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 -