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Phosphorylation of FE65 at threonine 579 by GSK3? stimulates amyloid precursor protein processing.

ABSTRACT: Excessive generation of amyloid-? peptide (A?) 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 3? (GSK3?). Moreover, FE65 T579 phosphorylation potentiates ?- and ?-secretases-mediated APP processing and A? liberation. Additionally, the phosphorylation suppresses FE65 PTB2 intermolecular dimerization but enhances FE65/APP complex formation. Hence, our findings reveal a novel mechanism that GSK3? stimulates amyloidogenic processing of APP by phosphorylation of FE65 at T579.

SUBMITTER: Lee YS

PROVIDER: S-EPMC5622059 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Lee Yat Shing YS Chow Wan Ning Vanessa WNV Lau Kwok-Fai KF

Scientific reports 20170929 1

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). ...[more]

PMID: 28963516

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