RETRACTED: An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer's Disease Patients

Abstract

Alzheimer's disease (AD) is the most common cause of dementia and is likely caused by defective amyloid precursor protein (APP) trafficking and processing in neurons leading to amyloid plaques containing the amyloid-β (Aβ) APP peptide byproducts. Understanding how APP is targeted to selected destinations inside neurons and identifying the mechanisms responsible for the generation of Aβ are thus the keys for the advancement of new therapies. We previously developed a mouse model with a mutation at tyrosine (Tyr) 682 in the C-terminus of APP. This residue is needed for APP to bind to the coating protein Clathrin and to the Clathrin adaptor protein AP2 as well as for the correct APP trafficking and sorting in neurons. By extending these findings to humans, we found that APP binding to Clathrin is decreased in neural stem cells from AD sufferers. Increased APP Tyr phosphorylation alters APP trafficking in AD neurons and it is associated to Fyn Tyr kinase activation. We show that compounds affecting Tyr kinase activity and counteracting defects in AD neurons can control APP location and compartmentalization. APP Tyr phosphorylation is thus a potential therapeutic target for AD.

Structure of APP-C991–99 and implications for role of extra-membrane domains in function and oligomerization

“…[56] Y 86 has been identified to be phosphorylated at higher concentrations in the brains of AD patients, and is suspected to prevent the interaction of APP with adaptor proteins. [54]…”

Structure of APP-C991-99and Implications for Role of Extra-Membrane Domains in Function and Oligomerization

“…[51] The phosphorylation of S 59 enhances trafficking of APP to the golgi apparatus. [52] It has been noted that Ala point mutation at T 72 may enhance the production of Aβ 40 and Aβ 42 , [53][54][55] impacting interaction of APP with some enzymes. [56] Y 86 has been identified to be phosphorylated at higher concentrations in the brains of AD patients, and is suspected to prevent the interaction of APP with adaptor proteins.…”

“…[56] Y 86 has been identified to be phosphorylated at higher concentrations in the brains of AD patients, and is suspected to prevent the interaction of APP with adaptor proteins. [54] The C-Loop and C-Helix are known to interact with several proteins in the cytoplasm, forming complexes in which these domains adopt an α-helical structure. [57] The C99 sequence binds to many cytoplasmic proteins including the G protein G0 with residues H 61 -K 80 , [58] the adaptor protein Fe65 with residues D 68 -N 99 , [59] the adaptor protein X11 with residues Q 83 -Q 96, [60] the adaptor protein mDab1 with a similar residues to X11, [61] and the kinase Jip-1with residues N 84 -F 93 .…”

Phosphorylation Signaling in APP Processing in Alzheimer’s Disease

“…Zhou and colleagues discovered that the overexpression of the Grb2-SH2 domain elevates the production of Aβ40 in human embryonic kidney (HEK) 293 cells [66]. A recent study noted that the Y682 phosphorylation of APP is associated with the activation of the non-tyrosine kinase Fyn [69]. The increased phosphorylation at Y682 residues disrupts the binding of APP to clathrin and AP2 and its colocalization with these proteins [69].…”

“…A recent study noted that the Y682 phosphorylation of APP is associated with the activation of the non-tyrosine kinase Fyn [69]. The increased phosphorylation at Y682 residues disrupts the binding of APP to clathrin and AP2 and its colocalization with these proteins [69]. In addition, the trafficking and sorting of APP after phosphorylation is also altered as more APP molecules accumulate in the trans-Golgi network (TGN) and late endosomes [69].…”