LATE MITOCHONDRIAL DEFICITS IN APP KNOCK-IN MOUSE HIPPOCAMPUS ARE PRECEDED BY PREMATURE UPREGULATION OF MITOCHONDRIAL METABOLISM
- Luana Naia, Sweden
Abstract
Aims
Mitochondrial dysfunction is a hallmark of Alzheimer’s disease (AD). However, how mitochondria activity varies along pathology progression is still poorly understood. Additionally, untangling the effects of elevated Aβ from those due to APP overexpression is a common challenge when interpreting mitochondrial phenotypes.
Methods
We performed several functional analyses using isolated hippocampal mitochondria at different disease stages as well as primary neurons from AppNL-F and AppNL-G-F mouse models containing a humanized Aβ region with pathogenic mutations.
Results
Hippocampal mitochondria isolated from pre-/early-symptomatic AppNL-G-F mice show upregulated mitochondrial complex I and IV activities and higher capacity to generate ATP as compared to wildtype. This results in increased basal and maximal mitochondrial respiration. Primary AppNL-F neurons follow a similar pattern, with increased mitochondrial respiration to compensate for glycolytic defects, suggesting that embryonic neurons may mimic early disease stages. Interestingly, both isolated mitochondria from 2 months-old AppNL-G-F mice and primary AppNL-F neurons show lower mitochondrial calcium handling capacity. Additionally, AppNL-F neurons show significant deficits in anterograde mitochondrial movement. These data reveal an early mitochondrial dysfunction, despite increased ATP production. With pathology progression, AppNL-G-F mitochondria show severe deficits on mitochondrial complex I-III activities, and decreased mitochondrial maximal respiration induced by the uncoupler FCCP. Moreover, synapses from both 12 months-old AppNL-F and AppNL-G-F mice show lower number of mitochondria, suggesting that mitochondrial deficits may influence synaptic integrity.
Conclusions
Overall, we show that App knock-in mice have an early upregulation of mitochondrial activity accompanied by deficits on mitochondrial calcium handling and movement, which may influence late mitochondrial activity decay.