Aging is a major risk factor forboth genetic and sporadic neurodegenerative disorders. However, it is unclearhow aging interacts with genetic predispositions to promote neurodegeneration.Here, we investigate how partial loss of function of TBK1, a major geneticcause for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)comorbidity, leads to age-dependent neurodegeneration. We show that TBK1 is anendogenous inhibitor of RIPK1 and the embryonic lethality of Tbk1-/- mice isdependent on RIPK1 kinase activity. In aging human brains, another endogenousRIPK1 inhibitor, TAK1, exhibits a marked decrease in expression. We show thatin Tbk1+/- mice, the reduced myeloid TAK1 expression promotes all the keyhallmarks of ALS/FTD, including neuroinflammation, TDP-43 aggregation, axonaldegeneration, neuronal loss, and behavior deficits, which are blocked uponinhibition of RIPK1. Thus, aging facilitates RIPK1 activation by reducing TAK1expression, which cooperates with genetic risk factors to promote the onset ofALS/FTD.
参考文献：TBK1 Suppresses RIPK1-DrivenApoptosis and Inflammation during Development and in Aging. Cell. 2018 Sep6;174(6):1477-1491.e19.
icroglia are embryonically seededmacrophages that contribute to brain development, homeostasis, and pathologies.It is thus essential to decipher how microglial properties are temporallyregulated by intrinsic and extrinsic factors, such as sexual identity and themicrobiome. Here, we found that microglia undergo differentiation phases,discernable by transcriptomic signatures and chromatin accessibilitylandscapes, which can diverge in adult males and females. Remarkably, theabsence of microbiome in germ-free mice had a time and sexually dimorphicimpact both prenatally and postnatally: microglia were more profoundlyperturbed in male embryos and female adults. Antibiotic treatment of adult micetriggered sexually biased microglial responses revealing both acute andlong-term effects of microbiota depletion. Finally, human fetal microgliaexhibited significant overlap with the murine transcriptomic signature. Ourstudy shows that microglia respond to environmental challenges in a sex- andtime-dependent manner from prenatal stages, with major implications for our understandingof microglial contributions to health and disease.
参考文献：Microbiome Influences Prenataland Adult Microglia in a Sex-Specific Manner. Cell. 2018 Jan25;172(3):500-516.e16.
Inflammatory disorders of the CNSare frequently accompanied by synaptic loss, which is thought to involvephagocytic microglia and complement components. However, the mechanismsaccounting for aberrant synaptic connectivity in the context of CD8+ Tcell-driven neuronal damage are poorly understood. Here, we profiled theneuronal translatome in a murine model of encephalitis caused by CD8+ T cellstargeting antigenic neurons. Neuronal STAT1 signaling and downstream CCL2expression were essential for apposition of phagocytes, ensuing synaptic lossand neurological disease. Analogous observations were made in the brains ofRasmussen's encephalitis patients. In this devastating CD8+ T cell-drivenautoimmune disease, neuronal STAT1 phosphorylation and CCL2 expressionco-clustered with infiltrating CD8+ T cells as well as phagocytes. Takentogether, our findings uncover an active role of neurons in coordinatingphagocyte-mediated synaptic loss and highlight neuronal STAT1 and CCL2 ascritical steps in this process that are amenable to pharmacologicalinterventions.
参考文献：Neurons under T Cell AttackCoordinate Phagocyte-Mediated Synaptic Stripping. Cell. 2018 Oct4;175(2):458-471.e19.
Variants of TREM2 are associatedwith Alzheimer's disease (AD). To study whether increasing TREM2 gene dosagecould modify the disease pathogenesis, we developed BAC transgenic miceexpressing human TREM2 (BAC-TREM2) in microglia. We found that elevated TREM2expression reduced amyloid burden in the 5xFAD mouse model. Transcriptomicprofiling demonstrated that increasing TREM2 levels conferred a rescuingeffect, which includes dampening the expression of multiple disease-associatedmicroglial genes and augmenting downregulated neuronal genes. Interestingly,5xFAD/BAC-TREM2 mice showed further upregulation of several reactive microglialgenes linked to phagocytosis and negative regulation of immune cell activation.Moreover, these mice showed enhanced process ramification and phagocytic markerexpression in plaque-associated microglia and reduced neuritic dystrophy.Finally, elevated TREM2 gene dosage led to improved memory performance in ADmodels. In summary, our study shows that a genomic transgene-driven increase inTREM2 expression reprograms microglia responsivity and amelioratesneuropathological and behavioral deficits in AD mouse models.
1. Elevated TREM2 Gene DosageReprograms Microglia Responsivity and Ameliorates Pathological Phenotypes inAlzheimer's Disease Models.Neuron. 2018 Mar 7;97(5):1032-1048.
2. TREM2 Is a Receptor forβ-Amyloid that Mediates Microglial Function. Neuron. 2018 Mar7;97(5):1023-1031.
五. 《Cellstem cell》：巨噬细胞分泌的琥珀酸可调控神经干细胞进而抑制神经炎症。
Neural stem cell (NSC)transplantation can influence immune responses and suppress inflammation in theCNS. Metabolites, such as succinate, modulate the phenotype and function ofimmune cells, but whether and how NSCs are also activated by such immunometabolitesto control immunoreactivity and inflammatory responses is unclear. Here, weshow that transplanted somatic and directly induced NSCs ameliorate chronic CNSinflammation by reducing succinate levels in the cerebrospinal fluid, therebydecreasing mononuclear phagocyte (MP) infiltration and secondary CNS damage.Inflammatory MPs release succinate, which activates succinate receptor 1(SUCNR1)/GPR91 on NSCs, leading them to secrete prostaglandin E2 and scavengeextracellular succinate with consequential anti-inflammatory effects. Thus, ourwork reveals an unexpected role for the succinate-SUCNR1 axis in somatic anddirectly induced NSCs, which controls the response of stem cells toinflammatory metabolic signals released by type 1 MPs in the chronically inflamedbrain.
参考文献：Macrophage-DerivedExtracellular Succinate Licenses Neural Stem Cells to Suppress ChronicNeuroinflammation. Cell Stem Cell. 2018 Mar 1;22(3):355-368.
六. 《Cell stemcell》：Th17细胞诱导iPSC PD模型的神经元死亡。
Parkinson's disease (PD) is aneurodegenerative disorder characterized by the progressive degeneration ofmidbrain neurons (MBNs). Recent evidence suggests contribution of the adaptiveimmune system in PD. Here, we show a role for human T lymphocytes as cell deathinducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD.Higher Th17 frequencies were found in the blood of PD patients and increasednumbers of T lymphocytes were detected in postmortem PD brain tissues. Wemodeled this finding using autologous co-cultures of activated T lymphocytesand iPSC-derived MBNs of sporadic PD patients and controls. After co-culturewith T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwentincreased neuronal death driven by upregulation of IL-17 receptor (IL-17R) andNFκB activation. Blockage of IL-17 or IL-17R, or the addition of theFDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Ourfindings indicate a critical role for IL-17-producing T lymphocytes in sporadicPD.
参考文献：Th17 Lymphocytes Induce NeuronalCell Death in a Human iPSC-Based Model of Parkinson's Disease. Cell Stem Cell.2018 Jul 5;23(1):123-131.
Strong evidence implicates thecomplement pathway as an important contributor to amyloid pathology inAlzheimer's disease (AD); however, the role of complement in tau modulationremains unclear. Here we show that the expression of C3 and C3a receptor(C3aR1) are positively correlated with cognitive decline and Braak staging inhuman AD brains. Deletion of C3ar1 in PS19 mice results in the rescue of taupathology and attenuation of neuroinflammation, synaptic deficits, andneurodegeneration. Through RNA sequencing and cell-type-specific transcriptomicanalysis, we identify a C3aR-dependent transcription factor network thatregulates a reactive glial switch whose inactivation amelioratesdisease-associated microglia and neurotoxic astrocyte signatures. Strikingly,this C3aR network includes multiple genes linked to late-onset AD.Mechanistically, we identify STAT3 as a direct target of C3-C3aR signaling thatfunctionally mediates tau pathogenesis. All together our findings demonstrate acrucial role for activation of the C3-C3aR network in mediatingneuroinflammation and tau pathology.
参考文献：Complement C3aR Inactivation Attenuates Tau Pathology and Reverses anImmune Network Deregulated in Tauopathy Models and Alzheimer's Disease. Neuron.2018 Dec 19;100(6):1337-1353.
八. 《Sci Transl Med》：抑制炎症小体改善α-synuclein病理改变和多巴胺能神经元变性。
Parkinson'sdisease (PD) is characterized by a profound loss of dopaminergic neurons in thesubstantia nigra, accompanied by chronic neuroinflammation, mitochondrialdysfunction, and widespread accumulation of α-synuclein-rich protein aggregatesin the form of Lewy bodies. However, the mechanisms linking α-synucleinpathology and dopaminergic neuronal death to chronic microglialneuroinflammation have not been completely elucidated. We show that activationof the microglial NLR family pyrin domain containing 3 (NLRP3) inflammasome isa common pathway triggered by both fibrillar α-synuclein and dopaminergicdegeneration in the absence of α-synuclein aggregates. Cleaved caspase-1 andthe inflammasome adaptor protein apoptosis-associated speck-like protein containinga C-terminal caspase recruitment domain (ASC) were elevated in the substantianigra of the brains of patients with PD and in multiple preclinical PD models.NLRP3 activation by fibrillar α-synuclein in mouse microglia resulted in adelayed but robust activation of the NLRP3 inflammasome leading toextracellular interleukin-1β and ASC release in the absence of pyroptosis.Nanomolar doses of a small-molecule NLRP3 inhibitor, MCC950, abolishedfibrillar α-synuclein-mediated inflammasome activation in mouse microglialcells and extracellular ASC release. Furthermore, oral administration of MCC950in multiple rodent PD models inhibited inflammasome activation and effectivelymitigated motor deficits, nigrostriatal dopaminergic degeneration, and accumulationof α-synuclein aggregates. These findings suggest that microglial NLRP3 may bea sustained source of neuroinflammation that could drive progressivedopaminergic neuropathology and highlight NLRP3 as a potential target fordisease-modifying treatments for PD.
参考文献：Inflammasomeinhibition prevents α-synuclein pathology and dopaminergic neurodegeneration inmice.Sci Transl Med. 2018 Oct 31;10(465).
九. 《Nature neurosci》：脑膜淋巴管调控中枢淋巴流通和神经炎症。
Neuroinflammatorydiseases, such as multiple sclerosis, are characterized by invasion of thebrain by autoreactive T cells. The mechanism for how T cells acquire theirencephalitogenic phenotype and trigger disease remains, however, unclear. Theexistence of lymphatic vessels in the meninges indicates a relevant linkbetween the CNS and peripheral immune system, perhaps affecting autoimmunity.Here we demonstrate that meningeal lymphatics fulfill two critical criteria:they assist in the drainage of cerebrospinal fluid components and enable immunecells to enter draining lymph nodes in a CCR7-dependent manner. Unlike othertissues, meningeal lymphatic endothelial cells do not undergo expansion duringinflammation, and they express a unique transcriptional signature. Notably, theablation of meningeal lymphatics diminishes pathology and reduces theinflammatory response of brain-reactive T cells during an animal model ofmultiple sclerosis. Our findings demonstrate that meningeal lymphatics governinflammatory processes and immune surveillance of the CNS and pose a valuabletarget for therapeutic intervention.
参考文献：CNSlymphatic drainage and neuroinflammation are regulated by meningeal lymphaticvasculature. Nat Neurosci. 2018 Oct;21(10):1380-1391.
十. 《Sci Transl Med》：神经元IL-4信号通路是神经炎症的重要治疗靶点。
Ongoingaxonal degeneration is thought to underlie disability in chronicneuroinflammation, such as multiple sclerosis (MS), especially during itsprogressive phase. Upon inflammatory attack, axons undergo pathologicalswelling, which can be reversible. Because we had evidence for beneficialeffects of T helper 2 lymphocytes in experimental neurotrauma and discoveredinterleukin-4 receptor (IL-4R) expressed on axons in MS lesions, we aimed atunraveling the effects of IL-4 on neuroinflammatory axon injury. We demonstratethat intrathecal IL-4 treatment during the chronic phase of severalexperimental autoimmune encephalomyelitis models reversed disease progressionwithout affecting inflammation. Amelioration of disability was abrogated uponneuronal deletion of IL-4R. We discovered direct neuronal signaling via theIRS1-PI3K-PKC pathway underlying cytoskeletal remodeling and axonal repair.Nasal IL-4 application, suitable for clinical translation, was equallyeffective in improving clinical outcome. Targeting neuronal IL-4 signaling mayoffer new therapeutic strategies to halt disability progression in MS andpossibly also neurodegenerative conditions.
参考文献：Fastdirect neuronal signaling via the IL-4 receptor as therapeutic target inneuroinflammation.Sci Transl Med.2018 Feb 28;10(430).
27、神经科学临床和基础Learning & Memory亚群；