Pgrmc1/KLF4 Signaling Mediates the Neuron-Glia Crosstalk As A Neuroprotective Mechanism

We have recently found that Pgrmc1,a novel membrane-associated progesterone receptor,mediates P4-triggered BDNF release specifically from glia.To date,downstream signaling transduction consequent to Pgrmc1 activation has not been revealed.Here we provide evidence that P4 elicits a Pgrmc1/ERK5/KLF4 signaling cascade,which in turn,orchestrates glia-neuron communication via a BDNF (Brain-derived neurotrophic factor)-mediated intercellular crosstalk. We show that P4 triggered a significant release of mature BDNF from glia,and this effect was abolished by RNAi-mediated knock-down of Pgrmc1 or KLF4. Treatment of neuronal cultures with conditioned media from P4-treated astrocytes (P4-CM) induced a robust increase of synaptic marker expression,while blocking neurotrophin signaling can attenuate this effect,supporting that glia-derived BDNF induced synaptogenesis in neurons. In addition,P4-CM from glia significantly protected neurons against oxidative stress.Interestingly,over-expression of KLF4 in neurons resulted in an increase of TrkB / p75 ratio,supporting that neuronal activation of the KLF4 pathway “prepares” the neurons to interpret the glia-derived mature BDNF signaling as favorable to survival.Finally, we determined that the levels of Pgrmc1, KLF4 and BDNF expression were decreased in the hippocampi of aged mice,as well as in the 5´FAD mouse model of AD when compared to age-matched controls,suggesting that both “normal” and “pathological” aging (i.e., Alzheimer's disease) may diminish the sensitivity of the brain to the protective effects of P4 through down-regulating the Pgrmc1/KLF4/BDNF signaling system.