Glaucoma is one of the leading causes of irreversible blindness worldwide. Glaucoma is defined clinically as the presence of optic nerve head (ONH) degeneration and progressive loss of retinal ganglion cells (RGCs). Intra-ocular pressure (IOP) has been considered a major cause of the disease, but accumulated evidence demonstrates that a significant number of patients develop glaucoma without having high IOP. Therefore understanding an IOP-independent underlying pathogenesis is crucial. The only approved medication for glaucoma is IOP-lowering ophthalmic solutions. However, it only slows disease progression. Thus, new therapeutic strategies beyond lowering IOP are required to prevent progressive optic nerve degeneration and RGC death in glaucoma. This dissertation focused on unconventional explanations of glaucoma pathogenesis that are not dependent on high IOP: 1) investigate the mechanism of action in glaucoma genetic risk factors, 2) protect RGC by preventing inflammatory cell death, and 3) improve vasculature function to protect the neuroretinal function. This effort may shed light on previously overlooked mechanisms in the retinal degenerative process and pave the way for potential therapeutic methods to treat neurodegenerative ocular disorders.