Understanding glaucoma as astrocyte-driven neurodegeneration in the optic nerve head: an integrative clinicopathological perspective

Abstract

Glaucoma is characterized by the progressive loss of retinal ganglion cells (RGCs), primarily driven by axonal degeneration within the optic nerve head (ONH). Recent advances in neurodegeneration and neuroinflammation research have opened new astrocyte-centered perspectives on glaucoma pathogenesis. Critical evaluation of emerging evidence suggests that ONH astrocyte changes may serve as the primary driver of pathogenesis, with loss of astrocytic support playing a substantial role. Evidence from experimental glaucoma models reveals that early intraocular pressure (IOP)-induced remodeling of the ONH astrocyte network precedes RGC axonal damage, potentially mediated by impaired astrocytic control of electrophysiological homeostasis within the surrounding extracellular space. Furthermore, the heterogeneous glia-neuron ratio (GNR) across the normal human ONH lamina cribrosa exhibits an inverse topographic association with the spatiotemporal pattern of regional vulnerability observed clinically in glaucoma, suggesting that regional variations in the astrocyte-to-neuron ratio, reflecting astrocytic support reserve, may critically determine local tissue susceptibility to glaucomatous stress. Recent optical coherence tomography–based insights into the regional vulnerability in human glaucoma are discussed. This clinicopathological interpretation may offer a comprehensive framework that coherently integrates diverse neurodegenerative mechanisms into a unified clinical entity, bridge the conventional mechanical and ischemic theories of glaucoma by highlighting astrocyte changes as a common primary target of risk factors, and ultimately redefine glaucoma as astrocyte-driven neurodegeneration in the biomechanically and bioenergetically vulnerable ONH.