Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice.

Nakai, A.; Lee, D.; Zhang, Y.; Shoda, C.; Imanishi, S.; Jeong, H.; Ikeda, S.-i.; Negishi, K.; Nakashizuka, H.; Yamagami, S.; Kubo, A.; Kurihara, T.

doi:10.1101/2023.12.07.570525

bioRxiv · 10.1101/2023.12.07.570525

Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice.

Nakai, A.·Lee, D.·Zhang, Y.·Shoda, C.·Imanishi, S.·Jeong, H.·Ikeda, S.-i.·Negishi, K.·Nakashizuka, H.·Yamagami, S.·Kubo, A.·Kurihara, T.

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Abstract

The early and intermediate age-related macular degeneration (AMD) is characterized by the presence of drusen and pigmentary abnormalities in the retinal pigment epithelial (RPE) cells which form the outer blood retinal barrier (oBRB). Fluid leakage through the disrupted oBRB from the choroid to the neural retina has been implicated in the pathogenesis of AMD, however; the molecular mechanisms still remain unclear. The family of four transmembrane proteins, claudins are known to form tight junctions (TJs) in the oBRB. Nonetheless, there are few reports showing how they function in the oBRB in vivo. We found that claudin-1 is dominantly expressed in TJs of the mouse RPE. To investigate the role of claudin-1 in the RPE, we generated RPE-specific Cldn1 conditional knockout mice (Best1-Cre+/- Cldn1flox/flox mice: Cldn1 cKO mice). Deficiency of Cldn1 led to age-related lipid deposits such as subretinal drusenoid deposits (SDD), increased lipid droplets in the RPE, basal lamellar deposits (BlamD) and membranous debris in the Bruchs membrane. In addition, pigmentary abnormalities such as RPE hypertrophy, multilayered-RPE cells, and ectopic pigment granules outside the RPE were observed in Cldn1 cKO mice. Our study provides new insights into the possible association of the TJ protein claudin-1 with lipid metabolism and cellular ageing in the RPE contributing to the early onset of AMD.

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Nakai, A., Lee, D., Zhang, Y., Shoda, C., Imanishi, S., Jeong, H., Ikeda, S.-i., Negishi, K., Nakashizuka, H., Yamagami, S., Kubo, A., Kurihara, T.. 2023-12-07. Tight junction component protein claudin-1 deficiency in retinal pigment epithelium leads to early and intermediate age-related macular degeneration phenotypes in mice.. https://doi.org/10.1101/2023.12.07.570525

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