College of Life Sciences, Northwest Normal University, Lanzhou, Gansu, 730070, China.
J Neuroinflammation. 2024 Sep 3;21(1):218. doi: 10.1186/s12974-024-03204-6.
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.
阿尔茨海默病（AD）是痴呆症的主要形式，其特征是大脑中淀粉样蛋白的积累和聚集。瞬时受体电位香草酸 2 型（TRPV2）是一种参与多种生理病理过程的离子通道，包括小胶质细胞吞噬作用。先前的研究表明，大麻素（CBD），一种 TRPV2 的激活剂，通过 TRPV2 调节改善小胶质细胞淀粉样蛋白-β（Aβ）吞噬作用。然而，TRPV2 在小胶质细胞 Aβ吞噬作用中的分子机制尚不清楚。在这项研究中，我们旨在研究 TRPV2 通道在小胶质细胞 Aβ吞噬作用中的参与及其潜在机制。利用人类数据集、小鼠原代神经元和小胶质细胞培养物以及 AD 模型小鼠，评估体内和体外的 TRPV2 表达和小胶质细胞 Aβ吞噬作用。TRPV2 在皮质、海马体和小胶质细胞中表达。大麻素（CBD）可以激活和敏化 TRPV2 通道。腹腔内（i.p.）短期 CBD（1 周）注射减少神经炎症和小胶质细胞吞噬受体的表达，但长期 CBD（3 周）给药（i.p.）诱导 APP/PS1 小鼠的神经炎症并抑制小胶质细胞吞噬受体的表达。此外，TRPV2 通道的超敏性是由蛋白酪氨酸激酶 JAK1 介导的分子位点 Tyr（338）、Tyr（466）和 Tyr（520）上的酪氨酸磷酸化介导的，这些位点的突变部分减少了对其定位的小胶质细胞 Aβ吞噬作用的依赖。虽然 TRPV2 在 Cys 277 位点被棕榈酰化，阻断 TRPV2 棕榈酰化可改善小胶质细胞 Aβ吞噬作用。此外，证明 TRPV2 棕榈酰化受 ZDHHC21 的动态调节。总的来说，我们的研究结果阐明了受酪氨酸磷酸化/去磷酸化和半胱氨酸棕榈酰化/去棕榈酰化调节的 TRPV2 通道之间复杂的相互作用，这对小胶质细胞 Aβ吞噬作用有不同的影响。这些发现为理解小胶质细胞吞噬作用和 TRPV2 敏感性之间的潜在机制提供了有价值的见解，并为 AD 的治疗提供了潜在的治疗策略。
