PI3K-AKT-mTOR signaling pathway regulates autophagy of hippocampal neurons in diabetic rats with chronic unpredictable mild stress

Abstract

It is reported that the co-morbidities of diabetes and depression will be a new challenge for humanity. However, the underlying mechanism is not clear. The present study investigated the histopathology, autophagy of hippocampal neurons, and the PI3K-AKT- mTOR signaling pathway in type 2 diabetes with depression（T2DD） rats. The results showed that, the chronic unpredictable mild stress (CUMS), Type 2 diabetes mellitus (T2DM) and T2DD in rats were induced successfully. Compared with the CUMS and T2DM groups, the T2DD group performed significantly fewer autonomic activities in the open-field test, and longer immobile in the force swimming test, and increasing of Corticosterone (CORT) in blood. The number of pyknotic neurons at cornu ammonis 1 (CA1) and dentate gyrus (DG) of the hippocampus in T2DD was significantly increased compared with CUMS and T2DM groups. Moreover, compared with the CUMS and T2DM groups, the mitochondrial autophagosomes were most abundant in the T2DD group. As shown in western blot and immunofluorescence, compared with the control group, in the CUMS, T2DM and T2DD groups, significantly increased expression of Beclin-1 and LC3B and decreased P62 were detected. In the PC12 cells, the relative amount of parkin and LC3B in the CORT+HG group was significantly higher than that in the CORT and HG groups. Compared with the control group, p-AKT/AKT and p-mTOR/mTOR in CUMS, T2DM and T2DD groups were significantly decreased. Compared with the CUMS group, p-AKT/AKT, p-PI3K/PI3K and p-mTOR/mTOR in the T2DD group exhibited further decrease. Similar results were obtained in PC12 cells in vitro. It is suggests that memory and cognitive impairment in rats with co-morbidities of diabetes and depression might be related with hippocampal neuronal damage and autophagy increase, which was involved in the PI3K-AKT-mTOR signaling pathway.

Keywords: Autophagy; Chronic unpredictable mild stress; Hippocampal; PI3K-AKT- mTOR signaling pathway; Type 2 diabetic model rats.