Recent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimer's disease (AD).
Objective
To characterize the composition of adaptive immune cells in the peripheral blood of AD patients.
Methods
We utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects.
Results
We found that the abundance of proinflammatory CXCR3 + CD127+ Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain protein. This correlation is apolipoprotein E (ApoE) ε4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3 + CD127+ Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3+ CD127+ Th1 cells in the CSF of AD patients was further increased compared to HCs.
Conclusions
These results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3 + CD127+ Th1 cells, may potentially be mediated by factors such as ApoE ε4 genotype.
HenekaMTCarsonMJEl KhouryJ, et al.Neuroinflammation in Alzheimer's disease. Lancet Neurol2015; 14: 388–405.
2.
HansenDVHansonJEShengM. Microglia in Alzheimer's disease. J Cell Biol2018; 217: 459–472.
3.
BartelsTDe SchepperSHongS. Microglia modulate neurodegeneration in Alzheimer's and Parkinson's diseases. Science2020; 370: 66–69.
4.
CarterSFHerholzKRosa-NetoP, et al.Astrocyte biomarkers in Alzheimer's disease. Trends Mol Med2019; 25: 77–95.
5.
CaoWZhengH. Peripheral immune system in aging and Alzheimer's disease. Mol Neurodegener2018; 13: 51.
6.
ChenXFirulyovaMManisM, et al.Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature2023; 615: 668–677.
7.
SuWSaraviaJRischI, et al.CXCR6 Orchestrates brain CD8(+) T cell residency and limits mouse Alzheimer's disease pathology. Nat Immunol2023; 24: 1735–1747.
8.
TanJTownTAbdullahL, et al.CD45 Isoform alteration in CD4+ T cells as a potential diagnostic marker of Alzheimer's disease. J Neuroimmunol2002; 132: 164–172.
9.
LuegGGrossCCLohmannH, et al.Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer's disease. Neurobiol Aging2015; 36: 81–89.
10.
GateDSaligramaNLeventhalO, et al.Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature2020; 577: 399–404.
11.
SchindowskiKEckertAPetersJ, et al.Increased T-cell reactivity and elevated levels of CD8 + memory T-cells in Alzheimer's disease-patients and T-cell hyporeactivity in an Alzheimer's disease-mouse model: implications for immunotherapy. Neuromolecular Med2007; 9: 340–354.
12.
PhongpreechaTFernandezRMrdjenD, et al.Single-cell peripheral immunoprofiling of Alzheimer's and Parkinson's diseases. Sci Adv2020; 6: eabd5575.
13.
LanutiPCiccocioppoFBonanniL, et al.Amyloid-specific T-cells differentiate Alzheimer's disease from Lewy body dementia. Neurobiol Aging2012; 33: 2599–2611.
14.
MonsonegoAZotaVKarniA, et al.Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Invest2003; 112: 415–422.
15.
CiccocioppoFLanutiPPierdomenicoL, et al.The characterization of regulatory T-cell profiles in Alzheimer's disease and multiple sclerosis. Sci Rep2019; 9: 8788.
16.
McKhannGMKnopmanDSChertkowH, et al.The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement2011; 7: 263–269.
17.
RybakowskaPVan GassenSMartorell MaruganJ, et al.Protocol for large scale whole blood immune monitoring by mass cytometry and cyto quality pipeline. STAR Protoc2022; 3: 101697.
18.
GeanonDLeeBGonzalez-KozlovaE, et al.A streamlined whole blood CyTOF workflow defines a circulating immune cell signature of COVID-19. Cytometry A2021; 99: 446–461.
19.
GePLiuCChanL, et al.High-dimensional immune profiling by mass cytometry revealed the circulating immune cell landscape in patients with intracranial aneurysm. Front Immunol2022; 13: 922000.
20.
SahafBRahmanAMaeckerHT, et al.High-parameter immune profiling with CyTOF. Methods Mol Biol2020; 2055: 351–368.
21.
RenXWenWFanX, et al.COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell2021; 184: 5838.
22.
LutgeAZyprych-WalczakJBrykczynska KunzmannU, et al.Cellmixs: quantifying and visualizing batch effects in single-cell RNA-seq data. Life Sci Alliance2021; 4: e202001004.
23.
ChenEYTanCMKouY, et al.Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics2013; 14: 128.
24.
KuleshovMVJonesMRRouillardAD, et al.Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res2016; 44: W90–W97.
25.
XieZBaileyAKuleshovMV, et al.Gene set knowledge discovery with enrichr. Curr Protoc2021; 1: e90.
26.
KimS. Ppcor: an R package for a fast calculation to semi-partial correlation coefficients. Commun Stat Appl Methods2015; 22: 665–674.
27.
DiedenhofenBMuschJ. Cocor: a comprehensive solution for the statistical comparison of correlations. PLoS One2015; 10: e0121945.
28.
SpitzerMHNolanGP. Mass cytometry: single cells, many features. Cell2016; 165: 780–791.
29.
KimballAKOkoLMBullockBL, et al.A beginner's guide to analyzing and visualizing mass cytometry data. J Immunol2018; 200: 3–22.
30.
Van GassenSCallebautBVan HeldenMJ, et al.FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A2015; 87: 636–645.
31.
SallustoFLenigDForsterR, et al.Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature1999; 401: 708–712.
32.
WeingartenMDLockwoodAHHwoSY, et al.A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A1975; 72: 1858–1862.
33.
SjolinKKultimaKLarssonA, et al.Distribution of five clinically important neuroglial proteins in the human brain. Mol Brain2022; 15: 52.
34.
ChangCWShaoEMuckeL. Tau: enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies. Science2021; 371: eabb8255.
35.
GoedertMWischikCMCrowtherRA, et al.Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A1988; 85: 4051–4055.
36.
LeiPAytonSFinkelsteinDI, et al.Tau protein: relevance to Parkinson's disease. Int J Biochem Cell Biol2010; 42: 1775–1778.
37.
MattssonNZetterbergHJanelidzeS, et al.Plasma tau in Alzheimer disease. Neurology2016; 87: 1827–1835.
38.
ChenLNiuXWangY, et al.Plasma tau proteins for the diagnosis of mild cognitive impairment and Alzheimer's disease: a systematic review and meta-analysis. Front Aging Neurosci2022; 14: 942629.
39.
ThijssenEHLa JoieRWolfA, et al.Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration. Nat Med2020; 26: 387–397.
40.
WangYLChenJDuZL, et al.Plasma p-tau181 level predicts neurodegeneration and progression to Alzheimer's dementia: a longitudinal study. Front Neurol2021; 12: 695696.
41.
LewczukPErmannNAndreassonU, et al.Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease. Alzheimers Res Ther2018; 10: 71.
42.
MattssonNAndreassonUZetterbergH, et al.Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol2017; 74: 557–566.
43.
AshtonNJLeuzyALimYM, et al.Increased plasma neurofilament light chain concentration correlates with severity of post-mortem neurofibrillary tangle pathology and neurodegeneration. Acta Neuropathol Commun2019; 7: 5.
44.
PreischeOSchultzSAApelA, et al.Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med2019; 25: 277–283.
45.
NakajimaCMukaiTYamaguchiN, et al.Induction of the chemokine receptor CXCR3 on TCR-stimulated T cells: dependence on the release from persistent TCR-triggering and requirement for IFN-gamma stimulation. Eur J Immunol2002; 32: 1792–1801.
46.
ZhangSYZhangZFuJL, et al.Progressive CD127 down-regulation correlates with increased apoptosis of CD8 T cells during chronic HIV-1 infection. Eur J Immunol2009; 39: 1425–1434.
47.
PaiardiniMCervasiBAlbrechtH, et al.Loss of CD127 expression defines an expansion of effector CD8+ T cells in HIV-infected individuals. J Immunol2005; 174: 2900–2909.
48.
WojciechowskiSJordanMBZhuY, et al.Bim mediates apoptosis of CD127(lo) effector T cells and limits T cell memory. Eur J Immunol2006; 36: 1694–1706.
49.
BondaDJLeeHGBlairJA, et al.Role of metal dyshomeostasis in Alzheimer's disease. Metallomics2011; 3: 267–270.
50.
GreenDRDroinNPinkoskiM. Activation-induced cell death in T cells. Immunol Rev2003; 193: 70–81.
51.
SallustoFZielinskiCELanzavecchiaA. Human Th17 subsets. Eur J Immunol2012; 42: 2215–2220.
52.
SallustoF. Heterogeneity of human CD4(+) T cells against microbes. Annu Rev Immunol2016; 34: 317–334.
53.
GeginatJParoniMMaglieS, et al.Plasticity of human CD4 T cell subsets. Front Immunol2014; 5: 630.
54.
SallustoFLanzavecchiaA. Heterogeneity of CD4 + memory T cells: functional modules for tailored immunity. Eur J Immunol2009; 39: 2076–2082.
55.
ZhuXZhuJ. CD4 T helper cell subsets and related human immunological disorders. Int J Mol Sci2020; 21: 8011.
56.
El MasriRDelonJ. RHO GTPases: from new partners to complex immune syndromes. Nat Rev Immunol2021; 21: 499–513.
57.
RotAvon AndrianUH. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol2004; 22: 891–928.
58.
OlsonTSLeyK. Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integr Comp Physiol2002; 283: R7–28.
59.
KoperOMKaminskaJSawickiK, et al.CXCL9, CXCL10, CXCL11, and their receptor (CXCR3) in neuroinflammation and neurodegeneration. Adv Clin Exp Med2018; 27: 849–856.
60.
ParhizkarSHoltzmanDM. APOE Mediated neuroinflammation and neurodegeneration in Alzheimer's disease. Semin Immunol2022; 59: 101594.
61.
EmraniSArainHADeMarshallC, et al.APOE4 Is associated with cognitive and pathological heterogeneity in patients with Alzheimer's disease: a systematic review. Alzheimers Res Ther2020; 12: 141.
62.
ZhouXShiQZhangX, et al.ApoE4-mediated blood-brain barrier damage in Alzheimer's disease: progress and prospects. Brain Res Bull2023; 199: 110670.
63.
BonacinaFCoeDWangG, et al.Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation. Nat Commun2018; 9: 3083.
64.
WangSYChenWXuW, et al.Neurofilament light chain in cerebrospinal fluid and blood as a biomarker for neurodegenerative diseases: a systematic review and meta-analysis. J Alzheimers Dis2019; 72: 1353–1361.
65.
BarroCChitnisTWeinerHL. Blood neurofilament light: a critical review of its application to neurologic disease. Ann Clin Transl Neurol2020; 7: 2508–2523.
66.
Malek-AhmadiMSuYGhisaysV, et al.Plasma NfL is associated with the APOE epsilon4 allele, brain imaging measurements of neurodegeneration, and lower recall memory scores in cognitively unimpaired late-middle-aged and older adults. Alzheimers Res Ther2023; 15: 74.
67.
KleinSLFlanaganKL. Sex differences in immune responses. Nat Rev Immunol2016; 16: 626–638.
68.
FerrettiMTIulitaMFCavedoE, et al.Sex differences in Alzheimer disease - the gateway to precision medicine. Nat Rev Neurol2018; 14: 457–469.
69.
FerrettiMTMartinkovaJBiskupE, et al.Sex and gender differences in Alzheimer's disease: current challenges and implications for clinical practice: position paper of the dementia and cognitive disorders panel of the European academy of neurology. Eur J Neurol2020; 27: 928–943.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
