High glucose-mediated PICALM and mTORC1 modulate processing of amyloid precursor protein via endosomal abnormalities

Abstract

Background and Purpose Although diabetes mellitus (DM) is an important risk factor for Alzheimer's disease (AD), the detailed mechanism(s) by which DM regulates amyloid beta (A beta) processing is still unclear. The longer residence time of amyloid precursor protein (APP) in endosomes is critical for A beta production and DM is known to cause endosomal dysregulation. Here we have examined the effects of high glucose on APP-producing endosomes and related signaling pathways. Experimental Approach To identify the underlying mechanisms, we investigated the effects of high glucose on abnormalities in early endosomes and related signalling pathways in human neuroblastoma cells. In vivo, diabetic mice treated with pharmacological inhibitors were used to examine endosomal dysfunction. Key Results The hippocampus of diabetic animals presented endosomal abnormalities and A beta up-regulation. High glucose increased A beta production through early endosomal enlargement achieved by increased lipid raft-mediated APP endocytosis. High glucose induced ROS-stimulated Sp1 activation, up-regulating phosphatidylinositol binding clathrin assembly protein (PICALM), clathrin heavy chain, and adaptor-related protein complex 2 alpha 1. PICALM facilitated clathrin-mediated APP endocytosis resulting in early endosomal enlargement. Meanwhile, AMPK/mTORC1-mediated autophagy defect and ROS- and mTORC1-mediated lysosomal dysfunction aggravated early endosomal enlargement under high glucose. Moreover, the increased A beta production and cognitive deficits in diabetic mice were reversed by inhibition of early endosomal enlargement. Conclusion and Implications High glucose induces early endosomal abnormalities through PICALM-induced APP endocytosis and mTORC1-inhibited endosomal clearance, up-regulating A beta production. Thus, targeting PICALM and mTORC1 to prevent endosomal disorders is a promising strategy for managing diabetes-induced AD.