连发两篇Neuron!大脑免疫细胞,治疗痴呆的关键?
2018/03/13
小胶质细胞是大脑中的吞噬细胞,负责清除受损的神经细胞、毒性蛋白等有害物质,其表面的TREM2受体一直是阿尔兹海默症研究领域的热门靶标。近期,科学家们在《Neuron》期刊同时发表两篇文章揭示TREM2与β-淀粉样蛋白之间“纠葛”,并提供了新的治疗策略。


Huaxi Xu, Ph.D., professor and director of SBP's Neuroscience Initiative. Credit: Sanford Burnham Prebys Medical Discovery Institute

阿尔兹海默症(AD)威胁着全世界4700多万人的健康,而且伴随着人口老龄化,这一数字仍在上涨。这一常见疾病的典型病症包括大脑中β-淀粉样蛋白过度累积、Tau蛋白缠结。科学家们一直试图通过清除致病蛋白的累积来减缓、阻止阿尔兹海默症的发生,但是成效甚微。

3月7日,在《Neuron》期刊发表的两篇文章揭示,大脑中的“清道夫”——小胶质细胞表面的受体TREM2,有望在治疗AD中发挥潜在作用。

论文一:TREM2受体负责结合淀粉样蛋白

TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function


DOI: https://doi.org/10.1016/j.neuron.2018.01.031

来自于Sanford Burnham Prebys 医学研究所(SBP)的神经学教授Huaxi Xu博士和团队发现,TREM2通过结合β-淀粉样蛋白,刺激小胶质细胞包围、清除蛋白病斑,从而遏制神经细胞的损伤。

而且,TREM2与淀粉样蛋白的互作相当特别——TREM2与淀粉样蛋白寡聚体(蛋白最毒的结构)结合。一旦缺乏TREM2,小胶质细胞则不能高效结合淀粉样蛋白,最终无法清除致病蛋白。而且,去除TREM2会进一步抑制下游神经细胞的钾离子通道,从而影响大脑免疫细胞相关的电流活动。

这一最新研究揭示了TREM2与淀粉样蛋白之间的关联细节,并提供了一个潜在的治疗策略。

论文二:上调TREM2,减缓痴呆症状

Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models


DOI: https://doi.org/10.1016/j.neuron.2018.02.002

加州大学洛杉矶分校的X. William Yang教授和Huaxi Xu团队合作发现,上调AD小鼠大脑内TREM2的水平,可以预防或者减缓神经衰退性疾病的发生、发展。

具体而言,上调TREM2水平可以增加小胶质细胞的敏感性,从而阻止AD小鼠的病情恶化,甚至于恢复其一定的认知能力。这意味着,除了解决与AD相关的病理之外,靶向TREM2还可以减少行为缺陷。

研究意义

“在生病初期增强小胶质细胞活性,利用其清除淀粉样蛋白,这是一个有效的治疗方案。但是我们需要治疗副作用,例如过度激活免疫细胞容易释放过多的细胞因子,从而破坏健康的神经连接。” Huaxi Xu教授强调道。

他认为,研究小胶质细胞,而不是淀粉样蛋白,可能是治疗阿尔兹海默症的新思路。换句话说,我们可以利用大脑免疫细胞解决健康危机!

参考资料:

The brain's immune system may be key to new Alzheimer's treatments

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  • TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function

    Mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to increased Alzheimer’s disease (AD) risk. Neurobiological functions of TREM2 and its pathophysiological ligands remain elusive. Here we found that TREM2 directly binds to β-amyloid (Aβ) oligomers with nanomolar affinity, whereas AD-associated TREM2 mutations reduce Aβ binding. TREM2 deficiency impairs Aβ degradation in primary microglial culture and mouse brain. Aβ-induced microglial depolarization, K+ inward current induction, cytokine expression and secretion, migration, proliferation, apoptosis, and morphological changes are dependent on TREM2. In addition, TREM2 interaction with its signaling adaptor DAP12 is enhanced by Aβ, regulating downstream phosphorylation of SYK and GSK3β. Our data demonstrate TREM2 as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ.

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  • Elevated TREM2 Gene Dosage Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer’s Disease Models

    Variants of TREM2 are associated with Alzheimer’s disease (AD). To study whether increasing TREM2 gene dosage could modify the disease pathogenesis, we developed BAC transgenic mice expressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2 expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomic profiling demonstrated that increasing TREM2 levels conferred a rescuing effect, which includes dampening the expression of multiple disease-associated microglial genes and augmenting downregulated neuronal genes. Interestingly, 5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglial genes linked to phagocytosis and negative regulation of immune cell activation. Moreover, these mice showed enhanced process ramification and phagocytic marker expression in plaque-associated microglia and reduced neuritic dystrophy. Finally, elevated TREM2 gene dosage led to improved memory performance in AD models. In summary, our study shows that a genomic transgene-driven increase in TREM2 expression reprograms microglia responsivity and ameliorates neuropathological and behavioral deficits in AD mouse models.

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