Chief Investigator: A/Prof Vivek Gupta
Co-investigators: Prof Stuart Graham, A/Prof Mehdi Mirzaei
Aim
The aim of this study was to determine whether amyloid accumulation and Tau
hyperphosphorylation are causes of neurodegenerative pathology in glaucoma. We
aimed to elucidate whether the direct targeting of amyloid and tau can protect the retinal ganglion cells and optic nerve in glaucoma.
Methods
Adeno associated virus (AAV) constructs encoding amyloid precursor and tau genes were administered intravitreally into the mice. Mice were subjected to experimental glaucoma conditions using microbead injections to understand the effects of amyloid and tau protein modulation in both healthy and glaucoma conditions. The downstream effects of the modulation of these proteins on the retinal biochemical networks in health and glaucoma conditions were also examined.
Implications for Clinical Practice/Science and Future Research
The initial results are very promising. The experiments will need to be carried out using a
larger animal model, which will help improve the translational potential of the study. Future studies will identify whether targeting of amyloid and tau proteins is protective only if the treatment is started before the injury or if it also protects the RGCs once the glaucoma injury has initiated.
Lay summary of outcomes
Glaucoma involves RGC degeneration along with optic nerve excavation. The mechanisms underlying this damage are not yet clear, however recent studies indicate that dysregulation of amyloid and /or tau proteins which are key pathological molecules in Alzheimer’s and other neurodegenerative disorders may play a role. Our results indicate that modulating amyloid and/or tau proteins may serve as a mechanism-based strategy
in vision preservation and provide new avenues for glaucoma treatment.
Role of amyloid and tau proteins in Retinal Ganglion Cell and Optic Nerve Injury in Glaucoma Immunostaining of retinal sections and immunoblotting analysis revealed that amyloid precursor protein and tau proteins are well expressed in the retina. Amyloid and tau protein expression in different regions of the retina were assessed in human glaucoma tissues as well as in experimental glaucoma. Modulation of tau protein using adeno associated virus AAV was detrimental for the retina in healthy conditions. However, tau silencing imparted protection against retinal degenerative change sin glaucoma. Targeting amyloid precursor protein using AAV also was protective against selected degenerative markers in the retina.
Our results indicate that both amyloid and tau protein are important for maintaining retinal
functional and structural microenvironment. Targeting these two molecules shows significant protective effects for RGCs in experimental glaucoma. Our results indicate that targeting of these two proteins could provide significant insights into the mechanisms underlying cellular degenerative change sin glaucoma and for future mechanism-based drug development.
Presentations / Publications
D Basavarajappa, C Galindo-Romero, Vivek Gupta, M Agudo-Barriuso, V Gupta, S Graham, N Chitranshi.
Signalling pathways and cell death mechanisms in glaucoma: Insights into the molecular
pathophysiology, Molecular Aspects of Medicine, 94, 2023, 101216.
This research was funded in 2022 by Australian Vision Research.