Astrocytes in human central nervous system diseases: a frontier for new therapies

Abstract

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.

Multitracer Approach to Understanding the Complexity of Reactive Astrogliosis in Alzheimer’s Brains

“…4,5 An increase in GFAP levels does not always reflect pathology and can be observed after different physiological stimulation such as enriched environment and physical activity. 1 In fact, it has been suggested that a heterogeneous population of reactive astrocytes exists, varying among distinct brain regions with specific responses to differing pathologies. 5−7 Thus, identifying new biomarkers, beyond GFAP, is crucial for capturing the full picture of reactive astrogliosis and improving our understanding of astrocytic heterogeneity in AD.…”

“…It might be challenging to measure early reactive astrocytes in brain and, for years, increased glial fibrillary acidic protein (GFAP) immunoreactivity in postmortem tissue has been used as a general marker for reactive astrogliosis . However, recent evidence in biomarker research indicates that the potential to represent the whole population of reactive astrocytes in the human brain may be lost if testing is confined to changes in GFAP levels. , An increase in GFAP levels does not always reflect pathology and can be observed after different physiological stimulation such as enriched environment and physical activity . In fact, it has been suggested that a heterogeneous population of reactive astrocytes exists, varying among distinct brain regions with specific responses to differing pathologies. − Thus, identifying new biomarkers, beyond GFAP, is crucial for capturing the full picture of reactive astrogliosis and improving our understanding of astrocytic heterogeneity in AD .…”

“…Brain astrocytes are important components in many neurodegenerative diseases. Astrocytic pathological changes represent a multifaceted phenomenon in the brain, which is not limited to reactive astrogliosis, and could range from nonreactive to reactive states in different CNS pathologies (further reading on astrogliopathologies and reactive astrogliosis, see Verkhratsky et al 1 and Escartin et al, 2…”

“…Brain astrocytes are important components in many neurodegenerative diseases. Astrocytic pathological changes represent a multifaceted phenomenon in the brain, which is not limited to reactive astrogliosis, and could range from nonreactive to reactive states in different CNS pathologies (further reading on astrogliopathologies and reactive astrogliosis, see Verkhratsky et al and Escartin et al, respectively). It might be challenging to measure early reactive astrocytes in brain and, for years, increased glial fibrillary acidic protein (GFAP) immunoreactivity in postmortem tissue has been used as a general marker for reactive astrogliosis .…”

Amyloid precursor protein induces reactive astrogliosis

“…[10][11][12][13] Brain lesions trigger reactive astrogliosis which, together with microgliosis and reactive remodeling of oligodendrocyte precursor cells, represents evolutionary conserved defensive response aimed at protection and postlesional restoration of the nervous tissue from various forms of pathological stressors and insults. 14,15 Reactive astrogliosis proceeds through complex, still poorly understood, reorganization of astrocytic biochemistry, morphology, and physiology to create multiple contexts-and disease-specific reactive phenotypes. 16,17 Reactive astrogliosis is linked to the activation of several cellular programs and second messenger signaling pathways 15,18 that await to be fully elucidated.…”