Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Sydney, NSW, 2109, Australia.
Division of Ophthalmology, Department of Biomedical and Clinical Sciences, Linköping University, 58183, Linköping, Sweden.
Acta Neuropathol Commun. 2024 Jun 7;12(1):89. doi: 10.1186/s40478-024-01804-0.
The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.
微管相关蛋白 Tau 是多种神经退行性疾病的关键参与者，包括阿尔茨海默病（AD）和 Tau 病，其过度磷酸化会破坏神经元微管晶格的稳定性。青光眼是一种影响视网膜的神经退行性疾病，通过损伤视网膜神经节细胞和视神经导致不可逆转的视力丧失，通常与眼内压升高有关。先前的研究表明，AD 和青光眼患者的视网膜中存在 Tau 表达和磷酸化改变，但 Tau 蛋白在这些病变中的变化是因果关系还是下游关系尚不清楚。本研究探讨了 Tau 蛋白调节对正常和实验性青光眼条件下视网膜神经元的影响。采用 AAV9 介导的 Tau 过表达和敲低基因治疗，这两种操作都被发现对健康条件下的视网膜结构和功能测量以及神经保护 Akt/Erk 存活信号有不利影响。在实验性青光眼模型中，Tau 过表达加剧了内视网膜变性，而 Tau 沉默对这些退行性变化提供了显著的保护作用。这些发现强调了内源性 Tau 蛋白水平在维持视网膜完整性方面的关键作用，并强调了在青光眼病理中靶向 Tau 的治疗潜力。
