Tanshinone IIA Promotes Hippocampal Neurogenesis in ApoE^-/- Mice Through cAMP/PKA/CREB/BDNF Signaling Pathway

New cells are generated from neural stem cells (NSCs) in the subgranular zone (SGZ) of the dentate gyrus of the hippocampus throughout life to shape brain function. Apolipoprotein E (ApoE) deficiency impairs hippocampal dentate gyrus development by affecting the neural progenitor pool over time. Impaired adult hippocampal neurogenesis has been reported in human ApoE4 and ApoE-knockout (ApoE^-/-) mice. The ApoE gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Our previous studies indicated that tanshinone IIA (tan IIA) has a broad range of pharmacological actions on AD. Here, we aimed to investigate the effects of 2 weeks of tan IIA (15 mg/kg, intraperitoneally, once daily) treatment on hippocampal neurogenesis in 1- and 3-month-old ApoE^-/- mice. The results showed that tan IIA treatment significantly promoted cell proliferation and increased the density of immature neurons in the hippocampus. Mechanistically, tan IIA treatment elevated the levels of cyclic adenosine monophosphate (cAMP), cAMP/protein kinase A (PKA), and cAMP response element binding protein (CREB) phosphorylation, and subsequently increasing the production of brain-derived neurotrophic factor (BDNF). Furthermore, tan IIA is capable of promoting NSCs proliferation, differentiation, and survival in vitro. Collectively, the above findings indicated that tan IIA stimulates neurogenesis in the adult hippocampus of ApoE^-/- mice possibly through the cAMP/PKA/CREB/BDNF signaling pathway. These results suggested that tan IIA may have neuroprotective effects against neurogenesis decline in ApoE^-/- mice.