Schaefer 2016 PLOS ONE
| Schaefer PM, von Einem B, Walther P, Calzia E, von Arnim CA (2016) Metabolic characterization of intact cells reveals intracellular amyloid beta but not its precursor protein to reduce mitochondrial respiration. PLOS ONE 11:e0168157. |
Schaefer PM, von Einem B, Walther P, Calzia E, von Arnim CA (2016) PLOS ONE
Abstract: One hallmark of Alzheimerยดs disease are senile plaques consisting of amyloid beta (Aฮฒ), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of Alzheimerยดs disease and both Aฮฒ and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and Aฮฒ, it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus Aฮฒ in inducing mitochondrial alterations with respect to their subcellular localization. We performed an overexpression of APP or beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), increasing APP and Aฮฒ levels or Aฮฒ alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular Aฮฒ levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an Aฮฒ-mediated mitochondrial toxicity. Analyzing Aฮฒ localization revealed that intracellular levels of Aฮฒ and an increased spatial association of APP/Aฮฒ with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular Aฮฒ accumulation in Alzheimerยดs disease associated mitochondrial dysfunction. Thereby it highlights the importance of the localization of APP processing and intracellular transport as a decisive factor for mitochondrial function, linking two prominent hallmarks of neurodegenerative diseases.
Labels: MiParea: Respiration, Comparative MiP;environmental MiP
Pathology: Alzheimer's
Organism: Human, Mouse Tissue;cell: Nervous system, HEK Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ETS"ETS" is not in the list (LEAK, ROUTINE, OXPHOS, ET) of allowed values for the "Coupling states" property.
Pathway: CIV, ROX
HRR: Oxygraph-2k
Labels
