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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Vaillant-Beuchot, Loan ^[1] ; Mary, Arnaud ^[1] ; Pardossi-Piquard, Raphaelle ^[1] ; Bourgeois, Alexandre ^[1] ; Lauritzen, Inger ^[1] ; Eysert, Fanny ^[1] ; Kinoshita, Paula Fernanda ^{[1, 2]} ; Cazareth, Julie ^[1] ; Badot, Celine ^[1] ; Fragaki, Konstantina ^[3] ; Bussiere, Renaud ^{[1, 4]} ; Martin, Cecile ^[1] ; Mary, Rosanna ^[1] ; Bauer, Charlotte ^[1] ; Pagnotta, Sophie ^[5] ; Paquis-Flucklinger, Veronique ^[3] ; Buee-Scherrer, Valerie ^{[6, 7]} ; Buee, Luc ^{[6, 7]} ; Lacas-Gervais, Sandra ^[5] ; Checler, Frederic ^[1] ; Chami, Mounia ^[1]

Afiliação do(s) autor(es)

^[1] Univ Cote Azur, Inst Mol & Cellular Pharmacol, Lab Excellence DistALZ, CNRS, INSERM, F-06560 Valbonne - France

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Pharmacol, Sao Paulo - Brazil

^[3] Univ Cote Azur, CHU Nice, CNRS, INSERM, IRCAN, Nice - France

^[4] Imperial Coll London, UK Dementia Res Inst, Dept Med, Burlington Danes Bldg, Hammersmith Hosp Campus, London W12 0NN - England

^[5] Univ Cote Azur, Ctr Commun Microscopie Appl CCMA, Parc Valrose, F-06108 Nice - France

^[6] Univ Lille, CHU Lille, Lille Neurosci & Cognit, INSERM, Pl Verdun, F-59045 Lille - France

^[7] INSERM, UMR S 1172, Lab Excellence DistALZ Alzheimer & Tauopathies, Batiment Biserte, Rue Polonovski, F-59045 Lille - France

• Tipo de documento: Artigo Científico
• Fonte: ACTA NEUROPATHOLOGICA; v. 141, n. 1, p. 39-65, JAN 2021.
• Citações Web of Science: 2

Resumo

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 beta-secretase-derived APP-CTF fragment (C99) combined with beta- and gamma-secretase inhibition, that APP-CTFs accumulation independently of A beta 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 gamma-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 A beta 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. (AU)

• Processo FAPESP: 18/14289-6 - O papel da proteína Klotho na doença de Alzheimer
• Beneficiário: Paula Fernanda Kinoshita
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado