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Updated: Jun 18, 2026
An In Vitro Model for Studying Tau Aggregation Using Lentiviral-mediated Transduction of Human Neurons
Published on: May 23, 2019
Mitochondrial NADK2-dependent NADPH controls tau oligomer uptake in human neurons
Evelyn Pardo1, Taylor Kim1, Horst Wallrabe1,2
1Department of Biology, University of Virginia, Charlottesville, Virginia, USA.
Introduction:
Reduced brain energy metabolism, mitochondria dysfunction, and extracellular tau oligomer buildup characterize Alzheimer's disease (AD), but how these phenomena cooperatively promote neurodegeneration is poorly understood. We now report that tau oligomers (TauOs) pathologically coordinate mitochondrial metabolism with increased expression of a plasma membrane (PM) tau receptor.
Methods:
Mitochondrial energy metabolism was recorded using two-photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain.
Results:
Recombinant or human brain-derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension, de novo NADPH synthesis. This process controls expression of low-density lipoprotein receptor-related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2-NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient-derived neurons.
Discussion:
Upregulation of mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.
