Maki Takahito, Sawahata Masahito, Uta Daisuke, Irie Kazuhiro, Kume Toshiaki
Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama.
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University.
Biol Pharm Bull. 2023;46(2):359-363. doi: 10.1248/bpb.b22-00855.
Amyloid β (Aβ) plays a key role in the pathology of Alzheimer's disease (AD) and is toxic owing to its ability to aggregate into oligomers and fibrils. Aβ has high aggregative ability and potent toxicity due to the "toxic turn" at positions 22 and 23. Furthermore, APP knock-in mice producing E22P-Aβ with the toxic turn exhibited AD-related phenotypes such as cognitive impairment, Aβ plaque accumulation, and tau hyperphosphorylation. In these mice, it is suggested that the activation of neuroinflammation and dysregulation of hypoxia-inducible factor (HIF) expression in the hippocampus contribute to the pathogenesis of AD-related phenotype. However, it remains unclear which cells are responsible for the dysregulation of HIF expression and the neuroinflammation which was induced by E22P-Aβ with the toxic turn. Here, we investigated the effects of chronic treatment with E22P-Aβ42 and lipopolysaccharides (LPS) on the inflammatory response in BV-2 microglia. Chronic treatment with E22P-Aβ42 and LPS increased nitric oxide production and the expression of interleukin-6 (IL-6), whereas it reduced the expression of HIF-1α and HIF-3α in BV-2 microglia. The reduction of HIF-1α caused by E22P-Aβ42 and LPS was milder than that caused by LPS. Furthermore, chronic treatment with E22P-Aβ42 and LPS increased the nuclear translocation of nuclear factor-kappaB (NF-κB). E22P-Aβ42 could enhance the inflammatory response of microglia with abnormal HIF signaling and contribute to the progression of AD pathology.
淀粉样β蛋白（Aβ）在阿尔茨海默病（AD）的病理过程中起关键作用，因其能够聚集成寡聚体和原纤维而具有毒性。由于22位和23位的“毒性转折”，Aβ具有高聚集能力和强毒性。此外，产生具有毒性转折的E22P - Aβ的APP基因敲入小鼠表现出与AD相关的表型，如认知障碍、Aβ斑块积累和tau蛋白过度磷酸化。在这些小鼠中，提示海马体中神经炎症的激活和缺氧诱导因子（HIF）表达的失调促成了AD相关表型的发病机制。然而，尚不清楚哪些细胞负责HIF表达的失调以及由具有毒性转折的E22P - Aβ诱导的神经炎症。在此，我们研究了用E22P - Aβ42和脂多糖（LPS）长期处理对BV - 2小胶质细胞炎症反应的影响。用E22P - Aβ42和LPS长期处理增加了一氧化氮的产生和白细胞介素 - 6（IL - 6）的表达，而降低了BV - 2小胶质细胞中HIF - 1α和HIF - 3α的表达。E22P - Aβ42和LPS引起的HIF - 1α的降低比LPS引起的更轻微。此外，用E22P - Aβ42和LPS长期处理增加了核因子κB（NF - κB）的核转位。E22P - Aβ42可增强具有异常HIF信号的小胶质细胞的炎症反应，并促进AD病理进程。
