Sex-related upregulation of bone morphogenetic protein signaling inhibits adult neurogenesis in APPNL-G-F alzheimer's disease model mice.

BACKGROUND: Bone morphogenetic proteins (BMPs) have been reported in many studies to be related to adult neurogenesis. Neurogenic impairment is a hallmark of Alzheimer's disease (AD), while the involvement of BMPs remains unclear. METHODS: AD models were established using APPNL-G-F transgenic mice and C57BL/6 mice subjected to intracerebral injection of Aβ(25-35) peptide. Female APPNL-G-F mice received pharmacological inhibitor treatment, whereas Neuro2a cells were exposed to estrogen stimulation in vitro. Immunofluorescence staining was conducted to evaluate hippocampal neural stem cell proliferation. The hippocampus and cellular pellets were isolated, and quantitative PCR (qPCR) was employed to determine mRNA expression levels. RESULTS: Our study revealed that APPNL-G-F mice and Aβ-injected mice exhibited impaired neurogenesis in the brain, with a clear sex-dependent difference only in APP mice. Several BMPs were markedly upregulated in the hippocampus of AD model mice, with significantly higher expression in females than in males. BMP inhibitor attenuated neural stem cell proliferation deficits in female APPNL-G-F mice. Estrogen stimulation robustly enhanced BMP6 expression in Neuro2a cells. CONCLUSIONS: Our findings reveal a sex-dependent impairment of neurogenesis in APPNL-G-F mice driven by BMP signaling. Blocking BMP signaling enhances adult neural stem cell proliferation in female APPNL-G-F mice, providing a potential therapeutic target for AD.