Single-Cell RNA-Sequencing: Astrocyte and Microglial Heterogeneity in Health and Disease

Abstract

Astrocytes and microglia are non-neuronal cells that maintain homeostasis within the central nervous system via their capacity to regulate neuronal transmission and prune synapses. Both astrocytes and microglia can undergo morphological and transcriptomic changes in response to infection with human immunodeficiency virus (HIV). While both astrocytes and microglia can be infected with HIV, HIV viral proteins in the local environment can interact with and activate these cells. Given that both astrocytes and microglia play critical roles in maintaining neuronal function, it will be critical to have an understanding of their heterogeneity and to identify genes and mechanisms that modulate their responses to HIV. Heterogeneity may include a depletion or increase in one or more astrocyte or microglial subtypes in different regions of the brain or spine as well as the gain or loss of a specific function. Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful tool that can be used to characterise these changes within a given population. The use of this method facilitates the identification of subtypes and changes in cellular transcriptomes that develop in response to activation and various disease processes. In this review, we will examine recent studies that have used scRNA-seq to explore astrocyte and microglial heterogeneity in neurodegenerative diseases including Alzheimer’s disease and amyotrophic lateral sclerosis as well as in response to HIV infection. A careful review of these studies will expand our current understanding of cellular heterogeneity at homeostasis and in response to specific disease states.

Caspase-dependent apoptosis induces reactivation and gliogenesis of astrocytes in adult mice

“…Astrocytes, similar to neurons, are heterogeneous in that they can be responsible for different shapes and functions in each area of the brain ( Miller, 2018 ; Spurgat and Tang, 2022 ). Although we investigated the function of astrocytes in the hippocampal region in this study, it is possible to study the role of astrocytes in various brain regions using cTg mice.…”

“…In fact, many subsequent studies have shown that inflammatory responses caused by disease and aging promote the activation of A1 astrocytes ( Zhang et al, 2016 ; Clarke et al, 2018 ; Xu et al, 2018 ; Qian et al, 2019 ; Zou et al, 2019 ; Li et al, 2020 ), and that A2 astrocytes are involved in the proliferation of astrocytes ( Liddelow and Barres, 2017 ). However, recent single-cell-level studies have suggested that astrocytes are heterogeneous and can be further subdivided and classified according to brain regions and stimuli-specific reactivity ( Miller, 2018 ; Wang et al, 2020 ; Hasel et al, 2021 ; Sadick et al, 2022 ; Spurgat and Tang, 2022 ). Gliogenesis occurs from late neural stem cells (NSCs) during development, but in adults, it can also occur by the proliferation of reactive astrocytes ( Wanner et al, 2013 ).…”

Synapse Dysfunctions in Multiple Sclerosis

“…As mentioned, the A1/A2 dichotomy of astrocytes is too simplified based on single-cell sequencing data but still useful as a simplified working model. Transcript analyses revealed markers common to all reactive astrocytes (e.g., GFAP [ 178 , 302 ]). The expression of complement protein C3 is a marker for inflammatory “A1” astrocytes [ 178 , 208 , 284 , 303 , 304 ].…”

Microglia and Alzheimer’s Disease

“…Recent genomic and transcriptome studies have supported the idea that pathways associated to microglia are essential for the risk and pathogenesis of AD [ 10 ]. It’s interesting to note that recent research has shown that microglia accumulate close to amyloid-beta plaques in the AD brain and increase disease severity [ 28 , 29 , 30 ]. Therefore, the topic of this review is to offer an overview on microglia involvement in neuroinflammation and AD pathology.…”