Schaefer 2016 PLOS ONE: Difference between revisions
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Revision as of 16:43, 26 July 2017
| 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 AlzheimerΒ΄s disease are senile plaques consisting of amyloid beta (AΞ²), which derives from the processing of the amyloid precursor protein (APP). Mitochondrial dysfunction has been linked to the pathogenesis of AlzheimerΒ΄s disease and both AΞ² and APP have been reported to affect mitochondrial function in isolated systems. However, in intact cells, considering a physiological localization of APP and AΞ², it is pending what triggers the mitochondrial defect. Thus, the aim of this study was to dissect the impact of APP versus AΞ² 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 AΞ² levels or AΞ² alone, respectively. Conducting a comprehensive metabolic characterization we demonstrate that only APP overexpression reduced mitochondrial respiration, despite lower extracellular AΞ² levels compared to BACE overexpression. Surprisingly, this could be rescued by a gamma secretase inhibitor, oppositionally indicating an AΞ²-mediated mitochondrial toxicity. Analyzing AΞ² localization revealed that intracellular levels of AΞ² and an increased spatial association of APP/AΞ² with mitochondria are associated with reduced mitochondrial respiration. Thus, our data provide marked evidence for a prominent role of intracellular AΞ² accumulation in AlzheimerΒ΄s 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
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