在突触核蛋白病小鼠模型中抑制 CSF-1R 后的小胶质细胞和神经元命运

IF 8.8 2区 医学 Q1 IMMUNOLOGY Brain, Behavior, and Immunity Pub Date : 2024-09-14 DOI:10.1016/j.bbi.2024.09.016
Michiyo Iba , Yeon-Joo Lee , Liam Horan-Portelance , Katherine Chang , Marcell Szabo , Robert A. Rissman , Sungyong You , Eliezer Masliah , Changyoun Kim
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引用次数: 0

摘要

突触核蛋白病是一种与年龄有关的神经系统疾病,其特征是α-突触核蛋白(α-syn)在神经元和非神经元细胞中异常聚集。有研究认为,小胶质细胞在突触核蛋白病的神经炎症中发挥着重要作用,在清除大脑中的α-syn聚集物等体内平衡方面也发挥着重要作用。在此,我们在突触核蛋白病小鼠模型中通过细胞耗竭研究了小胶质细胞对突触核蛋白病发病机制的影响。为此,我们用集落刺激因子1受体(CSF-1R)的酪氨酸激酶抑制剂pexidartinib(PLX3397)处理了非转基因(Non-tg)和α-突触核蛋白转基因(α-synuclein-tg)小鼠。神经病理学和免疫印迹分析证实,PLX3397治疗后,Non-tg和α-syn-tg小鼠的Iba-1免疫活性小胶质细胞减少了95%。α-syn-tg小鼠脑匀浆中Triton X-不溶性部分的总α-syn水平因小胶质细胞耗竭而显著下降,而Triton X-可溶性人α-syn水平不受影响。此外,α-syn-tg 小鼠经 PLX3397 处理后,p-α-syn 免疫活性包涵体的数量减少。小胶质细胞消耗也改善了α-syn-tg小鼠的神经元和突触退化,从而部分改善了α-syn-tg小鼠的运动行为缺陷。此外,我们还证明,PLX3397 治疗后存活的小胶质细胞(PLX 抗性小胶质细胞)的 CSF-1R 表达量较低,小胶质细胞转录组分析进一步阐明,相对于两种基因型的车辆治疗小胶质细胞,PLX 抗性小胶质细胞具有独特的形态和转录组特征;这些特征包括小胶质细胞在免疫反应、细胞移动性、细胞间通讯和神经稳态调节等明确功能方面的差异。因此,我们认为小胶质细胞在突触核蛋白病的发病机制中起着关键作用,调节小胶质细胞的状态可能是治疗突触核蛋白病的有效策略。
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Microglial and neuronal fates following inhibition of CSF-1R in synucleinopathy mouse model

Synucleinopathies are age-related neurological disorders characterized by the abnormal accumulation of α-synuclein (α-syn) in neuronal and non-neuronal cells. It has been proposed that microglial cells play an important role in synucleinopathy neuroinflammation, as well as homeostatically, such as in the clearance of α-syn aggregates in the brain. Here, we examined the effects of microglia on the pathogenesis of synucleinopathies by cell depletion in a mouse model of synucleinopathies. For this purpose, we treated non-transgenic (Non-tg) and α-synuclein transgenic (α-syn-tg) mice with pexidartinib (PLX3397), a tyrosine kinase inhibitor of colony-stimulating factor 1 receptor (CSF-1R). Neuropathological and immunoblot analysis confirmed that Iba-1 immunoreactive microglial cells were decreased by 95% following PLX3397 treatment in Non-tg and α-syn-tg mice. The level of total α-syn in the Triton X-insoluble fraction of brain homogenate was significantly decreased by microglial depletion in the α-syn-tg mice, while the level of Triton X-soluble human α-syn was not affected. Furthermore, the number of p-α-syn immunoreactive inclusions was reduced in α-syn-tg mice treated with PLX3397. Microglial depletion also ameliorated neuronal and synaptic degeneration in α-syn-tg mice, thereby resulted partially improving the motor behavioral deficit in α-syn-tg mice. Moreover, we demonstrated that microglia that survived post-PLX3397 treatment (PLX-resistant microglia) have lower expressions of CSF-1R, and microglial transcriptome analysis further elucidated that PLX-resistant microglia have unique morphology and transcriptomic signatures relative to vehicle-treated microglia of both genotypes; these include differences in definitive microglial functions such as their immune response, cell mobility, cell–cell communications, and regulation of neural homeostasis. Therefore, we suggest that microglia play a critical role in the pathogenesis of synucleinopathies, and that modulation of microglial status might be an effective therapeutic strategy for synucleinopathies.

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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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