Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons

Alterations in NADH and NADPH metabolism are associated with aging, cancer, and Alzheimers Disease. Using 2P-FLIM imaging of the mitochondrial NAD(P)H in live human neurons and PS19 mouse brains, we show that tau oligomers (TauO) upregulate the mitochondrial de novo NADPH synthesis through NADK2. This process controls LRP1-mediated internalization of TauO, setting a vicious cycle for further TauO internalization. Thus, mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity.