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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.
Acta Neuropathol. 2021 01; 141(1):39-65.AN

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.

Authors+Show Affiliations

Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France. Department of Pharmacology, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, Nice, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France. Department of Medicine, Burlington Danes Building, Hammersmith Hospital Campus, Imperial College London, UK Dementia Research Institute, Du Cane Road, London, W12 0NN, UK.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Université Côte d'Azur, Centre Commun de Microscopie Appliquée (CCMA), Parc Valrose, 06108, Nice, France.Université Côte d'Azur, CHU, Inserm, CNRS, IRCAN, Nice, France.Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience and Cognition, Place de Verdun, 59045, Lille, France. Inserm UMR-S 1172, Laboratory of Excellence DistALZ, 'Alzheimer and Tauopathies', Bâtiment Biserte, rue Polonovski, 59045, Lille Cedex, France.Univ. Lille, Inserm, CHU-Lille, Lille Neuroscience and Cognition, Place de Verdun, 59045, Lille, France. Inserm UMR-S 1172, Laboratory of Excellence DistALZ, 'Alzheimer and Tauopathies', Bâtiment Biserte, rue Polonovski, 59045, Lille Cedex, France.Université Côte d'Azur, Centre Commun de Microscopie Appliquée (CCMA), Parc Valrose, 06108, Nice, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France.Institut of Molecular and Cellular Pharmacology, Laboratory of Excellence DistALZ, Université Côte d'Azur, INSERM, CNRS, Sophia-Antipolis, 06560, Valbonne, France. mchami@ipmc.cnrs.fr.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33079262

Citation

Vaillant-Beuchot, Loan, et al. "Accumulation of Amyloid Precursor Protein C-terminal Fragments Triggers Mitochondrial Structure, Function, and Mitophagy Defects in Alzheimer's Disease Models and Human Brains." Acta Neuropathologica, vol. 141, no. 1, 2021, pp. 39-65.
Vaillant-Beuchot L, Mary A, Pardossi-Piquard R, et al. Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains. Acta Neuropathol. 2021;141(1):39-65.
Vaillant-Beuchot, L., Mary, A., Pardossi-Piquard, R., Bourgeois, A., Lauritzen, I., Eysert, F., Kinoshita, P. F., 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., ... Chami, M. (2021). Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains. Acta Neuropathologica, 141(1), 39-65. https://doi.org/10.1007/s00401-020-02234-7
Vaillant-Beuchot L, et al. Accumulation of Amyloid Precursor Protein C-terminal Fragments Triggers Mitochondrial Structure, Function, and Mitophagy Defects in Alzheimer's Disease Models and Human Brains. Acta Neuropathol. 2021;141(1):39-65. PubMed PMID: 33079262.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains. AU - Vaillant-Beuchot,Loan, AU - Mary,Arnaud, AU - Pardossi-Piquard,Raphaëlle, AU - Bourgeois,Alexandre, AU - Lauritzen,Inger, AU - Eysert,Fanny, AU - Kinoshita,Paula Fernanda, AU - Cazareth,Julie, AU - Badot,Céline, AU - Fragaki,Konstantina, AU - Bussiere,Renaud, AU - Martin,Cécile, AU - Mary,Rosanna, AU - Bauer,Charlotte, AU - Pagnotta,Sophie, AU - Paquis-Flucklinger,Véronique, AU - Buée-Scherrer,Valérie, AU - Buée,Luc, AU - Lacas-Gervais,Sandra, AU - Checler,Frédéric, AU - Chami,Mounia, Y1 - 2020/10/20/ PY - 2020/06/09/received PY - 2020/10/01/accepted PY - 2020/09/03/revised PY - 2020/10/21/pubmed PY - 2021/10/26/medline PY - 2020/10/20/entrez KW - APP-CTFs KW - Alzheimer’s disease KW - Amyloid beta KW - Amyloid precursor protein KW - C83 KW - C99 KW - Mitochondria KW - Mitophagy SP - 39 EP - 65 JF - Acta neuropathologica JO - Acta Neuropathol VL - 141 IS - 1 N2 - 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. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/33079262/Accumulation_of_amyloid_precursor_protein_C_terminal_fragments_triggers_mitochondrial_structure_function_and_mitophagy_defects_in_Alzheimer's_disease_models_and_human_brains_ L2 - https://dx.doi.org/10.1007/s00401-020-02234-7 DB - PRIME DP - Unbound Medicine ER -