Activation of Lysosomal Function Ameliorates Amyloid-β-Induced Tight Junction Disruption in the Retinal Pigment Epitheliumopen access
- Authors
- Jo, Dong Hyun; Lee, Su Hyun; Jeon, Minsol; Cho, Chang Sik; Kim, Da-Eun; Kim, Hyunkyung; Kim, Jeong Hun
- Issue Date
- Nov-2023
- Publisher
- 한국분자세포생물학회
- Keywords
- age-related macular degeneration; amyloid-beta; autophagy-lysosome pathway; LAMP2; PP242; Torin
- Citation
- Molecules and Cells, v.46, no.11, pp 675 - 687
- Pages
- 13
- Indexed
- SCIE
SCOPUS
- Journal Title
- Molecules and Cells
- Volume
- 46
- Number
- 11
- Start Page
- 675
- End Page
- 687
- URI
- https://scholarworks.korea.ac.kr/kumedicine/handle/2021.sw.kumedicine/65311
- DOI
- 10.14348/molcells.2023.0056
- ISSN
- 1016-8478
0219-1032
- Abstract
- Accumulation of pathogenic amyloid-beta disrupts the tight junction of retinal pigment epithelium (RPE), one of its senescence-like structural alterations. In the clearance of amyloid-beta, 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-beta by inducing the autophagy-lysosome pathway in a mouse model with pathogenic amyloid-beta with tight junction disruption of RPE, which is evident in dry age-related macular degeneration. High concentration of amyloid-beta 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-beta in vitro and in vivo. Furthermore, clearance of amyloid-beta 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.
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Collections - 1. Basic Science > Department of Biochemistry and Molecular Biology > 1. Journal Articles
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