Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients

Abstract

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a few early detection strategies. We previously proposed the amyloid precursor protein (APP) tyrosine 682 (Tyr682) residue as a valuable target for the development of new innovative pharmacologic or diagnostic interventions in AD. Indeed, when APP is phosphorylated at Tyr682, it is forced into acidic neuronal compartments where it is processed to generate neurotoxic amyloid β peptides. Of interest, Fyn tyrosine kinase (TK) interaction with APP Tyr682 residue increases in AD neurons. Here we proved that when Fyn TK was overexpressed it elicited APP Tyr682 phosphorylation in neurons from healthy donors and promoted the amyloidogenic APP processing with Aβ peptides accumulation and neuronal death. Phosphorylation of APP at Tyr (pAPP-Tyr) increased in neurons of AD patients and AD neurons that exhibited high pAPP-Tyr also had higher Fyn TK activity. Fyn TK inhibition abolished the pAPP-Tyr and reduced Aβ42 secretion in AD neurons. In addition, the multidomain adaptor protein Fe65 controlled the Fyn-mediated pAPP-Tyr, warranting the possibility of targeting the Fe65-APP-Fyn pathway to develop innovative strategies in AD. Altogether, these results strongly emphasize the relevance of focusing on pAPP Tyr682 either for diagnostic purposes, as an early biomarker of the disease, or for pharmacological targeting, using Fyn TKI.

Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue

“…Our group have previously underlined the crucial role of APP Tyr 682 residue in the processes responsible for the generation of Aβ peptides in human neurons [ 2 , 3 ]. APP Tyr 682 residue is located in the highly conserved 682 YENPTY 687 motif, which binds specific adaptor proteins depending on its phosphorylation/dephosphorylation state [ 4 ].…”

“…Consequently, APP accumulates in the acidic neuronal compartments, such as late endosomes and lysosomes, where it is preferentially cleaved to generate Aβ peptides [ 3 ]. Notably, we previously showed that high levels of phosphorylation of APP Tyr 682 residue in neurons differentiated from neuronal stem cells of AD patients [ 2 , 3 , 10 ] preceding Aβ accumulation, and promoting neuronal degeneration. We therefore suggested that this high levels of APP Tyr 682 phosphorylation might be an early marker of neuronal degeneration [ 5 , 6 ].…”

“…We therefore suggested that this high levels of APP Tyr 682 phosphorylation might be an early marker of neuronal degeneration [ 5 , 6 ]. Furthermore, we identified Fyn tyrosine kinase (TK) in AD neurons as being responsible for the increased levels of APP Tyr 682 phosphorylation, that in turn triggers biochemical events downstream, finally resulting in Aβ production and neuronal death [ 2 ]. Consistently, the reduction in Fyn activity, using Fyn TK inhibitors (TKI) or Fyn mRNA silencing, led to the decrease in APP Tyr 682 phosphorylation and Aβ release in AD neurons [ 2 , 3 ].…”

“…Furthermore, we identified Fyn tyrosine kinase (TK) in AD neurons as being responsible for the increased levels of APP Tyr 682 phosphorylation, that in turn triggers biochemical events downstream, finally resulting in Aβ production and neuronal death [ 2 ]. Consistently, the reduction in Fyn activity, using Fyn TK inhibitors (TKI) or Fyn mRNA silencing, led to the decrease in APP Tyr 682 phosphorylation and Aβ release in AD neurons [ 2 , 3 ]. These findings opened up a promising perspective for the use of APP Tyr 682 residue as a biomarker to identify patients with high levels of APP Tyr 682 phosphorylation that may benefit from personalised treatments with Fyn TKI.…”

“…The increased APP Tyr phosphorylation in fibroblasts of mutant minipigs was associated to the same defects in APP trafficking that we also reported in neurons from AD patients carrying the same PSEN1 M146L mutation [ 3 ]. Relevantly, both APP Tyr phosphorylation and the defects in APP trafficking were rescued by Fyn TKI [ 2 , 3 ]. Of note, minipigs carrying PSEN1 M146L mutation displayed Aβ plaques and tau tangles in brain [ 11 ].…”