Alzheimer's disease (AD) is a neurodegenerative condition primarily affecting older adults, with a higher prevalence in women. The biological origins of these sex-based differences remain largely unknown. Bone morphogenetic proteins (BMPs), which are important for adult neurogenesis, have an unclear role in AD pathogenesis.
A research team led by Xingyu Su from Waseda University, Japan, investigated the role of BMP signaling in neurogenic impairment and observed sex-based differences in AD mouse models. The study aimed to clarify how BMP signaling influences AD and to identify potential therapeutic targets.
The researchers used two AD mouse models: APPNL-G-F transgenic mice and age- and sex-matched wild-type controls. They found that both AD models exhibited impaired neurogenesis in the brain and significantly increased expression of BMP4, BMP6, and BMP7 compared to controls. Notably, female APPNL-G-F mice displayed more severe neurogenesis impairment and higher BMP expression than male mice, indicating a link between activated BMP signaling and impaired neurogenesis in AD.
Further experiments involved treating female APPNL-G-F mice with a pharmacological inhibitor of BMP, which effectively reduced neurogenic impairment and restored neurogenesis to levels comparable to wild-type mice. In vitro studies using Neuro2a cells, which express estrogen receptors, revealed that estrogen stimulation increased BMP6 levels. This finding suggests a potential mechanistic explanation for the observed sex differences in AD.
This research offers new insights into the involvement of BMP signaling activation in AD-related neurogenic impairment. The findings are intended to guide future translational research and contribute to the development of new intervention strategies for AD.