YUHSpace

BROWSE

Export
0 1

Cited 0 times in

Cited 0 times in

Targeted autophagic clearance of Tau protects against Alzheimer's disease through amelioration of Tau-mediated lysosomal stress

Authors
 Bo Hyun Yoon  ;  Jinho Kim  ;  Sandip Sengupta  ;  Chan-Jung Park  ;  Minjoo Ko  ;  Ji Hee Kang  ;  Young Tag Ko  ;  Yeji Kim  ;  Seung Min Lim  ;  Yoonhee Bae  ;  MooYoung Choi  ;  Yunyeong Jang  ;  Ho Jeong Kwon  ;  Hyo Jin Son  ;  Hee Jin Kim  ;  Taebo Sim  ;  Keun-A Chang  ;  Myung-Shik Lee 
Citation
 THERANOSTICS, Vol.15(17) : 9240-9260, 2025-08 
Journal Title
THERANOSTICS
Issue Date
2025-08
MeSH
0
Keywords
Alzheimer Disease* / drug therapy ; Alzheimer Disease* / metabolism ; Alzheimer Disease* / pathology ; Amyloid beta-Peptides / metabolism ; Animals ; Autophagy* / drug effects ; Disease Models, Animal ; Humans ; Induced Pluripotent Stem Cells / metabolism ; Lysosomes* / drug effects ; Lysosomes* / metabolism ; Mice ; Mice, Transgenic ; Neurons / drug effects ; Neurons / metabolism ; tau Proteins* / genetics ; tau Proteins* / metabolism
Abstract
Alzheimer's disease; Tau; autophagy; lysosomal stress; specificity
Article Number
 10.7150/thno.118409 
DOI
Background: Lysosomal dysfunction could be an underlying cause of Alzheimer's disease, with Tau oligomer being an important inducer or amplifier of lysosomal stress associated with the disease. Tau oligomer is a well-known substrate of autophagy, and selective degradation of Tau with Tau-specific autophagy degrader might be feasible. Methods: Tau-specific autophagic degraders were synthesized by combining leucomethylene blue, linkers and a lysosomal degradation tag (Autac). Tau clearance and changes of Tau-mediated lysosomal stress by these degraders were studied in vitro. In vivo effects of a Tau-specific degrader were investigated employing a combined Tau/Aβ mutant mouse model characterized by an accelerated onset of neurological deficits. Human relevance was investigated using induced pluripotent stem cell (iPSC)-derived neuronal cells from an Alzheimer's disease patient. Results: Among Tau-specific Autac degraders, TauAutac-3 (TA-3) efficiently degraded Tau oligomer and monomer, an effect inhibited by bafilomycin A1, suggesting lysosomal Tau degradation. TA-3 treatment induced LC3, K63, OPTN or NDP52 puncta, which was partially colocalized with Tau oligomer. Signs of lysosomal stress, such as galectin-3 puncta, pHluorin fluorescence, altered lysosomal pH and CHMP2B recruitment, induced by Tau expression were reversed by TA-3. Autophagy impairment by Tau expression in vitro, likely due to lysosomal stress, was also reversed by TA-3. In vivo, TA-3 administration markedly reduced the accumulation of both Tau and Aβ in 6xTg mice, which was associated with amelioration of Tau-mediated lysosomal stress and autophagy impairment. Neuroinflammation characterized by increased numbers of GFAP+ glial cells and Iba1+ microglial cells, was also reduced following TA-3 administration. TA-3 remarkably improved neurologic deficits in 6xTg mice, such as impaired memory and reduced exploratory behavior. TA-3 reduced Tau and phospho-Tau accumulation in iPSC-derived neuronal cells from an Alzheimer's disease patient. Conclusion: These results suggest that Tau-specific autophagic (Autac) degraders could serve as novel therapeutic agents for Alzheimer's disease through reduction of Tau-mediated lysosomal stress.
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Sim, Taebo(심태보)
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/207447
사서에게 알리기
  feedback
Show full item record Find it @ YMLIB

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

  • License
    sherpa_romeo
    sherpa_juliet

OAK

DSpace Software Copyright © 2002-2017 Duraspace Yonsei University Medical Library All right Reserves. / TEL:02-2228-2915 /
YUHSpace는 국립중앙도서관 OAK 보급사업으로 구축되었습니다.

Browse

Links