Hainan Province Key Laboratory for Sustainable Utilization of Tropical Bioresources, Hainan University, Hainan, China.
Laboratory of Biotechnology and Molecular Pharmacology, School of Life and Pharmaceutical Sciences, Hainan University, Hainan, China.
FASEB J. 2020 Apr;34(4):5092-5105. doi: 10.1096/fj.201902230RR. Epub 2020 Feb 17.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β-amyloid peptide 1-42 (Aβ ), and neuronal loss. The self-association of Aβ monomers (Aβ-M) into soluble oligomers seems to be crucial for the development of neurotoxicity. Previous publications have shown that Aβ oligomers and dimers might play key roles in inducing AD. The role of Aβ-M was rarely investigated and still unclear in AD. To understand the effects of Aβ-M on neurons and other cell types in the brain could be the key to understand its function. In our study, we found that Aβ-M expression slowly induced cell apoptosis within 48 hours after transfection, β2 adrenergic receptor (β2AR) interacted with Aβ-M in the pull-down and the yeast two-hybrid assays, and Aβ-M played a major role in inducing phosphorylation of Tau at Ser-214, c-Jun N-terminal kinase (JNK) at Thr-183/Tyr-185, p70 ribosomal protein S6 kinase (p70S6K) at Thr-389. We also discovered that β2AR, G protein-coupled receptor kinase 2 (GRK2), and protein kinase A (PKA) mediated the phosphorylation of Tau and JNK. Aβ-M induced phosphorylation of Tau at Ser-214 through both β2AR-cAMP/PKA-JNK and β2AR-GRK signaling pathways. Mitogen-activated protein kinase kinase (MEK) mediated the phosphorylation of p70S6K induced by Aβ-M.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，与突触功能障碍、β-淀粉样肽 1-42（Aβ）的病理性积累和神经元丧失有关。Aβ 单体（Aβ-M）自缔合形成可溶性寡聚体似乎对神经毒性的发展至关重要。先前的出版物表明，Aβ 寡聚体和二聚体可能在诱导 AD 中发挥关键作用。Aβ-M 在 AD 中的作用很少被研究，目前仍不清楚。了解 Aβ-M 对大脑中神经元和其他细胞类型的影响可能是理解其功能的关键。在我们的研究中，我们发现 Aβ-M 表达在转染后 48 小时内缓慢诱导细胞凋亡，β2 肾上腺素能受体（β2AR）在下拉和酵母双杂交实验中与 Aβ-M 相互作用，Aβ-M 在诱导 Tau 在 Ser-214 处磷酸化、c-Jun N-末端激酶（JNK）在 Thr-183/Tyr-185 处磷酸化、p70 核糖体蛋白 S6 激酶（p70S6K）在 Thr-389 处磷酸化方面起着主要作用。我们还发现β2AR、G 蛋白偶联受体激酶 2（GRK2）和蛋白激酶 A（PKA）介导 Tau 和 JNK 的磷酸化。Aβ-M 通过β2AR-cAMP/PKA-JNK 和 β2AR-GRK 信号通路诱导 Tau 在 Ser-214 处的磷酸化。丝裂原活化蛋白激酶激酶（MEK）介导 Aβ-M 诱导的 p70S6K 磷酸化。
