Abstract
Excessive generation of amyloid-β peptide (Aβ) by aberrant proteolysis of amyloid precursor protein (APP) is a key event in Alzheimer's disease (AD) pathogenesis. FE65 is a brain-enriched phospho-adaptor protein that interacts with APP and has been shown to modulate APP processing. However, the mechanism(s) that FE65 alters APP processing is still not fully understood. In the present study, we demonstrate that FE65 is phosphorylated at threonine 579 (T579) by glycogen synthase kinase 3β (GSK3β). Moreover, FE65 T579 phosphorylation potentiates γ- and β-secretases-mediated APP processing and Aβ liberation. Additionally, the phosphorylation suppresses FE65 PTB2 intermolecular dimerization but enhances FE65/APP complex formation. Hence, our findings reveal a novel mechanism that GSK3β stimulates amyloidogenic processing of APP by phosphorylation of FE65 at T579.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Protein Precursor / genetics
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Amyloid beta-Protein Precursor / metabolism*
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Animals
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Base Sequence
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CHO Cells
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COS Cells
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Chlorocebus aethiops
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Cricetulus
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Genes, Reporter
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Glycogen Synthase Kinase 3 beta / genetics
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Glycogen Synthase Kinase 3 beta / metabolism*
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HEK293 Cells
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Humans
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Luciferases / genetics
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Luciferases / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphorylation
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Plasmids / chemistry
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Plasmids / metabolism
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Protein Binding
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Protein Processing, Post-Translational*
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Sequence Alignment
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Sequence Homology, Nucleic Acid
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Threonine / metabolism
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Transfection
Substances
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APBB1 protein, human
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APP protein, human
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Amyloid beta-Protein Precursor
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Nerve Tissue Proteins
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Nuclear Proteins
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Threonine
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Luciferases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta