Tyr687 dependent APP endocytosis and Abeta production.
The neurotoxic Abeta peptide is derived by proteolytic processing from the Alzheimer's amyloid precursor protein (APP), whose short cytoplasmic domain contains several phosphorylatable amino acids. The latter can be phosphorylated 'in vitro' and 'in vivo,' and in some cases phosphorylation appears to be associated with the disease condition. Using APP-GFP fusion proteins to monitor APP processing, the role of Tyr687 was addressed by mimicking its constitutive phosphorylation (Y687E) and dephosphorylation (Y687F). Contrasting effects on subcellular APP distribution were observed. Y687E-APP-GFP was targeted to the membrane but could not be detected in transferrin containing vesicular structures, and exhibited a concomitant and dramatic decrease in Abeta production. In contrast, Y687F-APP-GFP was endocytosed similarly to wild type APP, but was relatively favoured for beta-secretase cleavage. Overall, Tyr687 appears to be a critical residue determining APP targeting and processing via different pathways, including endocytosis and retrograde transport. Significantly, from a disease perspective, mimicking Tyr687 phosphorylation resulted in a hitherto undescribed inhibition of Abeta production. Our results provide novel insights into the role of direct APP phosphorylation on APP targeting, processing and Abeta production.
Rebelo
Sandra
S
Laboratório de Neurociências, Centro de Biologia Celular, Universidade de Aveiro, Aveiro 3810-193, Portugal.
Vieira
Sandra Isabel
SI
Esselmann
Hermann
H
Wiltfang
Jens
J
da Cruz e Silva
Edgar F
EF
da Cruz e Silva
Odete A B
OA
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004705:Endocytosis / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D016296:Mutagenesis; D010446:Peptide Fragments / Q000378:metabolism*; D010766:Phosphorylation; D014443:Tyrosine / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D049452:Green Fluorescent Proteins; D014443:Tyrosine