Nrf2 activator tertiary butylhydroquinone enhances neural stem cell differentiation and implantation in Alzheimer's disease by boosting mitochondrial function.

Aims: To investigate the effects of Nrf2 agonist tertiary butylhydroquinone (TBHQ)-stimulated neural stem cells (NSCs) transplantation (NSC(TBHQ)) on neuronal damage and cognitive deficits in an AD model and its underlying principles.

Methods: BHQ-treated NSCs were examined with or without Aβ1-42 to investigate the effects of TBHQ on the proliferation and differentiation functions. The mitophagy inhibitor Cyclosporine A (CSA) was used to explore the regulation of mitophagy by TBHQ. The no-, ethanol-, and TBHQ-treated NSCs were transplanted into the bilateral hippocampal region of model mice to explore the effects of NSC(TBHQ) on neuronal, cognitive, and mitochondrial functional impairments in mice.

Results: TBHQ reversed the Aβ1-42-caused inhibition on NSC proliferation and differentiation, as well as on levels of mitochondrial membrane potential, adenosine triphosphate (ATP), and mitochondrial fusion-associated proteins. TBHQ alleviated the Aβ1-42-induced increase in apoptosis, mitochondrial damage, mitochondria-derived reactive oxygen species (mtROS), and mitochondrial fission-related proteins. TBHQ activated the Parkin, Beclin, LC3II/I, and COXIV expression, while inhibiting the p62 expression. CSA reversed the effects of TBHQ on NSC proliferation and differentiation. After NSC(TBHQ) transplantation, it not only further extended the dwell time in the target quadrant and shorten the time and distance for finding the hidden platform, but also further decreased the Aβ and p-Tau/Tau levels, while increasing the expression of NeuN. The effects of NSC(TBHQ) transplantation on mitochondrial function were consistent with the in vitro experiments.

Conclusions: The study shows that NSC(TBHQ) intensifies the beneficial impact of NSCs transplantation on cognitive impairment and neuronal damage in AD models, likely due to TBHQ's role in promoting NSCs growth and differentiation via mitophagy, thus laying a theoretical foundation for improving NSCs transplantation for AD.