scholarly journals Increased Number of Plasma B Cells Producing Autoantibodies Against Aβ42 Protofibrils in Alzheimer’s Disease

2015 ◽  
Vol 48 (1) ◽  
pp. 63-72 ◽  
Author(s):  
Sofia Söllvander ◽  
Frida Ekholm-Pettersson ◽  
Rose-Marie Brundin ◽  
Gabriel Westman ◽  
Lena Kilander ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
B Cells

scholarly journals The Complexity of Microglial Interactions With Innate and Adaptive Immune Cells in Alzheimer’s Disease

2020 ◽  
Vol 12 ◽  
Author(s):  
Season K. Wyatt-Johnson ◽  
Randy R. Brutkiewicz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Immune Cells ◽  
Reactive Microglia ◽  
Adaptive Immune Cells ◽  
Affected Relative ◽  
Peripheral Immune Cells

In the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.

scholarly journals Single-cell RNA sequencing reveals B cell–related molecular biomarkers for Alzheimer’s disease

2021 ◽  
Author(s):  
Liu-Lin Xiong ◽  
Lu-Lu Xue ◽  
Ruo-Lan Du ◽  
Rui-Ze Niu ◽  
Li Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Rna Sequencing ◽  
Early Stage ◽  
Diagnostic Process ◽  
Sequencing Analysis ◽  
Single Cell Rna Sequencing

AbstractIn recent years, biomarkers have been integrated into the diagnostic process and have become increasingly indispensable for obtaining knowledge of the neurodegenerative processes in Alzheimer’s disease (AD). Peripheral blood mononuclear cells (PBMCs) in human blood have been reported to participate in a variety of neurodegenerative activities. Here, a single-cell RNA sequencing analysis of PBMCs from 4 AD patients (2 in the early stage, 2 in the late stage) and 2 normal controls was performed to explore the differential cell subpopulations in PBMCs of AD patients. A significant decrease in B cells was detected in the blood of AD patients. Furthermore, we further examined PBMCs from 43 AD patients and 41 normal subjects by fluorescence activated cell sorting (FACS), and combined with correlation analysis, we found that the reduction in B cells was closely correlated with the patients’ Clinical Dementia Rating (CDR) scores. To confirm the role of B cells in AD progression, functional experiments were performed in early-stage AD mice in which fibrous plaques were beginning to appear; the results demonstrated that B cell depletion in the early stage of AD markedly accelerated and aggravated cognitive dysfunction and augmented the Aβ burden in AD mice. Importantly, the experiments revealed 18 genes that were specifically upregulated and 7 genes that were specifically downregulated in B cells as the disease progressed, and several of these genes exhibited close correlation with AD. These findings identified possible B cell-based AD severity, which are anticipated to be conducive to the clinical identification of AD progression.

scholarly journals Therapeutic B-cell depletion reverses progression of Alzheimer’s disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ki Kim ◽  
Xin Wang ◽  
Emeline Ragonnaud ◽  
Monica Bodogai ◽  
Tomer Illouz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
B Cells ◽  
Memory Deficits ◽  
Brain Parenchyma ◽  
Plaque Burden ◽  
B Cell Depletion ◽  
Transgenic Models ◽  
Immunoglobulin Deposits ◽  
The Brain

AbstractThe function of B cells in Alzheimer’s disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aβ) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around Aβ plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce Aβ plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFβ+ microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients.

scholarly journals Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer's Disease

2020 ◽  
Author(s):  
Manish D Paranjpe ◽  
Stella Belonwu ◽  
Jason K Wang ◽  
Tomiko Oskotsky ◽  
Aarzu Gupta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
B Cells ◽  
Whole Blood ◽  
Meta Analysis ◽  
The United States ◽  
Support Vector ◽  
Cell Type ◽  
Study Gene Expression

Abstract 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 (apoE4) AD risk compared to males, molecular signatures underlying these findings 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 apolipoprotein ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD signature. 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. Conclusions: These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.

scholarly journals Pulmonary B cells ameliorate Alzheimer’s disease-like neuropathology

2020 ◽  
Author(s):  
Weixi Feng ◽  
Yanli Zhang ◽  
Tianqi Wang ◽  
Ze Wang ◽  
Yan Chen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
B Cells ◽  
B Cell ◽  
Memory Deficits ◽  
Brain Parenchyma ◽  
Toll Like Receptor ◽  
Amyloid Aβ ◽  
5Xfad Mice ◽  
The Brain

Increasing evidence shows that the peripheral immune system is involved in the pathogenesis of Alzheimer’s disease (AD). Here, we report that pulmonary B cells mitigate beta-Amyloid (Aβ) pathology in 5xFAD mice. The proportion of B cells rather than T cells increases in brain, meningeal and lung tissues in 3-month-old 5xFAD mice. Deletion of B cells aggravates Aβ load and memory deficits of 5xFAD mice. Mechanimsly, pulmonary B cells can migrate to the brain parenchyma and produce interleukin-35 that inhibits neuronal β-site APP-cleaving enzyme 1 expression, subsequently reducing the production of Aβ. In turn, proliferation of pulmonary B cells is associated with activation of toll-like receptor/nuclear factor kappa-B pathway by elevated Aβ that is drained from the brain parenchyma to the lungs via meningeal lymphatics. Furthermore, promoting pulmonary B cell proliferation via overexpression of B-cell-activating factor ameliorates brain Aβ load and improves cognitive functions of 10-month-old 5xFAD mice. Together, these results highlight the lungs as both immune targets and effector organs in Aβ pathogenesis. Pulmonary B cells might be a potential target against AD.

scholarly journals Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer's Disease

2020 ◽  
Author(s):  
Manish Paranjpe ◽  
Stella Belonwu ◽  
Jason K Wang ◽  
Tomiko Oskotsky ◽  
Aarzu Gupta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
B Cells ◽  
Whole Blood ◽  
Meta Analysis ◽  
The United States ◽  
Support Vector ◽  
Cell Type ◽  
Study Gene Expression

Abstract 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 (apoE4) AD risk compared to males, molecular signatures underlying these findings 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 apolipoprotein ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD signature. 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. Conclusions: These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.

scholarly journals The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function

2016 ◽  
Vol 113 (9) ◽  
pp. E1316-E1325 ◽  
Author(s):  
Samuel E. Marsh ◽  
Edsel M. Abud ◽  
Anita Lakatos ◽  
Alborz Karimzadeh ◽  
Stephen T. Yeung ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
B Cells ◽  
Adaptive Immunity ◽  
Immune Cell ◽  
Adaptive Immune System ◽  
Phagocytic Capacity ◽  
Adaptive Immune ◽  
5Xfad Mice

The innate immune system is strongly implicated in the pathogenesis of Alzheimer’s disease (AD). In contrast, the role of adaptive immunity in AD remains largely unknown. However, numerous clinical trials are testing vaccination strategies for AD, suggesting that T and B cells play a pivotal role in this disease. To test the hypothesis that adaptive immunity influences AD pathogenesis, we generated an immune-deficient AD mouse model that lacks T, B, and natural killer (NK) cells. The resulting “Rag-5xfAD” mice exhibit a greater than twofold increase in β-amyloid (Aβ) pathology. Gene expression analysis of the brain implicates altered innate and adaptive immune pathways, including changes in cytokine/chemokine signaling and decreased Ig-mediated processes. Neuroinflammation is also greatly exacerbated in Rag-5xfAD mice as indicated by a shift in microglial phenotype, increased cytokine production, and reduced phagocytic capacity. In contrast, immune-intact 5xfAD mice exhibit elevated levels of nonamyloid reactive IgGs in association with microglia, and treatment of Rag-5xfAD mice or microglial cells with preimmune IgG enhances Aβ clearance. Last, we performed bone marrow transplantation studies in Rag-5xfAD mice, revealing that replacement of these missing adaptive immune populations can dramatically reduce AD pathology. Taken together, these data strongly suggest that adaptive immune cell populations play an important role in restraining AD pathology. In contrast, depletion of B cells and their appropriate activation by T cells leads to a loss of adaptive–innate immunity cross talk and accelerated disease progression.

Pulmonary B Lymphocytes Ameliorate Alzheimer's Disease-Like Neuropathology

2021 ◽  
Author(s):  
Weixi Feng ◽  
Yanli Zhang ◽  
Tianqi Wang ◽  
Qian Li ◽  
Ze Wang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Brain Parenchyma ◽  
Amyloid Aβ ◽  
5Xfad Mice ◽  
The Brain

Abstract Increasing evidences reveal that the peripheral immune system is involved in the pathogenesis of Alzheimer's disease (AD). Here, we report that pulmonary B lymphocytes mitigate beta-Amyloid (Aβ) pathology in 5xFAD mice. The proportion of B cells, rather than T cells, increases within the brain, meningeal and lung tissues in 3-month-old 5xFAD mice. Deletion of mature B cells aggravates Aβ load and memory deficits of 5xFAD mice. Mechanistically, pulmonary B cells can migrate to the brain parenchyma and produce interleukin-35, which inhibits neuronal β-site APP-cleaving enzyme 1 expression, and subsequently reduces the production of Aβ. In turn, pulmonary B cell proliferation is associated with activation of the toll-like receptor/nuclear factor kappa-B pathway through elevated Aβ that is drained from the brain parenchyma to the lungs via meningeal lymphatics. Furthermore, promoting pulmonary B cell proliferation via overexpression of B-cell-activating factor ameliorates brain Aβ load and improves cognitive functions of 10-month-old 5xFAD mice. Together, these results highlight the lungs as both immune targets and effector organs in Aβ pathogenesis. Pulmonary B cells could serve as a potential target against AD.

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