Microtubule acetylation induced by oxidative stress regulates subcellular distribution of lysosomal vesicles for amyloid-beta secretion
- Authors
- Jeong, Jangho; Kim, Ok-Hyeon; Shim, Jaeyeoung; Keum, Seula; Hwang, Ye Eun; Song, Seongeun; Kim, Jung-Woong; Choi, Jee-Hye; Lee, Hyun Jung; Rhee, Sangmyung
- Issue Date
- Dec-2023
- Publisher
- John Wiley and Sons Inc
- Keywords
- Aβ secretion; lysosomal vesicles; microtubule acetylation; oxidative stress
- Citation
- Journal of Cellular Physiology, v.238, no.12, pp 2812 - 2826
- Pages
- 15
- Journal Title
- Journal of Cellular Physiology
- Volume
- 238
- Number
- 12
- Start Page
- 2812
- End Page
- 2826
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/68545
- DOI
- 10.1002/jcp.31131
- ISSN
- 0021-9541
1097-4652
- Abstract
- Excessive production and accumulation of amyloid-beta (Aβ) in the brain are one of the hallmarks of Alzheimer's disease (AD). Although oxidative stress is known to trigger and promote the progression of AD, the molecular relationship between oxidative stress and Aβ production is not yet fully understood. In this study, we demonstrate that microtubule acetylation induced by oxidative stress plays a critical role in Aβ production and secretion by altering the subcellular distribution of Aβ precursor protein (APP)-containing lysosomal vesicles. Under oxidative stress, both H4-APPSwe/Ind and HEK293T-APPSwe/Ind cell lines showed increased microtubule acetylation and Aβ secretion. Knockdown (KD) of alpha-tubulin N-acetyltransferase 1 (ATAT1) by using a lentiviral shRNA not only inhibited the generation of intermediate APP fragments, such as β-CTF and AICD, but also suppressed Aβ secretion. Oxidative stress promoted the dispersion of LAMP1-positive vesicles to the periphery of the cell through microtubule acetylation, leading to the formation of neutralized lysosomal vesicles (NLVs), which was inhibited by ATAT1 KD. Treatment of the cells with the dynein ATPase inhibitor EHNA or downregulation of LIS1, a regulator of dynein-mediated intracellular transport, increased the peripheral localization of NLVs and promoted Aβ secretion, whereas KD of ADP ribosylation factor like GTPase 8B showed the opposite result. ATAT1 KD in the hippocampal region of the 5×FAD AD mouse model also showed significant reductions in Aβ plaque accumulation and memory loss. Taken together, these findings suggest that oxidative stress–induced microtubule acetylation promotes the peripheral localization of lysosomal vesicles to form NLVs, thereby enhancing Aβ secretion. © 2023 Wiley Periodicals LLC.
- Files in This Item
- There are no files associated with this item.
- Appears in
Collections - College of Medicine > College of Medicine > 1. Journal Articles
- College of Natural Sciences > Department of Life Science > 1. Journal Articles
![qrcode](https://api.qrserver.com/v1/create-qr-code/?size=55x55&data=https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/68545)
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.