Roles of metabolic factor APPL2 in depressive symptoms and its application as the drug target to traditional Chinese medicine compound baicalin

Abstract

Depression is a serious global issue that affects mental health of the patients in all ages. Due to lack of understanding for the biological underpinning of the depression, current antidepressant treatments still focus on attenuating the relative pathophysiologies. Thus, exploring the biological mechanism of depression is benefit for developing new antidepressant drugs. Adult neurogenesis, the life persist process of neuronal generations at specific brain regions, plays the primary roles in development of the depressive symptoms including emotional deficits and olfactory dysfunctions. Glucocorticoid receptor (GR) acts as the key to link the depression with adult neurogenesis as well as the target for antidepressant. Given the close relationship between metabolism disorders and psychiatric and neurological diseases, many metabolic factors have the potential to regulate adult neurogenesis. Therefore, investigating the functions of new found metabolic factors in adult neurogenesis would help to explore the antidepressant targets. Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper (APPLs) are one type of new identified factor participates in glucose metabolism and cell growth. However, if APPL2 could regulate adult neurogenesis and relative animal behaviors remains unknown. In current study, I employed APPL2 Tg mice carrying with overexpressed APPL2 to solve the questions. The results showed that APPL2 overexpression induced hyperactivity of GR at baseline and blocked GR sensitivity in response to stress, and such mechanism is critical in neurogenic mediating functions of APPL2. Moreover, APPL2 Tg mice presented the deficits in neurogenesis including limited proliferation, decreased neurogenic fate choice and delayed maturation of neural stem/progenitor cells (NSPCs). In behavioral tests, APPL2 Tg mice had the depressive-/anxiety- like behaviors. Additionally, APPL2 presented suppressed the neurogenesis at olfactory system and deficits of the olfactory behavior. Together, this study firstly identified the roles of APPL2 as the potential target to attenuating depressive symptoms via regulating adult neurogenesis. Scutellaria baicalensis is widely used in many Traditional Chinese Medicine (TCM) formulas for regulating emotional deficits. Baicalin, the main bioactive compound extracted from Scutellaria baicalensis, is well-established for its promoting hippocampal neurogenesis and antidepressant effects. However, whether baicalin could attenuate depression related olfactory deficits in correlation with APPL2/GR dependent mechanism remains unexplored. In current study, baicalin improves adult neurogenesis and behavioral patterns via APPL2 dependent mechanism. Moreover, chronic corticosterone (CORT) induced depression model was used to further investigate the functions of baicalin to attenuate depression associated olfactory deficit. Baicalin treatment improves the adult neurogenesis at both hippocampus and olfactory system. More importantly, treatment of baicalin cannot only attenuate the emotional deficits but also improves the olfactory functions in depression model. Overall, baicalin could perform as the potential antidepressant to improve emotional and olfactory functions by promoting adult neurogenesis via APPL2/GR dependent mechanism. In conclusion, this thesis identified the new functions of APPL2 in regulating adult neurogenesis. Moreover, this project also found APPL2 can be applied as the drug target for TCM compound baicalin, in its promotion of neurogenesis and protective effects against emotional and olfactory deficits induced by depression.