Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer’s disease neurons

https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12924

Pierre Theurey, Niamh M. C. Connolly, Ilaria Fortunati, Emy Basso, Susette Lauwen, Camilla Ferrante, Catarina Moreira Pinho, Alvin Joselin,  Anna Gioran, Daniele Bano, David S. Park,  Maria Ankarcrona, Paola Pizzo,  Jochen H. M. Prehn

• Many studies have focussed on the role of mitochondrial dysfunctions in Alzheimer's disease (AD), but most of them cannot tell whether mitochondrial defects are a cause or a consequence of AD.
• The authors use a combined experimental and computational approach to study mitochondrial function in the neurons of a transgenic mouse model.
• Experiments show that AD neurons have limited respiratory capacity. The computational model predicted that this could not be explained by any defect in the respiratory chain (RC),  but could be observed by simulating an impairment in the NADH flux to the RC.
• The authors used NAD(P)H autofluorescence measurements to validate the computationally predicted mitochondrial NADH defect in transgenic AD neurons.

Additionally, the authors investigated the cause of these reduced NADH flux and the resulting  mitochondrial NAD(P)H dyshomeostasis.

• Extracellular acidification experiments  measure the rate of excretion of lactic acid after its conversion from pyruvate, a product of glycolysis. These experiments  showed an impaired glycolytic flux in the transgenic AD neurons of the study.
• The authors supplemented neurons with pyruvate (therefore bypassing glycolysis), and this suppressed the NAD(P)H  impairment and the mitochondrial defects.
• This supports the hypothesis that a glycolytic defect is responsible for the unbalance of NAD(P)H observed in AD neurons.

The study shows that defects in glucose metabolism in vitro are detectable in neurons before the onset of any sign of pathology in transgenic AD mice.