Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing

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...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2017-09, Vol.7 (1), p.12456-10, Article 12456
Main Authors: Lee, Yat Shing, Chow, Wan Ning Vanessa, Lau, Kwok-Fai
Format: Article
Language:English
Subjects:
13/95
631/378/1689
631/378/340
82/1
82/29
82/80
96/109
Alzheimer's disease
Amyloid precursor protein
Amyloidogenesis
Dimerization
Glycogen
Glycogen synthase kinase 3
Humanities and Social Sciences
Kinases
multidisciplinary
Neurodegenerative diseases
Phosphorylation
Protease inhibitors
Proteins
Proteolysis
Science
Science (multidisciplinary)
Threonine
β-Amyloid
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-12334-2