Tau modulation through AAV9 therapy augments Akt/Erk survival signalling in glaucoma mitigating the retinal degenerative phenotype.
tau Proteins
/ metabolism
Animals
Glaucoma
/ metabolism
Genetic Therapy
/ methods
Proto-Oncogene Proteins c-akt
/ metabolism
Dependovirus
/ genetics
Disease Models, Animal
Retinal Degeneration
/ metabolism
Retina
/ metabolism
MAP Kinase Signaling System
/ physiology
Signal Transduction
/ physiology
Mice
Mice, Inbred C57BL
Retinal Ganglion Cells
/ metabolism
Phenotype
Glaucoma
Intraocular pressure
Microtubules
Neurodegeneration
Optic nerve
Retinal ganglion cells
Tau
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
07 Jun 2024
07 Jun 2024
Historique:
received:
07
12
2023
accepted:
27
05
2024
medline:
7
6
2024
pubmed:
7
6
2024
entrez:
6
6
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38845058
doi: 10.1186/s40478-024-01804-0
pii: 10.1186/s40478-024-01804-0
doi:
Substances chimiques
tau Proteins
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
89Subventions
Organisme : National Health and Medical Research Council
ID : GNT1139560
Informations de copyright
© 2024. The Author(s).
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