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Open Access 01-01-2021 | Alzheimer's Disease | Original Paper

Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer’s disease models and human brains

Authors: Loan Vaillant-Beuchot, Arnaud Mary, Raphaëlle Pardossi-Piquard, Alexandre Bourgeois, Inger Lauritzen, Fanny Eysert, Paula Fernanda Kinoshita, Julie Cazareth, Céline Badot, Konstantina Fragaki, Renaud Bussiere, Cécile Martin, Rosanna Mary, Charlotte Bauer, Sophie Pagnotta, Véronique Paquis-Flucklinger, Valérie Buée-Scherrer, Luc Buée, Sandra Lacas-Gervais, Frédéric Checler, Mounia Chami

Published in: Acta Neuropathologica | Issue 1/2021

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.

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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: Loan Vaillant-Beuchot
Arnaud Mary
Raphaëlle Pardossi-Piquard
Alexandre Bourgeois
Inger Lauritzen
Fanny Eysert
Paula Fernanda Kinoshita
Julie Cazareth
Céline Badot
Konstantina Fragaki
Renaud Bussiere
Cécile Martin
Rosanna Mary
Charlotte Bauer
Sophie Pagnotta
Véronique Paquis-Flucklinger
Valérie Buée-Scherrer
Luc Buée
Sandra Lacas-Gervais
Frédéric Checler
Mounia Chami
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Alzheimer's Disease
Alzheimer's Disease
Published in: Acta Neuropathologica / Issue 1/2021
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-020-02234-7

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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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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