The Role of Microglial Polarization in Adult Hippocampal Neurogenesis and Possible Depression Therapy

Depression is a complex psychiatric disorder that is closely related to neuroinflammation and adult hippocampal neurogenesis (AHN). Microglia polarised into pro-inflammatory M1 and anti-inflammatory M2 states play a key role in the regulation of AHN. M1 microglia release inflammatory cytokines, leading to neuroinflammation and neuronal damage, while M2 microglia promote neuroprotection and neurogenesis by secreting anti-inflammatory factors. Microglia produce BDNF (brain-derived neurotrophic factor), which is essential for neuronal survival and synaptic plasticity. BDNF is often attenuated in depression, further damaging the AHN. This study explores the role of BACE1 (-secretase 1) in regulating microglial polarisation. Increased BACE1 expression promotes M1 polarisation and inflammation, while BACE1 knockout transitions microglia to the M2 state, enhances BDNF production and restores AHN. The study uses a chronic mild stress model in mice, hypothesising that BACE1 knockout will reduce neuroinflammation, improve AHN, and attenuate depression-like behaviour. These findings aim to elucidate how targeting microglial polarisation and the BDNF pathway can provide a new therapeutic strategy for the treatment of depression by promoting hippocampal neurogenesis and reducing neuroinflammation.