haFGF14-154 attenuates Aβ1-42-induced neurotoxicity by facilitating BDNF maturation in a neuron-astrocyte co-culture system.

haFGF14-154 improves cognitive impairment in animal models of Alzheimer's disease (AD), but the effects and mechanisms of astrocytes on the neuroprotection mediated by haFGF14-154 remain unclear. Here, a neuron-astrocyte co-culture system was established to investigate the functions of astrocytes. The results showed that astrocytes strengthened the protective effect of haFGF14-154 on Aβ1-42-treated neurons. This enhanced protective function of haFGF14-154 correlates with phenotypic transition in astrocytes, as demonstrated by the suppression of Aβ1-42-induced A1-like genes and the elevation of A2-like markers in vitro. These observations are consistent with the reduction of GFAP and C3 levels in the hippocampus and prefrontal cortex of APP/PS1 mice treated with haFGF14-154. haFGF14-154 modified the function of astrocytes by activating the AKT/CREB/BDNF pathway, thereby promoting neurite growth. Moreover, haFGF14-154 up-regulated the expression of Furin and MMP9 in astrocytes, leading to the processing of pro-BDNF. This effect was replicated in APP/PS1 mice administered with haFGF14-154. Compared to the Aβ group, the BDNF level in the co-culture system supernatant was increased, while the IL-1β level was decreased following haFGF14-154 treatment. Additionally, haFGF14-154 inhibited neuronal apoptosis in the co-culture system, as evidenced by a decrease in pro-BDNF/P75NTR, an increase in Bcl-2, and a reduction of Bad and Cleaved-caspase-3. In conclusion, current results demonstrate that astrocytes are crucial for mediating the protective effect of haFGF14-154 against neuronal damage, and underline the importance of the AKT/CREB/BDNF pathway in promoting neurite growth and attenuating neuronal apoptosis.