2019年神经炎症领域十大基础研究进展

1. Nature— β-Synuclein反应性T细胞诱导多发性硬化中自身免疫性灰质变性

英文摘要：

Thegrey matter is a central target of pathological processes in neurodegenerativedisorders such as Parkinson's and Alzheimer's diseases. The grey matter isoften also affected in multiple sclerosis, an autoimmune disease of the centralnervous system. The mechanisms that underlie grey matter inflammation anddegeneration in multiple sclerosis are not well understood. Here we show that,in Lewis rats, T cells directed against theneuronal protein β-synuclein specifically invade the grey matter and that thisis accompanied by the presentation of multifaceted clinical disease. Theexpression pattern of β-synuclein induces the local activation of these T cells and, therefore, determined inflammatory primingof the tissue and targeted recruitment of immune cells. The resultinginflammation led to significant changes in the grey matter, which ranged fromgliosis and neuronal destruction to brain atrophy.In humans, β-synuclein-specific T cells wereenriched in patients with chronic-progressive multiple sclerosis. Thesefindings reveal a previously unrecognized role of β-synuclein in provokingT-cell-mediated pathology of the central nervous system.

参考文献：

Lodyginet al (2019). β-Synuclein-reactive T cells induce autoimmune CNS grey matterdegeneration. Nature.2019 Feb;566(7745):503-508.

2. Nature—大脑调节性T细胞抑制胶质细胞增生并促进缺血性卒中后的神经修复

英文摘要：

Inaddition to maintaining immune tolerance, FOXP3⁺ regulatory T (T_reg)cells perform specialized functions in tissue homeostasis and remodelling^1,2.However, the characteristics and functions of brain T_reg cells arenot well understood because there is a low number of T_reg cells inthe brain under normal conditions. Here we show that there is massiveaccumulation of T_reg cells in the mouse brain after ischaemicstroke, and this potentiates neurological recovery during the chronic phase ofischaemic brain injury. Although brain T_reg cells are similar to T_regcells in other tissues such as visceral adipose tissue and muscle^3-5,they are apparently distinct and express unique genes related to the nervoussystem including Htr7, which encodes the serotonin receptor 5-HT₇.The amplification of brain T_reg cells is dependent on interleukin(IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration intothe brain is driven by the chemokines CCL1 and CCL20. Brain T_regcells suppress neurotoxic astrogliosis by producing amphiregulin, alow-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is aleading cause of neurological disability, and there are currently few effectiverecovery methods other than rehabilitation during the chronic phase. Ourfindings suggest that T_reg cells and their products may providetherapeutic opportunities for neuronal protection against stroke andneuroinflammatory diseases.

参考文献：

Ito et al (2019). Brain regulatory T cells suppressastrogliosis and potentiate neurological recovery. Nature. 2019Jan;565(7738):246-250.

3. Science—研究解析了神经炎症过程中不同髓系免疫细胞亚型的单细胞转录组差异

英文摘要：

Theinnate immune cell compartment is highly diverse in the healthy central nervoussystem (CNS), including parenchymal and non-parenchymal macrophages. However,this complexity is increased in inflammatory settings by the recruitment ofcirculating myeloid cells. It is unclear which disease-specific myeloid subsetsexist and what their transcriptional profiles and dynamics during CNS pathologyare. Combining deep single-cell transcriptome analysis, fate mapping, in vivoimaging, clonal analysis, and transgenic mouse lines, we comprehensivelycharacterized unappreciated myeloid subsets in several CNS compartments during neuroinflammation. During inflammation, CNS macrophagesubsets undergo self-renewal, and random proliferation shifts toward clonalexpansion. Last, functional studies demonstrated that endogenous CNS tissuemacrophages are redundant for antigen presentation. Our results highlightmyeloid cell diversity and provide insights into the brain's innate immunesystem.

参考文献：

Jordãoet al (2019). Single-cell profiling identifies myeloid cell subsets withdistinct fates during neuroinflammation. Science. 2019 Jan 25;363(6425).

4. Cell—肠道IgA产生浆细胞通过IL-10调节神经炎症

英文摘要：

Plasmacells (PC) are found in the CNS of multiple sclerosis (MS) patients, yet theirsource and role in MS remains unclear. We find that some PC in the CNS of micewith experimental autoimmune encephalomyelitis (EAE) originate in the gut andproduce immunoglobulin A (IgA). Moreover, we show that IgA⁺ PC aredramatically reduced in the gut during EAE, and likewise, a reduction inIgA-bound fecal bacteria is seen in MS patients during disease relapse. Removalof plasmablast (PB) plus PC resulted in exacerbated EAE that was normalized bythe introduction of gut-derived IgA⁺ PC. Furthermore, mice with an over-abundanceof IgA⁺ PB and/or PC were specifically resistant to the effectorstage of EAE, and expression of interleukin (IL)-10 by PB plus PC was necessaryand sufficient to confer resistance. Our data show that IgA⁺ PBand/or PC mobilized from the gut play an unexpected role in suppressing neuroinflammation.

参考文献：

Rojas et al (2019). Recirculating IntestinalIgA-Producing Cells Regulate Neuroinflammation via IL-10. Cell. 2019 Jan24;176(3):610-624.e18.

5. Cell— 细胞代谢通过cPLA2-MAVS通路调控星形胶质细胞病理活动

英文摘要：

Metabolismhas been shown to control peripheral immunity, but little is known about itsrole in central nervous system (CNS) inflammation. Through a combination of proteomic,metabolomic, transcriptomic, and perturbation studies, we found thatsphingolipid metabolism in astrocytes triggers the interaction of the C2 domainin cytosolic phospholipase A2 (cPLA2) with the CARD domain in mitochondrialantiviral signaling protein (MAVS), boosting NF-κB-driven transcriptionalprograms that promote CNS inflammation in experimental autoimmuneencephalomyelitis (EAE) and, potentially, multiple sclerosis. cPLA2 recruitmentto MAVS also disrupts MAVS-hexokinase 2 (HK2) interactions, decreasing HKenzymatic activity and the production of lactate involved in the metabolicsupport of neurons. Miglustat, a drug used to treat Gaucher and Niemann-Pickdisease, suppresses astrocyte pathogenic activities and ameliorates EAE.Collectively, these findings define a novel immunometabolic mechanism thatdrives pro-inflammatory astrocyte activities, outlines a new role for MAVS inCNS inflammation, and identifies candidate targets for therapeuticintervention.

参考文献：

Chao  et al (2019).Metabolic Control of Astrocyte Pathogenic Activity via cPLA2-MAVS. Cell. 2019Dec 12;179(7):1483-1498.e22.

6. Nature— NLRP3炎症小体驱动tau蛋白病理

英文摘要：

Alzheimer'sdisease is characterized by the accumulation of amyloid-beta in plaques,aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting inneurodegeneration and cognitive decline¹. The NLRP3 inflammasomeassembles inside of microglia on activation, leading to increased cleavage andactivity of caspase-1 and downstream interleukin-1β release².Although the NLRP3 inflammasome has been shown to be essential for thedevelopment and progression of amyloid-beta pathology in mice³, theprecise effect on tau pathology remains unknown. Here we show that loss ofNLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation byregulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasomeand intracerebral injection of fibrillar amyloid-beta-containing brainhomogenates induced tau pathology in an NLRP3-dependent manner. These dataidentify an important role of microglia and NLRP3 inflammasome activation inthe pathogenesis of tauopathies and support the amyloid-cascade hypothesis inAlzheimer's disease, demonstrating that neurofibrillary tangles developdownstream of amyloid-beta-induced microglial activation.

参考文献：

Isinget al (2019). NLRP3 inflammasome activation drives tau pathology. Nature. 2019Nov;575(7784):669-673.

7. Immunity—抑制突触部位的补体C3可阻止脱髓鞘疾病中小胶质细胞对突触的吞噬

英文摘要：

Multiplesclerosis (MS) is a demyelinating, autoimmune disease of the central nervoussystem. While work has focused on myelin and axon loss in MS, less is knownabout mechanisms underlying synaptic changes. Using postmortem human MS tissue,a preclinical nonhuman primate model of MS, and two rodent models ofdemyelinating disease, we investigated synapse changes in the visual system.Similar to other neurodegenerative diseases, microglial synaptic engulfment andprofound synapse loss were observed. In mice, synapse loss occurredindependently of local demyelination and neuronal degeneration but coincidedwith gliosis and increased complement component C3, but not C1q, at synapses.Viral overexpression of the complement inhibitor Crry at C3-bound synapses decreasedmicroglial engulfment of synapses and protected visual function. These resultsindicate that microglia eliminate synapses through the alternative complementcascade in demyelinating disease and identify a strategy to prevent synapseloss that may be broadly applicable to other neurodegenerative diseases.

参考文献：

Werneburget al (2019). Targeted Complement Inhibition at Synapses Prevents MicroglialSynaptic Engulfment and Synapse Loss in Demyelinating Disease. Immunity. 2019Dec 23. pii: S1074-7613(19)30523-0.

8.Neuron—靶向于RAN蛋白的抗体可逆转C9orf72小鼠模型的C9ALS/FTD表型

英文摘要：

Theintronic C9orf72 G4C2 expansion, the most common genetic cause of ALS and FTD,produces sense- and antisense-expansion RNAs and six dipeptiderepeat-associated, non-ATG (RAN) proteins, but their roles in disease areunclear. We generated high-affinity human antibodies targeting GA or GP RANproteins. These antibodies cross the blood-brain barrier and co-localize withintracellular RAN aggregates in C9-ALS/FTD BAC mice. In cells, α-GA₁interacts with TRIM21, and α-GA₁ treatment reduced GA levels,increased GA turnover, and decreased RAN toxicity and co-aggregation ofproteasome and autophagy proteins to GA aggregates. In C9-BAC mice, α-GA₁reduced GA as well as GP and GR proteins, improved behavioral deficits,decreased neuroinflammation and neurodegeneration,and increased survival. Glycosylation of the Fc region of α-GA₁ isimportant for cell entry and efficacy. These data demonstrate that RAN proteinsdrive C9-ALS/FTD in C9-BAC transgenic mice and establish a novel therapeuticapproach for C9orf72 ALS/FTD and other RAN-protein diseases.

参考文献：

Nguyen et al (2019). Antibody Therapy Targeting RANProteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron. 2019 Dec4. pii: S0896-6273(19)30970-5.

9. Nat Neurosci—小胶质细胞释放的断裂线粒体激活A1型星形胶质细胞并放大神经炎症反应

英文摘要：

Inneurodegenerative diseases, debris of dead neurons are thought to triggerglia-mediated neuroinflammation, thus increasingneuronal death. Here we show that the expression of neurotoxic proteinsassociated with these diseases in microglia alone is sufficient to directlytrigger death of naive neurons and to propagate neuronal death through activationof naive astrocytes to the A1 state. Injury propagation is mediated, in greatpart, by the release of fragmented and dysfunctional microglial mitochondriainto the neuronal milieu. The amount of damaged mitochondria released frommicroglia relative to functional mitochondria and the consequent neuronalinjury are determined by Fis1-mediated mitochondrial fragmentation within theglial cells. The propagation of the inflammatory response and neuronal celldeath by extracellular dysfunctional mitochondria suggests a potential newintervention for neurodegeneration-one that inhibits mitochondrialfragmentation in microglia, thus inhibiting the release of dysfunctionalmitochondria into the extracellular milieu of the brain, without affecting therelease of healthy neuroprotective mitochondria.

参考文献：

Joshi et al (2019). Fragmented mitochondria released frommicroglia trigger A1 astrocytic response and propagate inflammatoryneurodegeneration. Nat Neurosci. 2019 Oct;22(10):1635-1648.

10. Neuron—CD33通过TREM2调控阿尔茨海默病中小胶质细胞的病理表型

英文摘要：

Themicroglial receptors CD33 and TREM2 have been associated with risk forAlzheimer's disease (AD). Here, we investigated crosstalk between CD33 andTREM2. We showed that knockout of CD33 attenuated amyloid beta (Aβ) pathologyand improved cognition in 5xFAD mice, both of which were abrogated byadditional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Aβpathology and neurodegeneration but reduced Iba1⁺ cell numbers, allof which could not be rescued by additional CD33 knockout. RNA-seq profiling ofmicroglia revealed that genes related to phagocytosis and signaling (IL-6,IL-8, acute phase response) are upregulated in 5xFAD;CD33^-/- anddownregulated in 5xFAD;TREM2^-/- mice. Differential gene expressionin 5xFAD;CD33^-/- microglia depended on the presence of TREM2,suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2includes regulation of the IL-1β/IL-1RN axis and a gene set in the "receptoractivity chemokine" cluster. Our results should facilitate AD therapeuticstargeting these receptors.

参考文献：

Griciucet al (2019). TREM2 Acts Downstream of CD33 in Modulating Microglial Pathologyin Alzheimer's Disease. Neuron. 2019 Sep 4;103(5):820-835.e7.

2019年十大研究进展名录

1. 年终盘点：2019年帕金森病十大基础研究进展

2. 年终盘点：2019年帕金森病十大临床研究进展

3. 年终盘点：2019年阿尔茨海默病十大基础研究进展

4. 年终盘点：2019年阿尔茨海默病十大临床研究进展

5. 年终盘点：2019年神经科学领域十大基础研究进展

6. 年终盘点：2019年抑郁症领域十大基础研究进展（一半来自中国）

7. 年终盘点：2019年脑血管病领域十大基础研究进展

2018年十大研究进展名录

1.盘点2018年阿尔茨海默病十大研究突破

2.盘点2018年帕金森病十大研究突破

3. 盘点2018年神经科学二十大研究突破

4. 盘点2018年渐冻症（ALS）十大研究进展

5. 盘点2018年全球脑卒中十大研究进展

6. 盘点2018年神经影像十大研究进展

7. 盘点2018年神经炎症领域的十大研究突破

8. 盘点2018年神经变性痴呆十大研究突破

9. 2018年神经科学“学习和记忆”领域十大研究进展

10. 2018年抑郁症领域的十大研究突破

11. 2018年痛觉和疼痛领域的十大研究突破

12. 2018年的神经干细胞研究十大研究进展

13. 2018年的神经干细胞研究十大研究进展

14. 2018年的十大睡眠研究突破

15. 2018年“衰老和长生不老”领域的十大研究突破

16. 2018年自闭症领域的十大研究突破

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20个神经科学领域的突破可能获得诺贝尔奖

1. 意识研究：意识的本质、组成、运行机制及其物质载体；不同意识层次的操控和干预，意识障碍性疾病的治疗。

2. 学习和记忆的机制及其调控：记忆的形成和消退机制，记忆的人为移植和记忆的人为消除等；

3. 痴呆研究：阿尔茨海默病的机制和治疗研究，血管性痴呆、额颞叶痴呆、路易体痴呆的机制研究和治疗。

4. 睡眠和睡眠障碍的机制和干预研究。

5. 情绪研究：喜、怒、哀、恐等基本情绪的机制和相关疾病的治疗。

6. 计算和逻辑推理的神经科学基础研究。

7. 语言的神经科学基础研究。

8. 视觉图像形成和运用的神经科学基础研究。

9. 创造力、想象力和艺术文学创造的神经基础研究。

10. 痛觉的神经科学基础及其干预研究

11. 性行为研究：性行为的神经科学基础研究和性行为的调控和干预。

12. 脑和脊髓损伤的机制及其干预研究，包括脑卒中、脊髓损伤机制研究，神经干细胞移植研究，新型神经修复技术，神经康复技术。

13. 精神类疾病的机制和干预研究：自闭症、精分、抑郁症、智能障碍、药物成瘾等；

14. 运动神经元病等神经变性病机制研究及其干预。

15. 衰老的机制和永生研究，包括大脑衰老的机制和寿命延长研究。

16. 神经系统遗传病的机制研究及基因治疗。

17. 神经操纵和调控技术：光遗传技术、药物遗传技术、基因编辑技术、经颅磁刺激、深部脑刺激和电刺激等。

18. 脑组织兼容性电子微芯片及脑机互动装置研究，包括脑机接口、神经刺激芯片、记忆存储芯片，意识存储芯片，人脑非语言互动装置等。

19. 半人半机器人的设计、完善和修复技术：包括任何机械肢体的人类移植，大脑移植入机器体内等。

20. 新型大脑成像和神经元活动记录技术：高分辨率成像技术、大型电极微阵列技术等。