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P1‐384: EXPRESSION OF MUTANT 3R TAU INDUCES A NEURODEGENERATIVE STATE IN MURINE RETINA
Author(s) -
Ngolab Jennifer,
Canchi Saranya,
Mante Michael,
Florio Jazmin B.,
Rasool Suhail,
Rissman Robert A.
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.939
Subject(s) - retina , retinal , genetically modified mouse , gene isoform , outer plexiform layer , biology , inner nuclear layer , gene expression , mutant , microbiology and biotechnology , pathology , neuroscience , transgene , medicine , gene , genetics , biochemistry
Background: A recent study has detected hyper phosphorylated tau, a pathological hallmark of Alzheimer’s Disease (AD), in the retina of AD postmortem retinas, suggesting that neurodegenerative pathology in the brain may be mirrored in the retina. In various tauopathies including AD, imbalances of 3 repeat (3R) and 4 repeat tau (4R) isoforms were observed yet how each isoform contributes to retinal pathology is not well understood. Methods: To understand the distinct molecular contributions of 3R tau overexpression to retinopathy, gene expression in retinas of 3-month and 9-month old transgenic mice overexpressing mutant 3R tau (3R tau tg) and age-matched non-transgenic controls (Non-tg) were assessed using RNA-Seq. Differentially expressed genes were generated by analyzing transcript expression over time for each genotype. Visual-spatial memory of 3R tau tg and Non-tg wasmeasured byMorris Water Maze. 3R tau tg and Non-tg retinas were analyzed with immunohistochemistry and immunoelectron microscopy for 3R tau expression. Retinal thickness was measured by optical coherence tomography. Results: Retinopathy-associated genes were differentially expressed in 3R tau tg mice compared to Non-tg. Genes involved in the Complex I pathway and RNA processing were downregulated in 3R tau tg retina. Starting at 6 months, 3R tau tg mice of age spent longer to locate the platform in the visual probe trial of the Morris Water Maze compared to Non-tg mice. Retinal thinning was observed in the peripheral inner plexiform layer (IPL) of 3R tau tg mice. Expression of 3R tau in the retina was detected through immunohistochemical analysis at 3 months, mainly in the ganglion cell layer and the IPL. Conclusions: Gene expression of biological pathways such as RNA processing and energetics were altered in 3R tau tg retina, similar to what is observed in AD Brain. Furthermore, 3R tau accumulation and retinal thinning was restricted to the periphery of the retina, similar to what has been reported in AD retina. These data suggest that 3R tau expression may in contribute to AD retinopathy.