Affiliations: [a] Centro de Biología Molecular “Severo Ochoa” (UAM-CSIC), Cantoblanco, Madrid, Spain
| [b] Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| [c]
Neuro-oncology Unit, Instituto de Salud Carlos III-UFIEC, Majadahonda, Madrid, Spain
| [d] Facultad de Ciencias Experimentales, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain
Correspondence:
[*]
Correspondence to: Jesús Avila and Vega García-Escudero, Centro de Biología, Molecular Severo Ochoa, Nicolás Cabrera, 1, Cantoblanco, 28049 Madrid, Spain. Tel.: +34 91 196 4564/4592; Fax: +34 91196 4420; E-mails: javila@cbm.csic.es; v.garcia-escudero@uam.es.
Note: [1] Present address: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
Note: [2] Present address: Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, UAM, Madrid, Spain.
Abstract: Mitochondrial alterations and oxidative stress are common features of Alzheimer’s disease brain and peripheral tissues. Moreover, mitochondrial recycling process by autophagy has been found altered in the sporadic form of the disease. However, the contribution of the main proteins involved in this pathology such as amyloid-β protein precursor (AβPP) and tau needs to be achieved. With this aim, human unmodified fibroblasts were transduced with lentivectors encoding APP and Tau and treated with CCCP to study the mitophagy process. Both AβPP and tau separately increased autophagy flux mainly by improving degradation phase. However, in the specific case of mitophagy, labeling of mitochondria by PINK1 and PARK2 to be degraded by autophagy seemed reduced, which correlates with the long-term accumulation of mitochondria. Nevertheless, the combination of tau and AβPP was necessary to cause a mitophagy functional impairment reflected in the accumulation of depolarized mitochondria labeled by PINK1. The overexpression of Tau and APP recapitulates the mitophagy failure previously found in sporadic Alzheimer’s disease.
Keywords: Alzheimer’s disease, amyloid-β protein precursor, mitochondria, mitophagy, tau
