The rise of astrocytes: are they guardians or troublemakers of the brain disorder?

Abstract

The brain is a highly complex, multicellular organ composed of diverse neuronal and nonneuronal cell types that function in concert to maintain central nervous system homeostasis. Among the glial populations, astrocytes are critical regulators of neuronal function. Under physiological conditions, astrocytes provide essential metabolic support, modulate neurotransmitter release and maintain neuronal health. Traditionally viewed as passive and supporting cells, astrocytes are now recognized as dynamic and responsive elements within the central nervous system. In response to pathological insults, astrocytes undergo significant changes in function, morphology and gene expression—a process known as reactive astrogliosis. Reactive astrocytes acquire heterogeneous characteristics that can contribute to brain disorders via the non-cell-autonomous mechanisms. However, the drivers of this transformation—and their shift from neuronal guardians to potential contributors to pathology—remain incompletely understood. Here we explore the complex, multidimensional roles of astrocytes and how reactive states alter their primary functions. We focus on the dual protective and pathological roles of astrocytes, particularly the transition from healthy to heterogeneous reactive forms, with the aim of understanding their overall impact on the progression of neurodegenerative diseases.