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Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains
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Vaillant-Beuchot2021_Article_AccumulationOfAmyloidPrecursor.pdf | Published version | 21.7 MB | Adobe PDF | View/Open |
Title: | Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains |
Authors: | Vaillant-Beuchot, L Mary, A Pardossi-Piquard, R Bourgeois, A Lauritzen, I Eysert, F Kinoshita, PF Cazareth, J Badot, C Fragaki, K Bussiere, R Martin, C Mary, R Bauer, C Pagnotta, S Paquis-Flucklinger, V Buée-Scherrer, V Buée, L Lacas-Gervais, S Checler, F Chami, M |
Item Type: | Journal Article |
Abstract: | Several lines of recent evidence indicate that the amyloid precursor protein-derived C-terminal fragments (APP-CTFs) could correspond to an etiological trigger of Alzheimer's disease (AD) pathology. Altered mitochondrial homeostasis is considered an early event in AD development. However, the specific contribution of APP-CTFs to mitochondrial structure, function, and mitophagy defects remains to be established. Here, we demonstrate in neuroblastoma SH-SY5Y cells expressing either APP Swedish mutations, or the β-secretase-derived APP-CTF fragment (C99) combined with β- and γ-secretase inhibition, that APP-CTFs accumulation independently of Aβ triggers excessive mitochondrial morphology alteration (i.e., size alteration and cristae disorganization) associated with enhanced mitochondrial reactive oxygen species production. APP-CTFs accumulation also elicit basal mitophagy failure illustrated by enhanced conversion of LC3, accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent Parkin and PINK1 recruitment to mitochondria, enhanced levels of membrane and matrix mitochondrial proteins, and deficient fusion of mitochondria with lysosomes. We confirm the contribution of APP-CTFs accumulation to morphological mitochondria alteration and impaired basal mitophagy in vivo in young 3xTgAD transgenic mice treated with γ-secretase inhibitor as well as in adeno-associated-virus-C99 injected mice. Comparison of aged 2xTgAD and 3xTgAD mice indicates that, besides APP-CTFs, an additional contribution of Aβ to late-stage mitophagy activation occurs. Importantly, we report on mitochondrial accumulation of APP-CTFs in human post-mortem sporadic AD brains correlating with mitophagy failure molecular signature. Since defective mitochondria homeostasis plays a pivotal role in AD pathogenesis, targeting mitochondrial dysfunctions and/or mitophagy by counteracting early APP-CTFs accumulation may represent relevant therapeutic interventions in AD. |
Issue Date: | Jan-2021 |
Date of Acceptance: | 1-Oct-2020 |
URI: | http://hdl.handle.net/10044/1/84524 |
DOI: | 10.1007/s00401-020-02234-7 |
ISSN: | 0001-6322 |
Publisher: | Springer |
Start Page: | 39 |
End Page: | 65 |
Journal / Book Title: | Acta Neuropathologica |
Volume: | 141 |
Copyright Statement: | © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: | Science & Technology Life Sciences & Biomedicine Clinical Neurology Neurosciences Pathology Neurosciences & Neurology Alzheimer's disease Amyloid precursor protein Amyloid beta APP-CTFs C99 C83 Mitochondria Mitophagy BETA-CTF FRAGMENT A-BETA MOUSE MODEL INTRANEURONAL ACCUMULATION LYSOSOMAL DYSFUNCTION TRANSGENIC MODEL ER MEMBRANES IN-VIVO APP DYNAMICS APP-CTFs Alzheimer’s disease Amyloid beta Amyloid precursor protein C83 C99 Mitochondria Mitophagy APP-CTFs Alzheimer’s disease Amyloid beta Amyloid precursor protein C83 C99 Mitochondria Mitophagy 1103 Clinical Sciences 1109 Neurosciences Neurology & Neurosurgery |
Publication Status: | Published |
Conference Place: | Germany |
Open Access location: | https://link.springer.com/article/10.1007%2Fs00401-020-02234-7 |
Online Publication Date: | 2020-10-20 |
Appears in Collections: | Faculty of Medicine Department of Brain Sciences |
This item is licensed under a Creative Commons License