Exploring Tau Protein’s Role in Glaucoma: New Insights and Therapeutic Potential

Glaucoma, a chronic neurodegenerative disorder, leads to irreversible vision loss by damaging retinal ganglion cells (RGCs) and the optic nerve, often associated with increased intraocular pressure (IOP). Despite the benefits of IOP-lowering treatments, the underlying disease often progresses, indicating the need for a deeper understanding of its molecular mechanisms.

The Role of Tau Protein in Neurodegenerative Diseases

Tau, a microtubule-associated protein, is central to several neurodegenerative diseases, including Alzheimer’s disease (AD) and various Tauopathies. In these conditions, hyperphosphorylation of Tau disrupts the stability of the neuronal microtubular lattice, leading to the formation of toxic aggregates. While Tau’s role in the brain is well-studied, its involvement in retinal neurodegeneration, particularly in glaucoma, remains less clear.

Investigating Tau in Glaucoma

Prior research has shown changes in Tau expression and phosphorylation in the retina in both AD and glaucoma, but the causative or downstream nature of these changes is unclear. This study aimed to elucidate the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions.

Methodology

Using AAV9-mediated gene therapy, researchers induced Tau overexpression and knockdown in mouse retinas. Both manipulations negatively affected retinal structure, function, and neuroprotective Akt/Erk signaling under normal conditions. In an experimental glaucoma model, Tau overexpression exacerbated inner retinal degeneration, while Tau silencing significantly protected against these changes.

Key Findings

1. Tau Overexpression and Knockdown: Both Tau overexpression and silencing disrupted retinal structural and functional measures under normal IOP conditions, highlighting the necessity of balanced Tau levels for retinal health.
2. Impact on Experimental Glaucoma: Tau overexpression worsened inner retinal degeneration in glaucoma, while Tau silencing provided significant protection, underscoring the therapeutic potential of targeting Tau.
3. Biochemical Pathways: Tau modulation affected various biochemical pathways, including ER stress markers and the Akt/Erk signaling pathways, crucial for cell survival and neuroprotection.
4. Synaptic Integrity: Changes in Tau expression influenced synaptic markers, suggesting Tau’s role in synaptic function and axonal signal transduction in the retina.

Conclusion

This study highlights the critical role of endogenous Tau protein levels in maintaining retinal integrity and provides compelling evidence for targeting Tau in glaucoma therapy. By elucidating the molecular mechanisms underlying Tau’s involvement in retinal degeneration, these findings pave the way for developing novel therapeutic strategies aimed at modulating Tau expression to preserve vision in glaucoma patients.

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