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.
Highlights
Deposition of extracellular amyloid-β (Aβ) plaques is a pathological hallmark of Alzheimer's disease (AD)
Since T579A mutation could preclude phosphorylation of the residue, our finding suggests that overexpression of glycogen synthase kinase 3β (GSK3β) leads to increased FE65 phosphorylation preferentially at threonine 579 (T579)
As we have found that GSK3β phosphorylates FE65 T579 within its amyloid precursor protein (APP) binding PTB2 domain, we enquired if GSK3β modulates FE65-mediated APP processing
Summary
Deposition of extracellular amyloid-β (Aβ) plaques is a pathological hallmark of Alzheimer's disease (AD). Emerging evidence reveals that the proteolytic cleavage of APP can be influenced by the APP intracellular domain (AICD) interacting proteins including FE651,2. FE65 possesses three conserved protein interaction domains, including an N-terminal WW domain and two C-terminal phosphotyrosine binding (PTB) domains, and is capable of recruiting different proteins to form multimolecular complexes. FE65 physically binds to AICD through its second PTB domain (PTB2), and serves as a bridging molecule between APP and a number of ApoE receptors including low-density lipoprotein receptor-related protein (LRP1), apolipoprotein E receptor 2 (ApoER2) and very-low-density-lipoprotein receptor (VLDLR) to modulate APP processing. Since T579 is located within the FE65 PTB2 domain which is for binding to APP, we speculated that FE65 T579 phosphorylation may alter APP metabolism, and attempted to identify the responsible kinase(s). We demonstrated that FE65 T579 phosphorylation promotes FE65-mediated APP processing and Aβ liberation by promoting FE65/APP interaction through suppressing the FE65 PTB2 dimerization
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