Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

Phongpreecha, Thanaphong; Fernandez, Rachel C.; Mrdjen, Dunja; Culos, Anthony; Gajera, Chandresh R.; Wawro, Adam M.; Stanley, Natalie; Gaudillière, Brice; Poston, Kathleen L.; Aghaeepour, Nima; Montine, Thomas J.

doi:10.1126/sciadv.abd5575

Cited by 40 publications

(36 citation statements)

References 65 publications

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“…Similar to single cell analyses in AD and other diseases ( 59, 60 ), conventional machine learning models were used for prediction and identification of important features. The input to the models was the mean expression matrix obtained after clustering.…”

Section: Methodsmentioning

confidence: 99%

Single-synapse analyses of Alzheimer’s disease implicate pathologic tau, DJ1, CD47, and ApoE

Phongpreecha

et al. 2021

Preprint

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Synaptic molecular characterization is limited for Alzheimers disease (AD). We used mass cytometry to quantify 38 probes in approximately 17 million single synaptic events from human brains without pathologic change or with pure AD or Lewy body disease (LBD), non-human primates (NHP), and PS/APP mice. Synaptic molecular integrity in humans and NHP was similar. Although not detected in human synapses, Aβ was in PS/APP mice synaptic events. Clustering and pattern identification of human synapses showed expected disease-specific differences, like increased hippocampal pathologic tau in AD and reduced caudate dopamine transporter in LBD, and revealed novel findings including increased hippocampal CD47 and lowered DJ1 in AD and higher ApoE in AD dementia. Our results were independently supported by multiplex ion beam imaging of intact tissue.

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Section: Methodsmentioning

confidence: 99%

Single-synapse analyses of Alzheimer’s disease implicate pathologic tau, DJ1, CD47, and ApoE

Phongpreecha

et al. 2021

Preprint

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“…Future approaches to better characterize sex-specific changes in AD would involve stratification by brain regions, age and disease stage, apoE genotype, as well as an analysis of single cell AD datasets. Interestingly, a recent study ( Phongpreecha et al, 2020 ) used single-cell approaches to quantify activation of 15 intracellular signaling pathway activation in peripheral blood mononuclear cells between individuals with AD and healthy controls. This study found increased activation of the STAT5 pathway in AD, consistent with our results demonstrating increased STAT5B in the blood of females with AD compared with healthy females.…”

Section: Limitationsmentioning

confidence: 99%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women With Alzheimer’s Disease

Paranjpe

Belonwu

Wang

et al. 2021

Front. Aging Neurosci.

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Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (APOE ε4) AD risk compared to males, molecular signatures underlying these differences remain elusive.Methods: We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls in seven independent datasets. Sex-specific gene expression patterns were investigated through use of gene-based, pathway-based and network-based approaches. The ability of a sex-specific AD gene expression signature to distinguish Alzheimer’s disease from healthy controls was assessed using a linear support vector machine model. Cell type deconvolution from whole blood gene expression data was performed to identify differentially regulated cells in males and females with AD.Results: Strikingly gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. In females, network-based analysis revealed a coordinated program of gene expression involving several zinc finger nuclease genes related to Herpes simplex viral infection whose expression was modulated by the presence of the APOE ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD patients. Cell type deconvolution identified an increase in neutrophils and naïve B cells and a decrease in M2 macrophages, memory B cells, and CD8+ T cells in AD samples compared to controls in females. Interestingly, among males with AD, no significant differences in immune cell proportions compared to controls were observed. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features produced an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males.Conclusion: These results help identify sex and APOE ε4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.

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“…All the stable isotopes of exogenous cellular elements across the mass range from 75 to 209 Da can be applied as reporters for CyTOF, which shows minimal spectral overlap and requires no compensation between detection channels. [ 5 ] To date, various metal isotopes, including yttrium (Y), [ 6 ] silver (Ag), [ 7 ] cadmium (Cd), [ 8 ] indium (In), [ 9 ] lanthanide elements (Ln, from La to Lu, except Pm), [ 10 ] tantalum (Ta), [ 11 ] and bismuth (Bi) [ 12 ] have been investigated for protein analysis (identity, function, modification, expression level), while tellurium (Te), [ 13 ] ruthenium (Ru), [ 14,15 ] rhodium (Rh), [ 16 ] iridium (Ir), [ 16 ] palladium (Pd), [ 17 ] osmium (Os), [ 15 ] iodine (I), [ 18 ] platinum (Pt) [ 19 ] have been tested for cell identification (nucleus, viability, cell cycle, cell barcode). In order to site‐specifically attach metal cations to an antibody for biomarker detection, elemental labeling strategies based on polymer and nanoparticles (NPs) have been developed.…”

Section: Introductionmentioning

confidence: 99%

New Structure Mass Tag based on Zr‐NMOF for Multiparameter and Sensitive Single‐Cell Interrogating in Mass Cytometry

Dang

Zhang

et al. 2021

Advanced Materials

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Mass cytometry, also called cytometry by time‐of‐flight (CyTOF), is an emerging powerful proteomic analysis technique that utilizes metal chelated polymer (MCP) as mass tags for interrogating high‐dimensional biomarkers simultaneously on millions of individual cells. However, under the typical polymer‐based mass tag system, the sensitivity and multiplexing detection ability has been highly restricted. Herein, a new structure mass tag based on a nanometal organic framework (NMOF) is reported for multiparameter and sensitive single‐cell biomarker interrogating in CyTOF. A uniform‐sized Zr‐NMOF (33 nm) carrying 105 metal ions is synthesized under modulator/reaction time coregulation, which is monodispersed and colloidally stable in water for over one‐year storage. On functionalization with an antibody, the Zr mass tag exhibits specific molecular recognition properties and minimal cross‐reaction toward nontargeted cells. In addition, the Zr‐mass tag is compatible with MCP mass tags in a multiparameter assay for mouse spleen cells staining, which exploits four additional channels, m/z = 90, 91, 92, 94, for single‐cell immunoassays in CyTOF. Compared to the MCP mass tag, the Zr‐mass tag provides an additional fivefold signal amplification. This work provides the fundamental technical capability for exploiting NMOF‐based mass tags for CyTOF application, which opens up possibility of high‐dimensional single‐cell immune profiling, low abundant antigen detection, and development of new barcoding systems.

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Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

Cited by 40 publications

References 65 publications

Single-synapse analyses of Alzheimer’s disease implicate pathologic tau, DJ1, CD47, and ApoE

Single-synapse analyses of Alzheimer’s disease implicate pathologic tau, DJ1, CD47, and ApoE

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women With Alzheimer’s Disease

New Structure Mass Tag based on Zr‐NMOF for Multiparameter and Sensitive Single‐Cell Interrogating in Mass Cytometry

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