May 22, 2020

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

British Journal of Pharmacology
Chang Woo ChaeHo Jae Han

Abstract

Although diabetes mellitus (DM) is an important risk factor for Alzheimer's disease (AD), the detailed mechanism by which DM regulates amyloid beta (Aβ) processing is still unclear. The increment of residence time of amyloid precursor protein (APP) in endosomes is critical for Aβ production and that DM causes endosomal dysregulation. Therefore, this study aims to examine the effects of high glucose on APP-producing endosomes and its related signaling pathways. To identify the mechanisms behind purpose, we investigated the effects of high glucose on early endosomal abnormalities and its related signaling pathway in neuroblastoma. Moreover, diabetic mice treated with pharmacological inhibitors were used to examine the endosomal dysfunction. The hippocampus of diabetic animals presented endosomal abnormalities and Aβ upregulation. High glucose increased Aβ production through early endosomal enlargement achieved by the increment of lipid raft-mediated APP endocytosis. High glucose induced ROS-stimulated Sp1 activation, which upregulated phosphatidylinositol binding clathrin assembly protein (PICALM), clathrin heavy chain, and adaptor-related protein complex 2 alpha 1. PICALM facilitated clathrin-mediated APP endocytosis resulting i...Continue Reading

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Mentioned in this Paper

Phosphatidylinositol-Binding Clathrin Assembly Protein
Protein Transport into Membrane Raft
Amyloid beta-Protein Precursor
Glucose Increased
Endocytosis
Positive Regulation of Binding
Inhibitors
Diabetes
Positive Regulation of Beta-amyloid Formation
Alzheimer's Disease

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