JEM：前沿！TLR5诱骗受体可作为治愈阿尔兹海默症(AD)的一种新颖且安全的免疫调节剂

阿尔兹海默症（AD，俗称老年痴呆）中的一个不变的病理学级联反应（cascade: a series of biochemical reactions, in which a product of the previous step is the substrate of the next）就是反应性神经胶质增生（gliosis: a nonspecific reactive change of glial cells in response to damage to the central nervous system），这表明先天性免疫的激活状态发生了潜在的改变。

单核苷酸多态性（SNPs）的关联性和免疫基因的功能性突变证实先天免疫在AD过程中具有重要作用【1】。AD转基因小鼠的研究发现：改变先天免疫通路对AD的免疫蛋白质稳态（immunoproteostasis：即蛋白质稳态、认知和神经退化的统称）有正向或负向的影响【2】。这些数据表明存在潜在的免疫蛋白质稳态靶标将有助对AD的治疗。

2018年8月29日，来自美国佛罗里达大学神经科学系与麦克奈特大脑研究所、美国梅奥诊所神经科学部与神经科、及美国系统生物学研究所的联合研究团队，将其一篇前沿性呀、研究成果以TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease为题在线发表在Journal of Experimental Medicine（IF=10.790）上。

研究表明：sTLR5/STLRFc可作为一种诱骗受体来治愈淀粉样蛋白聚集和淀粉样蛋白类聚物；其通过与Aβ直接发生相互作用，进而降低体内Aβ的水平，因此，具有特定功能的TLR5诱骗受体可作为治愈AD的一种新颖且安全的免疫调节剂( Bellow Graphical Abstract)【3】。

Graphical Abstract

TLRs即为先天免疫系统中的模式识别受体，且PAMP（pathogen-associated molecular pattern，PAMP）或DAMPs（damage-associated molecular patterns，DAMPs）可以激活TLRs【4】。TLRs会导致慢性炎症下的神经元损伤，同时会产生神经受损或局部缺血后的功能性恢复【5】。

AD中β-淀粉样蛋白（Aβ）聚集会诱发DAMPs，且两者会发生相互作用，然后激活内生型模式识别受体，包括TLR2，CD14和TLR4的复合物，最后引发慢性炎症反应【6】。另一方面，特异性TLRs可能会调控Aβ的清除，原因是：TLR4 ^−/− 小胶质细胞对Aβ的吞噬效率降低了，且在带有双转基因TLR4^−/−和APP（amyloid precursor protein，APP，即淀粉样前蛋白）的小鼠中，Aβ斑块增加了【7】。类似地，当使用特定配体后，内生型TLR4或TLR9有助于Aβ斑块的减少、削弱AD的病理学特征【8】。

因此，在本研究中，研究者们假定：带有配体和下游免疫信号的TLRs将对于减缓Aβ的病变有着积极作用，并验证是否能将胞外域可溶性多变TLRs做为免疫诱骗受体（decoy receptors：是指胞膜外区与功能性受体胞外区结构相似，因而能结合配体,但胞质区缺乏转导信号能力的一类受体）来改变APP转基因小鼠（TgCRND8 mouse model of AD）脑内的Aβ积累，且不激活慢性炎症反应。并再阐明：i. TLR在人脑中的表达模式；ii. 特定可溶性TLRs在影响Aβ斑块和调控TgCRND8小鼠方面的效率；iii. 单倍型TLR5与AD风险之间的关联性。

Fig.1 Expression of sTLR4 and sTLR5 reduces Aβ plaques in TgCRND8 mice.

Fig. 2  sTLR5Fc reduces Aβ plaques in TgCRND8 mice.

在本文中，首先，研究者们发现：腺相关病毒（AAV）介导的人类选择性TLR5（sTLR5）的单一胞外域表达，或是AAV介导的人类sTLR5与人类IgG4 Fc的混合，即sTLR5Fc的胞外域表达，都能促进带有Aβ 病理学特征的AD小鼠模型体内Aβ积累的减少(Fig.1-2)。

Fig. 3 Transcriptome characterization of sTLR5Fc-expressing TgCRND8 mice.

Fig.4 sTLR5Fc modulates flagellin-mediated TLR5 activation and binds Aβ with high specificity.

其次，研究表明sTLR5Fc能够与低聚态的且纤维状的Aβ亲密结合，形成复合物，从而抑制Aβ的毒性(Fig.4)。低聚态的且纤维状的Aβ会调控鞭毛蛋白（flagellin）介导的人类TLR5信号通路的激活(Fig.5)。且遗传学分析显示，在人类TLR5中，几乎无蛋白质的突变，这或许与AD的低风险因子有关。另外，转录组分析表明在，AD患者中，TLR基因表达发生了改变(Fig.3)。

最后，综合结果表明TLR5诱骗受体可作为AD中，以Aβ为靶标的一种新颖并安全的生物治疗剂。

Fig. 5 sTLR5Fc facilitates uptake of fibrillar Aβ42 and prevents Aβ-induced cell death in primary neuroglia. 

补充阅读

参考文献

【1】International Genomics of Alzheimer’s Disease Consortium (IGAP). 2015.Convergent genetic and expression data implicate immunity in Alzheimer’s disease. Alzheimers Dement. 11:658–671.

【2】Chakrabarty, et al. 2015. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 85:519–533.

【3】Chakrabarty, et al. 2018.TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease. J.Exp. Med. 215: 2247-2264

【4】Kawai, T., and S. Akira. 2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity. 34 :637–650.

【5】Rivest, S. 2009. Regulation of innate immune responses in the brain. Nat. Rev. Immunol. 9:429–439.

【6】Stewart, et al. 2010. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11:155–161.

【7】Tahara, et al. 2006. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain. 129:3006–3019.

【8】Michaud, et al. 2013. Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology. Proc. Natl. Acad. Sci. USA. 110:1941–1946.

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第一作者＆通讯作者 Dr. Paramita Chakrabarty 简介

Dr. Paramita Chakrabarty PhD

Assistant Professor

Email: [e-mail]

Research Aims
Immune Mediators in Alzheimer’s disease. Cytokines and chemokines have been intimately associated with neurodegenerative pathology in Alzheimer’s disease (AD) type dementia. However, the question remains whether neuroinflammation is the driving force behind the neurodegenerative pathology specifically leading to a self-reinforcing feedback loop to promote Aβ and/or tau pathophysiology in AD. Using recombinant adeno-associated virus mediated gene targeting in the brains of transgenic mice, some key questions that I am attempting to address are 1) the effect of different cytokines, chemokines and pattern recognition receptors on Aβ clearance and tau pathology in mice brain; 2) importance of microglial phenotype in AD type neurodegeneration; and 3) whether overexpression of soluble innate immune receptors in AD mice models can be harnessed as potential disease modifying therapies.

Neuroinflammation and nigrostriatal degeneration. Though neuroinflammation has been associated with Parkinson’s disease, a direct correlation between a specific immune mediator and selective vulnerability of nigrostriatal pathway has not been shown. We have recently demonstrated that Interferon-γ, an inflammatory cytokine, drives massive and selective nigrostriatal degeneration, locomotor impairment and calcinosis of the midbrain while sparing the hippocampus. We are continuing to refine these studies as they will be a crucial next step in a continuum of research that will elucidate the role of IFN-γ in Parkinsonism and provide information regarding IFN-γ signaling pathways as potential therapeutic targets.

Modeling of neurodegeneration using AAV gene targeting in the CNS or “somatic brain transgenesis”
Using recombinant adeno-associated virus mediated gene targeting paradigm, we have established dosage and spatially restricted cytokine gene expression patterns in the CNS that enable us to directly dissect neuroinflammation induced neurodegenerative phenotype that closely resemble the pathophysiology of traditionally constructed transgenic mice lines. Two key questions we are interested in investigating is 1) innate immune system mediated neuronal senescence and neurodegeneration and 2) role of peripheral inflammation in CNS neurodegeneration.

通讯作者 Dr. Todd Golde 简介

Dr. Todd Golde  PhD

Director, Evelyn F. and William L McKnight Brain Institute;
Director, 1Florida ADRC;
Member, Center for Translational Research in Neurodegnerative Disease
Professor, Department of Neuroscience, College of Medicine

Email: [e-mail]

Research Focus
Dr. Golde’s laboratory conduct’s disease oriented research with a specific, but not exclusive, focus on neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson Disease (PD). Our basic road map for this research is to try and understand the disease, create models that mimic aspects of the disease process in a time course that is amenable to study, identify targets for intervention, and opportunistically develop and evaluate therapies that might alter the disease course. We are highly collaborative laboratory and believe in leveraging our infrastructure with respect to disease models, knowledge, and technologies to help others move their research forward.

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