School of Chinese Medicine, The University of Hong Kong, 10 Sassoon Road, Hong Kong, Hong Kong SAR, China.
Department of Medicine, The University of Hong Kong, 21 Sassoon Road, Hong Kong, Hong Kong SAR, China.
Mol Neurobiol. 2018 Jul;55(7):5537-5547. doi: 10.1007/s12035-017-0785-y. Epub 2017 Sep 30.
Adaptor proteins containing the pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPLs) are multifunctional adaptor proteins involved in regulating many biological activities and processes. The newly identified metabolic factor APPL2 showed the potentials to modulate cell growth, but whether APPL2 could affect adult neurogenesis and animal mood behaviors remains unknown. In the present study, APPL2 transgenic (Tg) mice and wild-type littermates were used for testing our hypothesis that APPL2 could affect glucocorticoid receptor (GR) signaling and modulate hippocampal neurogenesis, which contributes to depressive and anxiety behaviors. Compared with WT littermates, APPL2 Tg mice had enhanced GR phosphorylation under basic condition but had no different plasma corticosterone (CORT) level and GR phosphorylation under stress stimulation. APPL2 Tg mice had decreased hippocampal neurogenesis that was reversed by GR antagonist RU486. APPL2 Tg mice also showed the impaired hippocampal neurogenesis and presented the depressive and anxiety behaviors. In conclusion, APPL2 could be an important regulator for adult neurogenesis. APPL2 overexpression could blunt the activation of glucocorticoid receptor when undergoing environmental stress. Our study suggests that APPL2 might be a new therapeutic target for mental disorders.
衔接蛋白含有pleckstrin 同源结构域、磷酸酪氨酸结合结构域和亮氨酸拉链基序（APPLs），是一种多功能衔接蛋白，参与调节许多生物活性和过程。新发现的代谢因子 APPL2 显示出调节细胞生长的潜力，但 APPL2 是否能影响成年神经发生和动物情绪行为尚不清楚。在本研究中，使用 APPL2 转基因（Tg）小鼠和野生型同窝仔鼠来检验我们的假设，即 APPL2 可以影响糖皮质激素受体（GR）信号转导，调节海马神经发生，从而导致抑郁和焦虑行为。与 WT 同窝仔鼠相比，APPL2 Tg 小鼠在基础条件下 GR 磷酸化增强，但应激刺激下的血浆皮质酮（CORT）水平和 GR 磷酸化没有差异。APPL2 Tg 小鼠的海马神经发生减少，GR 拮抗剂 RU486 可逆转这种减少。APPL2 Tg 小鼠还表现出海马神经发生受损，并出现抑郁和焦虑行为。总之，APPL2 可能是成年神经发生的重要调节因子。APPL2 过表达在经历环境应激时可能会使糖皮质激素受体的激活钝化。我们的研究表明，APPL2 可能是治疗精神障碍的新靶点。
