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.
Highlights
Alzheimer’s disease (AD) is a devastating public health problem
We searched for the tyrosine kinase (TK) that is involved in amyloid precursor protein (APP) phosphorylation at tyrosine 682 (Tyr682) in AD neurons and using mass spectrometry analysis we found that Fyn TK interacted only with this residue, and the interaction was elevated in brain tissue from AD modeling Gottingen minipigs [21] and patients both carrying presenilin 1 (PSEN1) gene mutations [20]
Fyn and determine whether Fyn plays a role in APP phosphorylation at Tyr, neural stem cells (NSCs) from healthy donors were transfected with C-terminal green fluorescent protein (GFP) tagged APP and
Summary
To generate Aβ peptides, the amyloid β precursor protein (APP) must first be cleaved by the aspartyl protease β-site APP-cleaving enzyme-1 (BACE-1). We and others previously reported that the tyrosine 682 (Tyr682) residue in the 682 YENPTY687 motif of APP is crucial for APP trafficking in neurons [6,7,8,9,10,11]. Tyr682 phosphorylation regulates APP binding to specific adaptors and controls APP endocytosis and distribution in neurons [8,12,13,14,15]. When Tyr682 is replaced by glycine (YG), APP endocytosis is affected, and APP is processed by α-secretase on the plasma membrane to generate soluble APPα (sAPPα) fragments [16,17]. YG mice exhibit alterations of APP subcellular trafficking [17] and deficits in autophagy, with enlarged and dysmorphic
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