Meta-analysis of human and mouse ALS astrocytes reveals multi-omic signatures of inflammatory reactive states

Astrocytes contribute to motor neuron death in amyotrophic lateral sclerosis (ALS), but whether they adopt deleterious features consistent with inflammatory reactive states remains incompletely resolved. To identify inflammatory reactive features in ALS human induced pluripotent stem cell (hiPSC)–derived astrocytes, we examined transcriptomics, proteomics, and glutamate uptake in VCP-mutant astrocytes. We complemented this by examining other ALS mutations and models using a systematic meta-analysis of all publicly-available ALS astrocyte sequencing data, which included hiPSC-derived astrocytes carrying SOD1, C9orf72, and FUS gene mutations as well as mouse ALS astrocyte models with SOD1G93A mutation, Tardbp deletion, and Tmem259 (also known as membralin) deletion. ALS astrocytes were characterized by up-regulation of genes involved in the extracellular matrix, endoplasmic reticulum stress, and the immune response and down-regulation of synaptic integrity, glutamate uptake, and other neuronal support processes. We identify activation of the TGFB, Wnt, and hypoxia signaling pathways in both hiPSC and mouse ALS astrocytes. ALS changes positively correlate with TNF, IL1A, and complement pathway component C1q-treated inflammatory reactive astrocytes, with significant overlap of differentially expressed genes. By contrasting ALS changes with models of protective reactive astrocytes, including middle cerebral artery occlusion and spinal cord injury, we uncover a cluster of genes changing in opposing directions, which may represent down-regulated homeostatic genes and up-regulated deleterious genes in ALS astrocytes. These observations indicate that ALS astrocytes augment inflammatory processes while concomitantly suppressing neuronal supporting mechanisms, thus resembling inflammatory reactive states and offering potential therapeutic targets.

Abnormal Ca2+ Signals in Reactive Astrocytes as a Common Cause of Brain Diseases

In pathological brain conditions, glial cells become reactive and show a variety of responses. We examined Ca2+ signals in pathological brains and found that reactive astrocytes share abnormal Ca2+ signals, even in different types of diseases. In a neuropathic pain model, astrocytes in the primary sensory cortex became reactive and showed frequent Ca2+ signals, resulting in the production of synaptogenic molecules, which led to misconnections of tactile and pain networks in the sensory cortex, thus causing neuropathic pain. In an epileptogenic model, hippocampal astrocytes also became reactive and showed frequent Ca2+ signals. In an Alexander disease (AxD) model, hGFAP-R239H knock-in mice showed accumulation of Rosenthal fibers, a typical pathological marker of AxD, and excessively large Ca2+ signals. Because the abnormal astrocytic Ca2+ signals observed in the above three disease models are dependent on type II inositol 1,4,5-trisphosphate receptors (IP3RII), we reanalyzed these pathological events using IP3RII-deficient mice and found that all abnormal Ca2+ signals and pathologies were markedly reduced. These findings indicate that abnormal Ca2+ signaling is not only a consequence but may also be greatly involved in the cause of these diseases. Abnormal Ca2+ signals in reactive astrocytes may represent an underlying pathology common to multiple diseases.

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

Traumatic central nervous system (CNS) injury, which includes both traumatic brain injury (TBI) and spinal cord injury (SCI), is associated with irreversible loss of neurological function and high medical care costs. Currently, no effective treatment exists to improve the prognosis of patients. Astrocytes comprise the largest population of glial cells in the CNS and, with the advancements in the field of neurology, are increasingly recognized as having key functions in both the brain and the spinal cord. When stimulated by disease or injury, astrocytes become activated and undergo a series of changes, including alterations in gene expression, hypertrophy, the loss of inherent functions, and the acquisition of new ones. Studies have shown that astrocytes are highly heterogeneous with respect to their gene expression profiles, and this heterogeneity accounts for their observed context-dependent phenotypic diversity. In the inured CNS, activated astrocytes play a dual role both as regulators of neuroinflammation and in scar formation. Identifying the subpopulations of reactive astrocytes that exert beneficial or harmful effects will aid in deciphering the pathological mechanisms underlying CNS injuries and ultimately provide a theoretical basis for the development of effective strategies for the treatment of associated conditions. Following CNS injury, as the disease progresses, astrocyte phenotypes undergo continuous changes. Although current research methods do not allow a comprehensive and accurate classification of astrocyte subpopulations in complex pathological contexts, they can nonetheless aid in understanding the roles of astrocytes in disease. In this review, after a brief introduction to the pathology of CNS injury, we summarize current knowledge regarding astrocyte activation following CNS injury, including: (a) the regulatory factors involved in this process; (b) the functions of different astrocyte subgroups based on the existing classification of astrocytes; and (c) attempts at astrocyte-targeted therapy.

Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.

PET imaging of reactive astrocytes in neurological disorders

The reactive astrocytes manifest molecular, structural, and functional remodeling in injury, infection, or diseases of the CNS, which play a critical role in the pathological mechanism of neurological diseases. A growing need exists for dependable approach to better characterize the activation of astrocyte in vivo. As an advanced molecular imaging technology, positron emission tomography (PET) has the potential for visualizing biological activities at the cellular levels. In the review, we summarized the PET visualization strategies for reactive astrocytes and discussed the applications of astrocyte PET imaging in neurological diseases. Future studies are needed to pay more attention to the development of specific imaging agents for astrocytes and further improve our exploration of reactive astrocytes in various diseases.

Activation and Role of Astrocytes in Ischemic Stroke

Ischemic stroke refers to the disorder of blood supply of local brain tissue caused by various reasons. It has high morbidity and mortality worldwide. Astrocytes are the most abundant glial cells in the central nervous system (CNS). They are responsible for the homeostasis, nutrition, and protection of the CNS and play an essential role in many nervous system diseases’ physiological and pathological processes. After stroke injury, astrocytes are activated and play a protective role through the heterogeneous and gradual changes of their gene expression, morphology, proliferation, and function, that is, reactive astrocytes. However, the position of reactive astrocytes has always been a controversial topic. Many studies have shown that reactive astrocytes are a double-edged sword with both beneficial and harmful effects. It is worth noting that their different spatial and temporal expression determines astrocytes’ various functions. Here, we comprehensively review the different roles and mechanisms of astrocytes after ischemic stroke. In addition, the intracellular mechanism of astrocyte activation has also been involved. More importantly, due to the complex cascade reaction and action mechanism after ischemic stroke, the role of astrocytes is still difficult to define. Still, there is no doubt that astrocytes are one of the critical factors mediating the deterioration or improvement of ischemic stroke.