Sex-specific effects of BDNF/TrkB and pro-BDNF/p75NTR signaling in modulating microglia state in the aging brain

Signaling of brain-derived neurotrophic factor (BDNF) and its precursor proBDNF via their receptors TrkB and p75NTR in the brain regulates several physiological processes including the development of the neuronal network, its functional and structural plasticity and learning and memory processes. Besides being expressed in neurons, BDNF has been shown to be expressed also in microglia, the resident macrophages in the brain and is suggested to regulate their activation state. Interestingly, while BDNF levels decrease, proBDNF has been shown to increase in the brain with age leading to a shift in the BDNF/proBDNF ratio in favor of the pro-form. Aging is also associated with a progressive alteration in the microglia activation state, so-called priming. The mechanisms underlying the priming of microglia during aging remain elusive and a possible role of the age-dependent changes in BDNF-TrkB and proBDNF-p75NTR signaling in this context is not yet understood. Therefore, this study investigated how specific manipulations of the BDNF/proBDNF signaling might influence microglia priming and how in turn the activation state of microglia may affect BDNF synthesis and release in the aging brain. The results indicate that pretreatment with BDNF or proBDNF attenuates LPS‐induced pro‐inflammatory cytokine production in enriched primary microglia and mixed glia culture in a dose‐ and sex‐dependent manner, yet has no effect in pure microglia or astrocyte cultures. Comparing heterozygous BDNF knockout (KO) mice with wild-type (WT) mice revealed that the lower BDNF levels are associated with a decrease in microglial complexity in an age- and sex‐dependent manner. Finally, sequestering BDNF with TrkB‐Fc or blocking proBDNF signaling with TAT-Pep5 decreased microglial structural dynamics. Overall, these findings decipher the potential of BDNF/proBDNF signaling as a critical modulator of microglial activation and morphology in an age- and sex-dependent manner, suggesting its therapeutic potential for counteracting chronic neuroinflammation.