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

Abstract

In 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.

Identification of diagnostic genes for both Alzheimer’s disease and Metabolic syndrome by the machine learning algorithm

“…In the immune infiltration analysis, RPL36AL was mainly on B cells. Single-cell RNA sequencing reveals significant decrease in B cells detected in blood of AD patients, and similar studies have previously yielded similar results (18).…”

“…Dataset acquisition, processing and differential expression analysis GSE63060 ( 17), GSE63061 and one AD single-cell RNAsequencing dataset GSE168522 (18); the same method was used to obtain the MetS dataset GSE (19). The software R (https://www.bioconductor.org/) was used for data analysis.…”

Cellular transcriptional alterations of peripheral blood in Alzheimer’s disease

“…3C) and also limited overlap with those identified from single-cell RNA sequencing datasets (Additional file 1: Fig. S13) [38,40,78], which may due to the differences of sample preparation, sequencing methods, and analytic protocols, as well as the heterogeneity of the participants. However, there was a convergence in dysregulated signaling pathways, such as the dysregulations of regulation of defense response, cellular response to cytokine stimulus, and regulation of inflammatory response in the majority of cell types, suggesting that pathway and network-based markers may be more robust [95].…”

“…Activated CD8 + T cells exhibit a higher proportion in the CSF of AD patients than healthy older adults and correlate with clinical and structural markers of AD pathology [37]. Several studies based on the single-cell RNA sequencing of peripheral blood mononuclear cells further have disclosed the cell-specific signatures in AD and mild cognitive impairment (MCI) [38][39][40]. However, the small sample size and underestimate of polymorphonuclear leukocytes (e.g., neutrophils) limit our understanding of the distribution and biological characteristics of all the peripheral blood immune cells.…”

Association of B cell profile and receptor repertoire with the progression of Alzheimer’s disease

“…Moreover, we could also speculate through the results from Figure 7 that changes in the B cell population and their secretion of IgG are related to brain microglial function regulating the expression of TGF-b in microglia (Li et al, 2017;Taylor et al, 2017). Since there is still debate that the decrease in the B cell population alleviates or exacerbates the deposition of Ab (Kim et al, 2021;Xiong et al, 2021), our acute or chronic models for Ab can partially explain this controversy in terms of microglial responses to IgG in the brain. In particular, our results correspond to those of Kim et al, who showed the therapeutic effect of B cell depletion through restoration of TGF-b in microglia (Kim et al, 2021).…”