TRPV1 alleviates APOE4-dependent microglial antigen presentation and T cell infiltration in Alzheimer's disease.

IF 10.8 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration Pub Date : 2024-10-29 DOI:10.1186/s40035-024-00445-6

Jia Lu, Kexin Wu, Xudong Sha, Jiayuan Lin, Hongzhuan Chen, Zhihua Yu

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Abstract

Background: Persistent innate and adaptive immune responses in the brain contribute to the progression of Alzheimer's disease (AD). APOE4, the most important genetic risk factor for sporadic AD, encodes apolipoprotein E4, which by itself is a potent modulator of immune response. However, little is known about the immune hub that governs the crosstalk between the nervous and the adaptive immune systems. Transient receptor potential vanilloid type 1 (TRPV1) channel is a ligand-gated, nonselective cation channel with Ca²⁺ permeability, which has been proposed as a neuroprotective target in AD.

Methods: Using Ca²⁺-sensitive dyes, dynamic changes of Ca²⁺ in microglia were measured, including exogenous Ca²⁺ uptake and endoplasmic reticulum Ca²⁺ release. The mRFP-GFP-tagged LC3 plasmid was expressed in microglia to characterize the role of TRPV1 in the autophagic flux. Transcriptomic analyses and flow cytometry were performed to investigate the effects of APOE4 on brain microglia and T cells from APOE-targeted replacement mice with microglia-specific TRPV1 gene deficiency.

Results: Both APOE4 microglia derived from induced pluripotent stem cells of AD patients and APOE4-related tauopathy mouse model showed significantly increased cholesterol biosynthesis and accumulation compared to their APOE3 counterparts. Further, cholesterol dysregulation was associated with persistent activation of microglia and elevation of major histocompatibility complex II-dependent antigen presentation in microglia, subsequently accompanied by T cell infiltration. In addition, TRPV1-mediated transient Ca²⁺ influx mitigated cholesterol biosynthesis in microglia by suppressing the transcriptional activation of sterol regulatory element-binding protein 2, promoted autophagic activity and reduced lysosomal cholesterol accumulation, which were sufficient to resolve excessive immune response and neurodegeneration in APOE4-related tauopathy mouse model. Moreover, microglia-specific deficiency of TRPV1 gene accelerated glial inflammation, T cell response and associated neurodegeneration in an APOE4-related tauopathy mouse model.

Conclusions: The findings provide new perspectives for the treatment of APOE4-dependent neurodegeneration including AD.

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TRPV1 可减轻阿尔茨海默病中 APOE4 依赖性小胶质细胞抗原呈递和 T 细胞浸润。

背景：大脑中持续存在的先天性和适应性免疫反应是阿尔茨海默病（AD）恶化的原因之一。APOE4 是散发性阿尔茨海默病最重要的遗传风险因素，它编码载脂蛋白 E4，而载脂蛋白 E4 本身就是免疫反应的强效调节剂。然而，人们对支配神经系统和适应性免疫系统之间相互协作的免疫中枢却知之甚少。瞬时受体电位类香草素1型（TRPV1）通道是一种配体门控的非选择性阳离子通道，具有Ca2+通透性，已被提出作为AD的神经保护靶点：方法：使用Ca2+敏感染料测量小胶质细胞中Ca2+的动态变化，包括外源性Ca2+摄取和内质网Ca2+释放。在小胶质细胞中表达了 mRFP-GFP 标记的 LC3 质粒，以确定 TRPV1 在自噬通量中的作用。通过转录组分析和流式细胞术研究了 APOE4 对脑小胶质细胞和小胶质细胞特异性 TRPV1 基因缺失的 APOE 靶向替代小鼠的 T 细胞的影响：结果：从AD患者诱导多能干细胞和APOE4相关tauopathy小鼠模型中提取的APOE4小胶质细胞与APOE3小胶质细胞相比，胆固醇的生物合成和积累显著增加。此外，胆固醇失调与小胶质细胞的持续活化和小胶质细胞中主要组织相容性复合体 II 依赖性抗原呈递的升高有关，随后伴随着 T 细胞的浸润。此外，TRPV1 介导的瞬时 Ca2+ 流入通过抑制固醇调节元件结合蛋白 2 的转录激活，减轻了小胶质细胞中胆固醇的生物合成，促进了自噬活性并减少了溶酶体中胆固醇的积累，这足以解决 APOE4 相关陶陶病小鼠模型中过度的免疫反应和神经退行性变。此外，在APOE4相关tauopathy小鼠模型中，小胶质细胞特异性TRPV1基因缺乏会加速胶质细胞炎症、T细胞反应和相关神经退行性变：结论：这些发现为治疗 APOE4 依赖性神经退行性病变（包括注意力缺失症）提供了新的视角。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Translational Neurodegeneration Neuroscience-Cognitive Neuroscience

CiteScore

19.50

自引率

0.80%

发文量

审稿时长

10 weeks

期刊介绍： Translational Neurodegeneration, an open-access, peer-reviewed journal, addresses all aspects of neurodegenerative diseases. It serves as a prominent platform for research, therapeutics, and education, fostering discussions and insights across basic, translational, and clinical research domains. Covering Parkinson's disease, Alzheimer's disease, and other neurodegenerative conditions, it welcomes contributions on epidemiology, pathogenesis, diagnosis, prevention, drug development, rehabilitation, and drug delivery. Scientists, clinicians, and physician-scientists are encouraged to share their work in this specialized journal tailored to their fields.