Effects of oxidized low-density lipoprotein on differentiation of mouse neural progenitor cells into neural cells

Abstract

In Alzheimer's disease (AD), a decline in function of neural progenitor cells (NPCs) results in a reduced capacity for neural regeneration. It has been shown that plasma oxidized low-density lipoprotein (ox-LDL) levels are positively correlated with severity in patients with AD. However, the direct effects of ox-LDL on NPCs are unknown. Thus, we examined the effects of ox-LDL on the proliferation and differentiation of mouse NPCs into neural cells. Mouse induced pluripotent stem (iPS) cell-derived embryoid bodies were stimulated with Noggin and SB431542 for 4 days. Mouse NPCs were then collected using anti-polysialic acid-neural cell adhesion molecule antibodies in a magnetic separator. The proliferation of mouse NPCs was examined using the MTT assay. The differentiation of mouse NPCs into neural cells was examined by the expression of NeuN (a neuronal-specific nuclear protein) using immunofluorescence staining and Western blot analysis. Treatment with ox-LDL did not affect the proliferation of mouse NPCs. While treatment with all-trans retinoic acid (ATRA), epidermal growth factor (EGF), and basic fibroblast growth factor (FGF) significantly induced NeuN expression in the differentiated NPCs (P < 0.01), the addition of ox-LDL significantly inhibited the NeuN expression (P < 0.05). Pretreatment with SC-79 (an Akt activator) significantly reversed the inhibitory effect of ox-LDL on NeuN expression (P < 0.05). Treatment with ox-LDL significantly inhibited Akt phosphorylation (P < 0.05) and CREB phosphorylation induced by ATRA, EGF, and basic FGF (P < 0.05). The present study indicates that treatment with ox-LDL inhibits the differentiation of mouse NPCs into neural cells by inhibiting Akt and CREB activation.