Article (Scientific journals)
Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains.
Vaillant-Beuchot, Loan; Mary, Arnaud; Pardossi-Piquard, Raphaëlle et al.
2021In Acta Neuropathologica, 141 (1), p. 39-65
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Keywords :
Aged; Aged, 80 and over; Alzheimer Disease/metabolism/pathology; Amyloid Precursor Protein Secretases/antagonists & inhibitors/metabolism; Amyloid beta-Protein Precursor/genetics/metabolism; Animals; Aspartic Acid Endopeptidases/antagonists & inhibitors/metabolism; Autopsy; Brain/pathology; Cell Line; Female; Humans; Membrane Potential, Mitochondrial; Mice; Mitochondria/metabolism/pathology/ultrastructure; Mitophagy/genetics; Peptide Fragments/genetics/metabolism; Reactive Oxygen Species/metabolism; APP-CTFs; Alzheimer’s disease; Amyloid beta; Amyloid precursor protein; C83; C99; Mitochondria; Mitophagy
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Vaillant-Beuchot, Loan 
Mary, Arnaud   ;  Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of excellence DistALZ, 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France.
Pardossi-Piquard, Raphaëlle
Bourgeois, Alexandre
Lauritzen, Inger
Eysert, Fanny
Kinoshita, Paula Fernanda
Cazareth, Julie
Badot, Céline
Fragaki, Konstantina
Bussiere, Renaud
Martin, Cécile
Mary, Rosanna
Bauer, Charlotte
Pagnotta, Sophie
Paquis-Flucklinger, Véronique
Buée-Scherrer, Valérie
Buée, Luc
Lacas-Gervais, Sandra
Checler, Frédéric
Chami, Mounia
More authors (11 more) Less
 These authors have contributed equally to this work.
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Language :
Title :
Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains.
Publication date :
Journal title :
Acta Neuropathologica
Publisher :
Springer, Germany
Volume :
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Peer reviewed :
Peer Reviewed verified by ORBi
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