G-protein coupled receptor, PI3K and Rho signaling pathways regulate the cascades of Tau and amyloid-β in Alzheimer's disease.
G-protein coupled receptor, PI3K and Rho signaling pathways regulate the cascades of Tau and amyloid-β in Alzheimer's disease.
复制标题
G蛋白耦合受体，PI3K和RHO信号通路在阿尔茨海默氏病中调节Tau和淀粉样蛋白β的层流。
DOI：
10.1186/s43556-021-00036-1
复制
发表时间：
2021-06-10
影响因子：
4
通讯作者：
Chinnathambi S
中科院分区：
文献类型：
--
作者：
Desale SE;Chidambaram H;Chinnathambi S
阿尔茨海默病是一种进行性神经退行性疾病，其特征是细胞外环境中存在淀粉样蛋白斑块和神经细胞中形成神经原纤维缠结(NFT)的β蛋白聚集体。除了这些病理蛋白外，该病还表现为神经炎症、神经元死亡、小胶质细胞免疫功能受损和突触丧失，这些都是由几个重要的信号通路介导的。PI3K/Akt介导的生存信号通路被许多受体激活，如G蛋白偶联受体(GPCRs)、触发髓系细胞上表达的受体2(TREM2)和溶血磷脂酸(LPA)受体。该信号通路不仅能增加神经元的存活率，还能调节炎症、吞噬、细胞保护、Tau磷酸化和Aβ的分泌。在本综述中，我们重点介绍了激活PI3K/Akt通路的受体及其治疗阿尔茨海默病的潜力。在几种膜受体中，GPCRs是治疗的主要药物靶点，GPCRs信号通路在阿尔茨海默病期间会发生变化。一些GPCRs参与了Tau蛋白的致病过程，通过激活多种细胞激酶使Tau蛋白磷酸化，并参与了淀粉样蛋白-β合成的淀粉样蛋白合成途径。在阿尔茨海默病的发病机制中，除了多种GPCRs信号通路外，GPCR3调节/相互作用蛋白也参与其中。这些包括几个小的GTP酶，脑中富含的RAS同系物，GPCR相关的分类蛋白，β-arrestins等，它们在疾病的发展中起着关键作用，本文对此进行了详细的阐述。
Alzheimer’s disease is a progressive neurodegenerative disease characterized by the presence of amyloid-β plaques in the extracellular environment and aggregates of Tau protein that forms neurofibrillary tangles (NFTs) in neuronal cells. Along with these pathological proteins, the disease shows neuroinflammation, neuronal death, impairment in the immune function of microglia and synaptic loss, which are mediated by several important signaling pathways. The PI3K/Akt-mediated survival-signaling pathway is activated by many receptors such as G-protein coupled receptors (GPCRs), triggering receptor expressed on myeloid cells 2 (TREM2), and lysophosphatidic acid (LPA) receptor. The signaling pathway not only increases the survival of neurons but also regulates inflammation, phagocytosis, cellular protection, Tau phosphorylation and Aβ secretion as well. In this review, we focused on receptors, which activate PI3K/Akt pathway and its potential to treat Alzheimer’s disease. Among several membrane receptors, GPCRs are the major drug targets for therapy, and GPCR signaling pathways are altered during Alzheimer’s disease. Several GPCRs are involved in the pathogenic progression, phosphorylation of Tau protein by activation of various cellular kinases and are involved in the amyloidogenic pathway of amyloid-β synthesis. Apart from various GPCR signaling pathways, GPCR regulating/ interacting proteins are involved in the pathogenesis of Alzheimer’s disease. These include several small GTPases, Ras homolog enriched in brain, GPCR associated sorting proteins, β-arrestins, etc., that play a critical role in disease progression and has been elaborated in this review.