Microglia Mediate the Occurrence and Development of Alzheimer's Disease Through Ligand-Receptor Axis Communication.

Chongdong Jian,Rongjie Li,Ruikang Mo,Ying Liu,Lei Wei,Chun Zou,Youshi Meng,Liechun Chen,Lucong Liang,Donghua Zou

doi:10.3389/fnagi.2021.731180

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disease. Its onset is insidious and its progression is slow, making diagnosis difficult. In addition, its underlying molecular and cellular mechanisms remain unclear. In this study, clustering analysis was performed on single-cell RNA sequencing (scRNA-seq) data from the prefrontal cortex of 48 AD patients. Each sample module was identified to be a specific AD cell type, eight main brain cell types were identified, and the dysfunctional evolution of each cell type was further explored by pseudo-time analysis. Correlation analysis was then used to explore the relationship between AD cell types and pathological characteristics. In particular, intercellular communication between neurons and glial cells in AD patients was investigated by cell communication analysis. In patients, neuronal cells and glial cells significantly correlated with pathological features, and glial cells appear to play a key role in the development of AD through ligand-receptor axis communication. Marker genes involved in communication between these two cell types were identified using five types of modeling: logistic regression, multivariate logistic regression, least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). LASSO modeling identified CXCR4, EGFR, MAP4K4, and IGF1R as key genes in this communication. Our results support the idea that microglia play a role in the occurrence and development of AD through ligand-receptor axis communication. In particular, our analyses identify CXCR4, EGFR, MAP4K4, and IGF1R as potential biomarkers and therapeutic targets in AD.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia and the most frequent type of progressive neurodegenerative disease
ScRNA-seq data were analyzed from the prefrontal cortex of individuals with clear AD pathology or with no or minimal pathology
These cells were divided into eight types (Figure 1B): excitatory neurons (Ex), oligodendrocytes (Oli), inhibitory neurons (In), microglia (Mic), oligodendrocyte progenitor cell (OPC), astrocytes (Ast), endothelial cells (End), and pericytes (Per)

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia and the most frequent type of progressive neurodegenerative disease. About 47 million people worldwide suffer from dementia, and the number is projected to increase to 131 million by 2,050 (Tiwari et al, 2019). Due to its insidious onset and slow progression, diagnosis of AD can be difficult (Hogh, 2017). Five drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of AD (Cummings et al, 2014). These drugs only alleviate disease progression or symptoms, without curing the disease. There is a critical need to explore the underlying pathogenesis of AD in order to develop therapeutic and even preventive interventions

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Conclusion