Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2.
3 repeat tau
Alzheimer's, tauopathy
Retina
Retinopathy
Tau
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
26
08
2020
revised:
20
01
2021
accepted:
24
01
2021
pubmed:
1
2
2021
medline:
4
1
2022
entrez:
31
1
2021
Statut:
ppublish
Résumé
The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick's Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma.
Identifiants
pubmed: 33516874
pii: S0969-9961(21)00026-7
doi: 10.1016/j.nbd.2021.105277
pmc: PMC8373010
mid: NIHMS1728427
pii:
doi:
Substances chimiques
MAPT protein, human
0
Protein Isoforms
0
tau Proteins
0
Caspase 2
EC 3.4.22.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
105277Subventions
Organisme : NIA NIH HHS
ID : P30 AG062429
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG018440
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG070595
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG018440
Pays : United States
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
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