Meur Shreyasi, Karati Dipanjan
Department of Pharmaceutical Technology, School of Pharmacy, Techno India University, Kolkata, 700091, West Bengal, India.
Mol Neurobiol. 2025 Jan;62(1):643-660. doi: 10.1007/s12035-024-04286-2. Epub 2024 Jun 18.
Alzheimer's disease, characterized by the accumulation of abnormal protein aggregates and neuronal damage in the brain, leads to a gradual decline in cognitive function and memory. As a complex neurodegenerative disorder, it involves disruptions in various biochemical pathways and neurotransmitter systems, contributing to the progressive loss of neurons and synaptic connections. The complexity of Alzheimer's signaling pathways complicates treatment, presenting a formidable challenge in the quest for effective therapeutic interventions. A member of the Src family of kinases (SFKs), Fyn, is a type of non-receptor tyrosine kinase that has been linked to multiple essential CNS processes, such as myelination and synaptic transmission. Fyn is an appealing target for AD treatments because it is uniquely linked to the two major pathologies in AD by its interaction with tau, in addition to being activated by amyloid-beta (Aβ) through PrP. Fyn mediates neurotoxicity and synaptic impairments caused by Aβ and is involved in regulating the process of Aβ synthesis.Additionally, the tau protein's tyrosine phosphorylation is induced by Fyn. Fyn is also a challenging target because of its widespread body expression and strong homology with other kinases of the Src family, which could cause unintentional off-target effects. This review emphasizes signaling pathways mediated by Fyn that govern neuronal development and plasticity while also summarizing the most noteworthy recent research relevant to Fyn kinase's function in the brain. Additionally, the therapeutic inhibition of Fyn kinase has been discussed, with a focus on the Fyn kinase inhibitors that are in clinical trials, which presents a fascinating opportunity for targeting Fyn kinase in the creation of possible therapeutic approaches for the management of Alzheimer's disease.
阿尔茨海默病的特征是大脑中异常蛋白质聚集体的积累和神经元损伤，导致认知功能和记忆力逐渐下降。作为一种复杂的神经退行性疾病，它涉及各种生化途径和神经递质系统的紊乱，导致神经元和突触连接的逐渐丧失。阿尔茨海默病信号通路的复杂性使治疗变得复杂，在寻求有效的治疗干预措施方面构成了巨大挑战。Src激酶家族（SFKs）的成员Fyn是一种非受体酪氨酸激酶，与多种重要的中枢神经系统过程有关，如髓鞘形成和突触传递。Fyn是阿尔茨海默病治疗的一个有吸引力的靶点，因为它通过与tau蛋白的相互作用与阿尔茨海默病的两种主要病理特征独特地联系在一起，此外还通过朊蛋白被β淀粉样蛋白（Aβ）激活。Fyn介导由Aβ引起的神经毒性和突触损伤，并参与调节Aβ的合成过程。此外，Fyn诱导tau蛋白的酪氨酸磷酸化。Fyn也是一个具有挑战性的靶点，因为它在体内广泛表达，并且与Src家族的其他激酶具有高度同源性，这可能会导致意外的脱靶效应。本综述强调了由Fyn介导的调控神经元发育和可塑性的信号通路，同时总结了与Fyn激酶在大脑中的功能相关的最新研究成果。此外，还讨论了对Fyn激酶的治疗性抑制，重点关注正在进行临床试验的Fyn激酶抑制剂，这为在开发可能的阿尔茨海默病治疗方法中靶向Fyn激酶提供了一个引人入胜的机会。
