Low Intensity Ultrasound-facilitated exosome delivery promotes hippocampal neurogenesis in Alzheimer's disease

BACKGROUND: Low-intensity ultrasound (LIUS) and human adipose-tissue mesenchymal stem cell-derived exosomes (hADSC-Exos) have shown neuroprotective potential, but their combined effects in Alzheimer's disease (AD) remain unclear. OBJECTIVE: To evaluate the safety and efficacy of intranasal hADSC-Exos alone or combined with LIUS in APP/PS1 mice, and explore underlying molecular mechanisms. METHODS: Female APP/PS1 mice (30 weeks) were randomized into five groups (n=6). Treatments included intranasal hADSC-Exos, LIUS, or both for 2 months. Behavioral tests, histology, and hippocampal RNA-seq were performed. RESULTS: LIUS enhanced Exo uptake in HT22 cells by ∼8% without toxicity. Combined treatment improved learning and memory (escape latency ↓45 s→20 s; P<0.01), increased neurogenesis markers (GFAP/SOX2, DCX, Ki67), and reduced amyloid and microglial activation. RNA-seq identified 93 specific DEGs in the combination group, with enrichment in synaptic and mitochondrial pathways. Fos and Kcnj13 were top DEGs and both downregulated after therapy (P<0.05). CONCLUSIONS: Intranasal hADSC-Exos combined with LIUS is safe, enhances brain delivery, and synergistically improves cognition and neurogenesis in AD mice. The Fos-Kcnj13 axis may mediate these effects, suggesting a promising noninvasive therapeutic strategy.