Functional Deficits of 5×FAD Neural Stem Cells Are Ameliorated by Glutathione Peroxidase 4

Alzheimer's disease (AD) is the most common cause of dementia affecting millions of people around the globe. Impaired neurogenesis is reported in AD as well as in AD animal models, although the underlying mechanism remains unclear. Elevated lipid peroxidation products are well-documented in AD. In current study, the role of lipid peroxidation on neural stem cell (NSCs) function is tested. Neural stem cells (NSCs) from 5×FAD mice, a widely used AD model with impaired neurogenesis, were observed to have increased levels of lipid reactive oxygen species compared to NSCs from control WT mice. 5×FAD NSCs exhibited altered differentiation potential as revealed by their propensity to differentiate into astrocytic lineage instead of neuronal lineage compared to WT NSCs. In addition, 5×FAD NSCs showed a reduced level of Gpx4, a key enzyme in reducing hydroperoxides in membrane lipids, and this reduction appeared to be caused by enhanced autophagy-lysosomal degradation of Gpx4 protein. To test if increasing Gpx4 could restore differentiation potential, NSCs from 5×FAD and Gpx4 double transgenic mice, i.e., 5×FAD/GPX4 mice were studied. Remarkably, upon differentiation, neuronal linage cells increased significantly in 5×FAD/GPX4 cultures compared to 5×FAD cultures. Taken together, the findings suggest that deficiency of lipid peroxidation defense contributes to functional decline of NSCs in AD.