Activation of Lysosomal Function Ameliorates Amyloid-β-Induced Tight Junction Disruption in the Retinal Pigment Epithelium

Dong Hyun Jo, Su Hyun Lee, Minsol Jeon, Chang Sik Cho, Da Eun Kim, Hyunkyung Kim, Jeong Hun Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Accumulation of pathogenic amyloid-β disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-β, the autophagy-lysosome pathway plays the crucial role. In this context, mammalian target of rapamycin (mTOR) inhibits the process of autophagy and lysosomal degradation, acting as a potential therapeutic target for age-associated disorders. However, efficacy of targeting mTOR to treat age-related macular degeneration remains largely elusive. Here, we validated the therapeutic efficacy of the mTOR inhibitors, Torin and PP242, in clearing amyloid-β by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-β with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-β oligomers induced autophagy-lysosome pathway impairment accompanied by the accumulation of p62 and decreased lysosomal activity in RPE cells. However, Torin and PP242 treatment restored the lysosomal activity via activation of LAMP2 and facilitated the clearance of amyloid-β in vitro and in vivo. Furthermore, clearance of amyloid-β by Torin and PP242 ameliorated the tight junction disruption of RPE in vivo. Overall, our findings suggest mTOR inhibition as a new therapeutic strategy for the restoration of tight junctions in age-related macular degeneration.

Original languageEnglish
Pages (from-to)675-687
Number of pages13
JournalMolecules and cells
Volume46
Issue number11
DOIs
Publication statusPublished - 2023

Bibliographical note

Publisher Copyright:
© The Korean Society for Molecular and Cellular Biology.

Keywords

  • age-related macular degeneration
  • amyloid-β
  • autophagy-lysosome pathway
  • LAMP2
  • PP242
  • Torin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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