Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled “Solving Neurodegeneration”. This “think-tank” style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world’s leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

Glaucoma is a neurodegenerative disease of the visual system and leading cause of blindness worldwide. The disease is associated with sensitivity to intraocular pressure (IOP), which over a large range of magnitudes stresses retinal ganglion cell (RGC) axons as they pass through the optic nerve head in forming the optic projection to the brain. Despite clinical efforts to lower IOP, which is the only modifiable risk factor for glaucoma, RGC degeneration and ensuing loss of vision often persist. A major contributor to failure of hypotensive regimens is the multifactorial nature of how IOP-dependent stress influences RGC physiology and structure. This stress is conveyed to the RGC axon through interactions with structural, glial, and vascular components in the nerve head and retina. These interactions promote pro-degenerative pathways involving biomechanical, metabolic, oxidative, inflammatory, immunological and vascular challenges to the microenvironment of the ganglion cell and its axon. Here, we focus on the contribution of vascular dysfunction and breakdown of neurovascular coupling in glaucoma. The vascular networks of the retina and optic nerve head have evolved complex mechanisms that help to maintain a continuous blood flow and supply of metabolites despite fluctuations in ocular perfusion pressure. In healthy tissue, autoregulation and neurovascular coupling enable blood flow to stay tightly controlled. In glaucoma patients evidence suggests these pathways are dysfunctional, thus highlighting a potential role for pathways involved in vascular dysfunction in progression and as targets for novel therapeutic intervention.

Significance: Astrocytes respond to neuronal energy needs by mobilizing metabolic stores. How these resources are mobilized during neurodegeneration, especially in nearby regions that are not actively degenerating, could impact new therapeutic approaches. We modeled neurodegeneration in glaucoma and measured how metabolites mobilize through astrocyte networks. We elevated pressure in one eye and determined how astrocyte-derived metabolites in the opposite eye and nerve responded. Remarkably, astrocyte networks expand and redistribute metabolites along distances nearly 1 cm in length to donate resources from unstressed to stressed tissue. While resource donation improves axon function and visual acuity, it renders the donating tissue susceptible to further stress, which could help explain why local neurodegeneration eventually impacts healthy regions of the brain.

The extracellular matrix is a richly bioactive composition of substrates that provides biophysical stability, facilitates intercellular signaling, and both reflects and governs the physiological status of the local microenvironment. The matrix in the central nervous system (CNS) is far from simply an inert scaffold for mechanical support, instead conducting an active role in homeostasis and providing broad capacity for adaptation and remodeling in response to stress that otherwise would challenge equilibrium between neuronal, glial, and vascular elements. A major constituent is collagen, whose characteristic triple helical structure renders mechanical and biochemical stability to enable bidirectional crosstalk between matrix and resident cells. Multiple members of the collagen superfamily are critical to neuronal maturation and circuit formation, axon guidance, and synaptogenesis in the brain. In mature tissue, collagen interacts with other fibrous proteins and glycoproteins to sustain a three-dimensional medium through which complex networks of cells can communicate. While critical for matrix scaffolding, collagen in the CNS is also highly dynamic, with multiple binding sites for partnering matrix proteins, cell-surface receptors, and other ligands. These interactions are emerging as critical mediators of CNS disease and injury, particularly regarding changes in matrix stiffness, astrocyte recruitment and reactivity, and pro-inflammatory signaling in local microenvironments. Changes in the structure and/or deposition of collagen impact cellular signaling and tissue biomechanics in the brain, which in turn can alter cellular responses including antigenicity, angiogenesis, gliosis, and recruitment of immune-related cells. These factors, each involving matrix collagen, contribute to the limited capacity for regeneration of CNS tissue. Emerging therapeutics that attempt to rebuild the matrix using peptide fragments, including collagen-enriched scaffolds and mimetics, hold great potential to promote neural repair and regeneration. Recent evidence from our group and others indicates that repairing protease-degraded collagen helices with mimetic peptides helps restore CNS tissue and promote neuronal survival in a broad spectrum of degenerative conditions. Restoration likely involves bolstering matrix stiffness to reduce the potential for astrocyte reactivity and local inflammation as well as repairing inhibitory binding sites for immune-signaling ligands. Facilitating repair rather than endogenous replacement of collagen degraded by disease or injury may represent the next frontier in developing therapies based on protection, repair, and regeneration of neurons in the central nervous system.

Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration of the retinal ganglion cell (RGC) projection to the brain through the optic nerve. Glaucoma is associated with sensitivity to intraocular pressure (IOP). Thus, mainstay treatments seek to manage IOP, though many patients continue to lose vision. To address neurodegeneration directly, numerous preclinical studies seek to develop protective or reparative therapies that act independently of IOP. These include growth factors, metabolics, anti-inflammatory and antioxidant agents, and neuromodulators. Despite success in experimental models, many of these approaches fail to translate into clinical benefits. Several factors contribute to this challenge. Firstly, the anatomic structure of the optic nerve head differs between rodents, nonhuman primates, and humans. Additionally, animal models do not replicate the complex glaucoma pathophysiology in humans. Therefore, to enhance the success of translating these findings, we propose two approaches. First, thorough evaluation of experimental targets in multiple animal models, including nonhuman primates, should precede clinical trials. Second, we advocate for combination therapy, which involves using multiple agents simultaneously, especially in the early and potentially reversible stages of the disease. These strategies aim to increase the chances of successful neuroprotective treatment for glaucoma.