Targeting Hsc70-based autophagy to eliminate amyloid β oligomers

Copyright © 2020 Elsevier Inc. All rights reserved..

Amyloid β (Aβ) oligomers may be a real culprit in the pathogenesis of Alzheimer's disease (AD); therefore, the elimination of these toxic oligomers may be of great significance for AD therapy. Autophagy is the catabolic process by which lysosomes degrade cytosolic components, and heat shock cognate 70 kDa protein (Hsc70) binds to proteins with their KFERQ-like motifs [also known as chaperone-mediated autophagy (CMA) motifs] and carries them to lysosomes through CMA or late endosomes through endosomal microautophagy (eMI) for degradation. In this study, our strategy is to make the pathological Aβ become one selective and suitable substrate for CMA and eMI (termed as Hsc70-based autophagy) by tagging its oligomers with multiple CMA motifs. First, we design and synthesize Aβ oligomer binding peptides with three CMA motifs. Second, we determine that the peptide can help Aβ oligomers enter endosomes and lysosomes, which can be further enhanced by ketone. More importantly, we find that the peptide can dramatically reduce Aβ oligomers in induced pluripotent stem cell (iPSC) cortical neurons derived from AD patient fibroblasts and protect primary cultured cortical neurons against the Aβ oligomer-induced neurotoxicity. In conclusion, we demonstrate that the peptide targeting Hsc70-based autophagy can effectively eliminate Aβ oligomers and have superior neuroprotective activity.

Medienart:

E-Artikel

Erscheinungsjahr:

2020

Erschienen:

2020

Enthalten in:

Zur Gesamtaufnahme - volume:524

Enthalten in:

Biochemical and biophysical research communications - 524(2020), 4 vom: 16. Apr., Seite 923-928

Sprache:

Englisch

Beteiligte Personen:

Dou, Juan [VerfasserIn]
Su, Peng [VerfasserIn]
Xu, Chongchong [VerfasserIn]
Wen, Zhexing [VerfasserIn]
Mao, Zixu [VerfasserIn]
Li, Wenming [VerfasserIn]

Links:

Volltext

Themen:

Aβ oligomers
Alzheimer’s disease
Amyloid beta-Peptides
Chaperone-mediated autophagy
HSC70 Heat-Shock Proteins
Hsc70
Journal Article
Neuroprotective Agents
Peptides
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Anmerkungen:

Date Completed 20.10.2020

Date Revised 14.05.2021

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.bbrc.2020.02.016

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM306515431