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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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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 Creative Commons