Abstract1

Toelucidate the role of Tau isoforms and post-translational modification (PTM)stoichiometry in Alzheimer's disease (AD), we generated a high-resolutionquantitative proteomics map of 95 PTMs on multiple isoforms of Tau isolatedfrom postmortem human tissue from 49 AD and 42 control subjects. Although TauPTM maps reveal heterogeneity across subjects, a subset of PTMs display highoccupancy and frequency for AD, suggesting importance in disease. Unsupervisedanalyses indicate that PTMs occur in an ordered manner, leading to Tauaggregation. The processive addition and minimal set of PTMs associated withseeding activity was further defined by analysis of size-fractionated Tau. Tosummarize, features in the Tau protein critical for disease intervention atdifferent stages of disease are identified, including enrichment of 0N and 4Risoforms, underrepresentation of the C terminus, an increase in negative chargein the proline-rich region (PRR), and a decrease in positive charge in themicrotubule binding domain (MBD).

Abstract2

Tauaggregation into insoluble filaments is the defining pathological hallmark oftauopathies. However, it is not known what controls the formation and templatedseeding of strain-specific structures associated with individual tauopathies.Here, we use cryo-electron microscopy (cryo-EM) to determine the structuresof tau filaments from corticobasal degeneration (CBD) human brain tissue.Cryo-EM and mass spectrometry of tau filaments from CBD reveal that thisconformer is heavily decorated with posttranslational modifications (PTMs),enabling us to map PTMs directly onto the structures. By comparing thestructures and PTMs of tau filaments from CBD and Alzheimer's disease, it isfound that ubiquitination of tau can mediate inter-protofilament interfaces.We propose a structure-based model in which cross-talk between PTMsinfluences tau filament structure, contributing to the structural diversity oftauopathy strains. Our approach establishes a framework for furtherelucidating the relationship between the structures of polymorphic fibrils,including their PTMs, and neurodegenerative disease.

参考文献1：Tau PTMProfiles Identify Patient Heterogeneity and Stages of Alzheimer's Disease. Cell.2020 Nov 10;S0092-8674(20)31393-3.

参考文献2：PosttranslationalModifications Mediate the Structural Diversity of Tauopathy Strains. Cell. 2020Feb 20;180(4):633-644.e12.

 

突破二：Naturegenetics—科学家聚焦AD特异性表观遗传学组改变及其潜在的表观遗传学因果变异位点。

Abstract1

Proteinaggregation is the hallmark of neurodegeneration, but the molecular mechanismsunderlying late-onset Alzheimer's disease (AD) are unclear. Here we integratedtranscriptomic, proteomic and epigenomic analyses of postmortem human brains toidentify molecular pathways involved in AD. RNA sequencing analysis revealedupregulation of transcription- and chromatin-related genes, including thehistone acetyltransferases for H3K27ac and H3K9ac. An unbiased proteomicscreening singled out H3K27ac and H3K9ac as the main enrichments specific toAD. In turn, epigenomic profiling revealed gains in the histone H3modifications H3K27ac and H3K9ac linked to transcription, chromatin and diseasepathways in AD. Increasing genome-wide H3K27ac and H3K9ac in a fly modelof AD exacerbated amyloid-β42-driven neurodegeneration. Together, thesefindings suggest that AD involves a reconfiguration of the epigenome, whereinH3K27ac and H3K9ac affect disease pathways by dysregulating transcription- andchromatin-gene feedback loops. The identification of this process highlightspotential epigenetic strategies for early-stage disease treatment.

Abstract2

Genome-wideassociation studies of neurological diseases have identified thousands ofvariants associated with disease phenotypes. However, most of these variants donot alter coding sequences, making it difficult to assign their function. Here,we present a multi-omic epigenetic atlas of the adult human brain throughprofiling of single-cell chromatin accessibility landscapes andthree-dimensional chromatin interactions of diverse adult brain regionsacross a cohort of cognitively healthy individuals. We developed a machine-learningclassifier to integrate this multi-omic framework and predict dozens offunctional SNPs for Alzheimer's and Parkinson's diseases, nominating targetgenes and cell types for previously orphaned loci from genome-wide associationstudies. Moreover, we dissected the complex inverted haplotype of the MAPT(encoding tau) Parkinson's disease risk locus, identifying putative ectopicregulatory interactions in neurons that may mediate this disease association.This work expands understanding of inherited variation and provides a roadmapfor the epigenomic dissection of causal regulatory variation in disease.

参考文献1：Anintegrated multi-omics approach identifies epigenetic alterations associatedwith Alzheimer's disease. Nat Genet. 2020 Oct;52(10):1024-1035.

参考文献2：Single-cellepigenomic analyses implicate candidate causal variants at inherited risk locifor Alzheimer's and Parkinson's diseases. Nat Genet. 2020 Nov;52(11):1158-1168.

 

突破三：Nature—科学家揭示固有免疫蛋白IFITM3激活γ-分泌酶并促进Aβ聚集

Abstract

Innateimmunity is associated with Alzheimer's disease1, but the influence of immuneactivation on the production of amyloid-β is unknown2,3. Here we identifyinterferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatoryprotein, and establish a mechanism by which inflammation affects thegeneration of amyloid-β. Inflammatory cytokines induce the expression ofIFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulatesits activity, thereby increasing the production of amyloid-β. Theexpression of IFITM3 is increased with ageing and in mouse models that expressfamilial Alzheimer's disease genes. Furthermore, knockout of IFITM3reduces γ-secretase activity and the formation of amyloid plaques in atransgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein isupregulated in tissue samples from a subset of patients with late-onsetAlzheimer's disease that exhibit higher γ-secretase activity. The amount ofIFITM3 in the γ-secretase complex has a strong and positive correlation withγ-secretase activity in samples from patients with late-onset Alzheimer'sdisease. These findings reveal a mechanism in which γ-secretase is modulated byneuroinflammation via IFITM3 and the risk of Alzheimer's disease is therebyincreased.

参考文献：Theinnate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease. Nature.2020 Oct;586(7831):735-740.

 

突破四：Science—科学家开发“突触修复手术刀”—CPTX，可修复AD特异性突触和认知损害

Abstract

Neuronalsynapses undergo structural and functional changes throughout life, which areessential for nervous system physiology. However, these changes may alsoperturb the excitatory-inhibitory neurotransmission balance and triggerneuropsychiatric and neurological disorders. Molecular tools to restore this balanceare highly desirable. Here, we designed and characterized CPTX, a syntheticsynaptic organizer combining structural elements from cerebellin-1 andneuronal pentraxin-1. CPTX can interact with presynaptic neurexins andpostsynaptic AMPA-type ionotropic glutamate receptors and induced the formationof excitatory synapses both in vitro and in vivo. CPTX restored synapticfunctions, motor coordination, spatial and contextual memories, and locomotionin mouse models for cerebellar ataxia, Alzheimer's disease, and spinal cordinjury, respectively. Thus, CPTX represents a prototype forstructure-guided biologics that can efficiently repair or remodel neuronalcircuits.

参考文献：Asynthetic synaptic organizer protein restores glutamatergic neuronal circuits. Science.2020 Aug 28;369(6507):eabb4853.

 

突破五：Cell—空间转录组揭示AD不同阶段Aβ老年斑周围细胞基因共表达网络异常改变

Abstract

Althoughcomplex inflammatory-like alterations are observed around the amyloid plaquesof Alzheimer's disease (AD), little is known about the molecular changes andcellular interactions that characterize this response. We investigate here,in an AD mouse model, the transcriptional changes occurring in tissue domainsin a 100-μm diameter around amyloid plaques using spatial transcriptomics. Wedemonstrate early alterations in a gene co-expression network enriched formyelin and oligodendrocyte genes (OLIGs), whereas a multicellular geneco-expression network of plaque-induced genes (PIGs) involving the complementsystem, oxidative stress, lysosomes, and inflammation is prominent in the laterphase of the disease. We confirm the majority of the observedalterations at the cellular level using in situ sequencing on mouse and humanbrain sections. Genome-wide spatial transcriptomics analysis provides anunprecedented approach to untangle the dysregulated cellular network in thevicinity of pathogenic hallmarks of AD and other brain diseases.

参考文献：SpatialTranscriptomics and In Situ Sequencing to Study Alzheimer's Disease. Cell. 2020Aug 20;182(4):976-991.e19.

 

突破六：Nature—科学家揭示APOE4通过诱导血脑屏障功能障碍以促进认知功能下降

Abstract

Vascularcontributions to dementia and Alzheimer's disease are increasinglyrecognized1-6. Recent studies have suggested that breakdown of the blood-brainbarrier (BBB) is an early biomarker of human cognitive dysfunction7, includingthe early clinical stages of Alzheimer's disease5,8-10. The E4 variant ofapolipoprotein E (APOE4), the main susceptibility gene for Alzheimer'sdisease11-14, leads to accelerated breakdown of the BBB and degeneration ofbrain capillary pericytes15-19, which maintain BBB integrity20-22. It isunclear, however, whether the cerebrovascular effects of APOE4 contribute tocognitive impairment. Here we show that individuals bearing APOE4 (with theε3/ε4 or ε4/ε4 alleles) are distinguished from those without APOE4 (ε3/ε3) bybreakdown of the BBB in the hippocampus and medial temporal lobe. This findingis apparent in cognitively unimpaired APOE4 carriers and more severe inthose with cognitive impairment, but is not related to amyloid-β or taupathology measured in cerebrospinal fluid or by positron emission tomography23.High baseline levels of the BBB pericyte injury biomarker soluble PDGFRβ7,8in the cerebrospinal fluid predicted future cognitive decline in APOE4 carriersbut not in non-carriers, even after controlling for amyloid-β and taustatus, and were correlated with increased activity of the BBB-degradingcyclophilin A-matrix metalloproteinase-9 pathway19 in cerebrospinal fluid. Ourfindings suggest that breakdown of the BBB contributes to APOE4-associatedcognitive decline independently of Alzheimer's disease pathology, and mightbe a therapeutic target in APOE4 carriers.

参考文献：APOE4leads to blood-brain barrier dysfunction predicting cognitive decline. Nature.2020 May;581(7806):71-76.

 

突破七：Nature—科学家揭示LRP1是tau蛋白摄取和播散的关键调控分子

Abstract

Thespread of protein aggregates during disease progression is a common themeunderlying many neurodegenerative diseases. The microtubule-associated proteintau has a central role in the pathogenesis of several forms of dementia knownas tauopathies-including Alzheimer's disease, frontotemporal dementia andchronic traumatic encephalopathy1. Progression of these diseases ischaracterized by the sequential spread and deposition of protein aggregates ina predictable pattern that correlates with clinical severity2. This observationand complementary experimental studies3,4 have suggested that tau can spreadin a prion-like manner, by passing to naive cells in which it templatesmisfolding and aggregation. However, although the propagation of tau hasbeen extensively studied, the underlying cellular mechanisms remain poorlyunderstood. Here we show that the low-density lipoprotein receptor-relatedprotein 1 (LRP1) controls the endocytosis of tau and its subsequent spread.Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and ininduced pluripotent stem cell-derived neurons. The interaction between tauand LRP1 is mediated by lysine residues in the microtubule-binding repeatregion of tau. Furthermore, downregulation of LRP1 in an in vivo mousemodel of tau spread was found to effectively reduce the propagation of taubetween neurons. Our results identify LRP1 as a key regulator of tauspread in the brain, and therefore a potential target for the treatment ofdiseases that involve tau spread and aggregation.

参考文献：LRP1is a master regulator of tau uptake and spread. Nature. 2020Apr;580(7803):381-385.

 

突破八：Nature—科学家揭示AD患者脑脊液中存在克隆性CD8+T细胞的扩增

Abstract

Alzheimer'sdisease is an incurable neurodegenerative disorder in which neuroinflammationhas a critical function1. However, little is known about the contribution ofthe adaptive immune response in Alzheimer's disease2. Here, using integratedanalyses of multiple cohorts, we identify peripheral and central adaptiveimmune changes in Alzheimer's disease. First, we performed mass cytometry ofperipheral blood mononuclear cells and discovered an immune signature ofAlzheimer's disease that consists of increased numbers of CD8+ T effectormemory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+TEMRA cells were negatively associated with cognition. Furthermore,single-cell RNA sequencing revealed that T cell receptor (TCR) signalling wasenhanced in these cells. Notably, by using several strategies of single-cellTCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRAcells in the cerebrospinal fluid of patients with Alzheimer's disease.Finally, we used machine learning, cloning and peptide screens todemonstrate the specificity of clonally expanded TCRs in the cerebrospinalfluid of patients with Alzheimer's disease to two separate Epstein-Barr virusantigens. These results reveal an adaptive immune response in the blood andcerebrospinal fluid in Alzheimer's disease and provide evidence of clonal,antigen-experienced T cells patrolling the intrathecal space of brains affectedby age-related neurodegeneration.

参考文献：Clonallyexpanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature.2020 Jan;577(7790):399-404.

 

突破九：Lancet—科学家揭示唐氏综合症成年患者AD特异的临床和生物标志物改变

Abstract

Background:Alzheimer's disease and its complications are the leading cause of deathin adults with Down syndrome. Studies have assessed Alzheimer's disease inindividuals with Down syndrome, but the natural history of biomarker changes inDown syndrome has not been established. We characterised the order andtiming of changes in biomarkers of Alzheimer's disease in a population ofadults with Down syndrome.

Methods:We did a dual-centre cross-sectional study of adults with Down syndromerecruited through a population-based health plan in Barcelona (Spain) andthrough services for people with intellectual disabilities in Cambridge (UK).Cognitive impairment in participants with Down syndrome was classified with theCambridge Cognitive Examination for Older Adults with Down Syndrome(CAMCOG-DS). Only participants with mild or moderate disability wereincluded who had at least one of the following Alzheimer's disease measures:apolipoprotein E allele carrier status; plasma concentrations of amyloid βpeptides 1-42 and 1-40 and their ratio (Aβ1-42/1-40), total tau protein, andneurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau),and NFL in cerebrospinal fluid (CSF); and one or more of PET with18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitivelyhealthy euploid controls aged up to 75 years who had no biomarker abnormalitieswere recruited from the Sant Pau Initiative on Neurodegeneration. We used afirst-order locally estimated scatterplot smoothing curve to determine theorder and age at onset of the biomarker changes, and the lowest ages at thedivergence with 95% CIs are also reported where appropriate.

Findings:Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009,and Dec 31, 2014 (Cambridge), we included 388 participants with Downsyndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease,and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls.CSF Aβ1-42/1-40 and plasma NFL values changed in individuals with Down syndromeas early as the third decade of life, and amyloid PET uptake changedin the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changesoccurred later in the fourth decade of life, followed by hippocampal atrophyand changes in cognition in the fifth decade of life. ProdromalAlzheimer's disease was diagnosed at a median age of 50·2 years (IQR47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2).Symptomatic Alzheimer's disease prevalence increased with age in individualswith Down syndrome, reaching 90-100% in the seventh decade of life.

Interpretation:Alzheimer's disease in individuals with Down syndrome has a long preclinicalphase in which biomarkers follow a predictable order of changes over more thantwo decades. The similarities with sporadic and autosomal dominantAlzheimer's disease and the prevalence of Down syndrome make this population asuitable target for Alzheimer's disease preventive treatments.

参考文献：Clinicaland biomarker changes of Alzheimer's disease in adults with Down syndrome: across-sectional study. Lancet. 2020 Jun 27;395(10242):1988-1997.

 

突破十：Cell—科学家揭示小胶质细胞泛素连接酶COP1通过降解c/EBPβ以抑制神经炎症反应

Abstract

Dysregulatedmicroglia are intimately involved in neurodegeneration, including Alzheimer'sdisease (AD) pathogenesis, but the mechanisms controlling pathogenicmicroglial gene expression remain poorly understood. The transcriptionfactor CCAAT/enhancer binding protein beta (c/EBPβ) regulatespro-inflammatory genes in microglia and is upregulated in AD. We showexpression of c/EBPβ in microglia is regulated post-translationally by the ubiquitinligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβaccumulates rapidly and drives a potent pro-inflammatory andneurodegeneration-related gene program, evidenced by increased neurotoxicity inmicroglia-neuronal co-cultures. Antibody blocking studies reveal thatneurotoxicity is almost entirely attributable to complement. Remarkably, lossof a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficientmicroglia markedly accelerated tau-mediated neurodegeneration in a mouse modelwhere activated microglia play a deleterious role. Thus, COP1 is animportant suppressor of pathogenic c/EBPβ-dependent gene expression programs inmicroglia.

参考文献：UbiquitinLigase COP1 Suppresses Neuroinflammation by Degrading c/EBPβ in Microglia. Cell.2020 Sep 3;182(5):1156-1169.e12.