ABSTRACT
A disintegrin and metalloproteinase 10 (ADAM10) is the constitutive α-secretase that governs the nonamyloidogenic pathway of ß-amyloid precursor protein processing and is an attractive drug target for treating Alzheimer's disease. To date, little is known about the mechanism by which ADAM10 is regulated in neurons. Using mouse primary cortical neurons, we show here that NMDA receptor (NMDAR) activation led to upregulation of the genes encoding ADAM10 and ß-catenin proteins. Interestingly, the ADAM10 upregulation was abolished by inhibitors of Wnt/ß-catenin signaling. Conversely, activation of the Wnt/ß-catenin signaling pathway by recombinant Wnt3a stimulated ADAM10 expression. We further showed that both the NMDAR- and Wnt3a-induced ADAM10 upregulation was blocked by ERK inhibitors. We suggest that the NMDARs control ADAM10 expression via a Wnt/MAPK signaling pathway.
Subject(s)
ADAM Proteins/biosynthesis , Amyloid Precursor Protein Secretases/biosynthesis , MAP Kinase Signaling System/physiology , Membrane Proteins/biosynthesis , Receptors, N-Methyl-D-Aspartate/metabolism , Up-Regulation/physiology , Wnt Signaling Pathway/physiology , Wnt3A Protein/biosynthesis , ADAM10 Protein , Animals , Cells, Cultured , Disintegrins/biosynthesis , Female , Male , Mice , Mice, Inbred C57BL , beta Catenin/biosynthesisABSTRACT
Conjugated linoleic acid (CLA) plays important roles in physiological conditions. The aim of present study was to explore the effects of CLA on the cleavage of amyloid precursor protein (APP) and the potential mechanism involved. The effects of CLA on intracellular APP, BACE1 (ß-site APP Cleaving Enzyme1, BACE1), a disintegrin and metalloprotease (ADAM10) and extracellular sAPPα (soluble) were analyzed by RT-PCR, Western blot and ELISA in SH-SY5Y cells. Our study indicated that CLA significantly decreased the expression of BACE1 and increased the extracellular secretion of sAPPα, but not affected the levels of APP and ADAM10. The study also revealed that the nuclear receptor peroxisome proliferators activated receptor γ (PPARγ) played an important role in the CLA-induced intracellular BACE1 decrease, as well as the extracellular sAPPα increase through knockdown of PPARγ transcription using siRNA. We hypothesize that CLA acts as an agonist or ligand, which binds with PPARγ and leads to the increase in APP cleavage via α-secretase-mediated pathway and the decrease in the deposition of Aß.
