Abstract
Glaucoma is a neurodegenerative disorder that leads to the slow degeneration of retinal ganglion cells, and results in damage to the optic nerve and concomitant vision loss. As in other disorders affecting the viability of central nervous system neurons, neurons affected by glaucoma do not have the ability to regenerate after injury. Recent studies indicate a critical role for optic nerve head astrocytes (ONHAs) in this process of retinal ganglion cell degeneration. Cleavage of tau, a microtubule stabilizing protein and constituent of neurofibrillary tangles (NFT), plays a major part in the mechanisms that lead to toxicity in CNS neurons and astrocytes. Here, we tested the hypothesis that estrogen, a pleiotropic neuro- and cytoprotectant with high efficacy in the CNS, prevents tau cleavage, and hence, protects ONHAs against cell damage caused by oxidative stress. Our results indicate that estrogen prevents caspase-3 mediated tau cleavage, and thereby decreases the levels of the resulting form of proteolytically cleaved tau protein, which leads to a decrease in NFT formation, which requires proteolytically cleaved tau protein. Overall, our data propose that by stopping the reduction of estrogen levels involved with aging the sensitivity of the optic nerve to glaucomatous damage might be reduced. Furthermore, our data suggest that therapeutic use of estrogen may be beneficial in slowing or preventing the onset or severity of neurodegenerative diseases such as glaucoma and potentially also other degenerative diseases of the CNS through direct control of posttranslational modifications of tau protein.
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Data Availability
The datasets of the present study are available from the corresponding author on reasonable request.
Abbreviations
- Aβ:
-
Amyloid β–peptide
- AD:
-
Alzheimer’s disease
- ANOVA:
-
Analysis of variance
- CNS:
-
Central nervous system
- GFAP:
-
Glial fibrillary acidic protein
- NFT:
-
Neurofibrillary tangle
- ONH:
-
Optic nerve head
- ONHA:
-
Optic nerve head astrocyte
- PBS:
-
Phosphate buffered saline
- PFA:
-
Paraformaldehyde
- tBHP:
-
Tert-butyl hydroperoxide
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Acknowledgements
The authors thank Margaret, Richard and Sara Koulen for generous support and encouragement.
Funding
Research reported in this publication was supported in part by grants from the National Institutes of Health, National Eye Institute Grants EY014227 and EY022774, National Institute on Aging Grant AG027956, National Center for Research Resources/National Institute of General Medical Sciences grant RR027093 (PK) and a National Institutes of Health Clinical and Translational Science Award Grant (UL1 TR002366) awarded to the University of Kansas. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research and a Challenge Grant from Research to Prevent Blindness (PK) is gratefully acknowledged.
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JCM and PK conceived and designed the experiments; JCM, AAL and PK performed the experiments; JCM, AAL, and PK analyzed the data and wrote the paper. All authors read and approved the final manuscript.
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Means, J.C., Lopez, A.A. & Koulen, P. Estrogen Protects Optic Nerve Head Astrocytes Against Oxidative Stress by Preventing Caspase-3 Activation, Tau Dephosphorylation at Ser422 and the Formation of Tau Protein Aggregates. Cell Mol Neurobiol 41, 449–458 (2021). https://doi.org/10.1007/s10571-020-00859-6
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DOI: https://doi.org/10.1007/s10571-020-00859-6