulation of AMPK‑GSK3β‑mediated tau phosphorylation may be dependent on phosphor‑epitope in tau or the region of brain.
衰老加速小鼠8型（SAMP8）是一种用于研究散发性阿尔茨海默病（AD）的非转基因动物模型，呈现出AD病理特征以及脑能量代谢的整体失调，这是AD早期致病特征之一。在本研究中，作者使用2月龄、5月龄和10月龄的SAMP8，检测磷酸化tau蛋白和能量代谢相关蛋白表达模式的时间变化，以评估tau磷酸化与代谢之间的关联。2月龄SAMP8皮质中苏氨酸172位点磷酸化的5'-AMP激活蛋白激酶（p-AMPK）和磷酸化糖原合酶激酶3β（p-GSK3βS9）水平显著高于衰老加速抗性小鼠1型（SAMR1）。在5月龄和10月龄时未检测到差异，这与丝氨酸396位点磷酸化tau（p-tauS396）水平的变化一致，但与p-tauS262的变化不一致。与SAMR1相比时，中年SAMP8皮质中p-tauS262水平显著更高，并在老年SAMP8中持续存在，但在年轻皮质中则不然。与SAMR1相比，年轻SAMP8皮质中沉默调节蛋白1（Sirt1）和胰岛素受体底物1（IRS-1）的表达水平显著更低。然而，在SAMP8的海马体中，相对于SAMR1，p-tau、p-AMPK、Sirt1和IRS-1的时间变化模式和水平与皮质中的不同。综上所述，结果表明，通过AMPK-GSK3β途径对tau磷酸化的调节与能量代谢失调同时发生，可能先于SAMP8皮质中病理性tau过度磷酸化，并且AMPK-GSK3β介导的tau磷酸化调节可能取决于tau中的磷酸化表位或脑区。
