阿尔茨海默病(AD)是痴呆的主要形式,以淀粉样蛋白在大脑中的积累和聚集为特征。瞬时受体电位香草酸2(TRPV2)是参与多种病理生理过程的离子通道,包括小胶质细胞吞噬作用。以前的研究表明,大麻二酚(CBD),TRPV2的激活剂,通过TRPV2调节改善小胶质淀粉样β(Aβ)吞噬作用。然而,TRPV2参与小胶质细胞Aβ吞噬的分子机制尚不清楚。在这项研究中,我们旨在探讨TRPV2通道在小胶质细胞Aβ吞噬作用中的作用及其机制。利用人类数据集,小鼠原代神经元和小胶质细胞培养物,和AD模型小鼠,在体内和体外评估TRPV2表达和小胶质细胞Aβ吞噬作用。TRPV2在皮质中表达,海马体,和小胶质细胞.大麻二酚(CBD)可以激活和致敏TRPV2通道。短期(1周)腹膜内(i.p.)注射CBD降低了神经炎症和小胶质细胞吞噬受体的表达,但是长期CBD(3周)给药(i.p.)会引起神经炎症并抑制APP/PS1小鼠小胶质细胞吞噬受体的表达。此外,TRPV2通道的高敏感性是由分子位点Tyr(338)的酪氨酸磷酸化介导的,Tyr(466),和Tyr(520)通过蛋白酪氨酸激酶JAK1,这些位点突变减少了小胶质细胞Aβ吞噬作用部分依赖于其定位。虽然TRPV2在Cys277位点被棕榈酰化,并且阻断TRPV2棕榈酰化改善了小胶质细胞Aβ吞噬作用。此外,证明TRPV2棕榈酰化是由ZDHHC21动态调节的。总的来说,我们的发现阐明了由酪氨酸磷酸化/去磷酸化调节的TRPV2通道与半胱氨酸棕榈酰化/脱棕榈酰化之间的复杂相互作用,对小胶质细胞Aβ吞噬有不同的作用。这些发现为小胶质细胞吞噬作用和TRPV2敏感性的潜在机制提供了有价值的见解。并提供管理AD的潜在治疗策略。
Alzheimer\'s disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-β (Aβ) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aβ phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aβ phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aβ phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aβ phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aβ phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aβ phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD.