Introduction: Reduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-β oligomer (xcAβO) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit N utrient-induced M itochondrial A ctivity (NiMA) in cultured neurons. We now report NiMA disruption in vivo .
Methods: Brain energy metabolism and oxygen consumption were recorded in APP SAA/+ mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.
Results: NiMA is inhibited in APP SAA/+ mice before other defects are detected in these amyloid-β-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. GSK3β signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with lithium or TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APP SAA mice.
Conclusion: NiMA disruption in vivo occurs before histopathological changes and cognitive decline in APP SAA mice, and may represent an early stage in human AD.