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.

中文翻译：

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Fyn酪氨酸激酶可诱发阿尔茨海默氏病患者神经元中的淀粉样前体蛋白Tyr682磷酸化。

阿尔茨海默氏病（AD）是一种无法治愈的神经退行性疾病，具有一些早期发现策略。我们先前提出淀粉样蛋白前体蛋白（APP）酪氨酸682（Tyr682）残基作为开发AD中新的创新药理或诊断干预措施的重要目标。确实，当APP在Tyr682处被磷酸化时，它被迫进入酸性神经元区室，在其中进行加工以产生神经毒性淀粉样β肽。有趣的是，AD神经元中Fyn酪氨酸激酶（TK）与APP Tyr682残基的相互作用增加。在这里，我们证明了当Fyn TK过表达时，它会引发来自健康供体的神经元中的APP Tyr682磷酸化，并促进Aβ肽积累和神经元死亡的淀粉样蛋白APP处理。在AD患者的神经元中，Tyr处的APP磷酸化（pAPP-Tyr）增加，而表现出高pAPP-Tyr的AD神经元也具有较高的Fyn TK活性。Fyn TK抑制消除了AD神经元中的pAPP-Tyr并减少了Aβ42的分泌。此外，多域衔接子蛋白Fe65控制Fyn介导的pAPP-Tyr，从而有可能针对Fe65-APP-Fyn途径开发AD中的创新策略。总而言之，这些结果强烈强调了使用Fyn TKI将pAPP Tyr682集中用于诊断目的（作为疾病的早期生物标记）或用于药理靶向的重要性。多结构域衔接蛋白Fe65控制Fyn介导的pAPP-Tyr，从而保证有可能针对Fe65-APP-Fyn途径开发AD中的创新策略。总而言之，这些结果强烈强调了使用Fyn TKI将pAPP Tyr682集中用于诊断目的（作为疾病的早期生物标记）或用于药理靶向的重要性。多结构域衔接蛋白Fe65控制Fyn介导的pAPP-Tyr，从而保证有可能针对Fe65-APP-Fyn途径开发AD中的创新策略。总而言之，这些结果强烈强调了使用Fyn TKI将pAPP Tyr682集中用于诊断目的（作为疾病的早期生物标记）或用于药理靶向的重要性。