Amyloid-beta accumulation in glioblastoma is driven by vascular remodeling and APP-processing pathways

Background: Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis.Identifying biomarkers for targeted therapies remains a major challenge in GBM treatment.Recently, we demonstrated that amyloid-beta (Abeta), a peptide classically associated with neurodegenerative diseases, accumulates in GBM tumors. This study aims to investigate the mechanism underlying Abeta accumulation in GBM tissues. Methods: Immunohistochemical analysis and confocal imaging were performed to assessAbeta localization in human GBM tissue sections. Glial fibrillary acidic protein (GFAP), ionizedcalcium-binding adaptor molecule 1 (Iba1), and CD31 were used as markers of astrocytes, microglia, and blood vessels, respectively. Western blot analysis was performed toevaluate the expression of Abeta and amyloid precursor protein (APP), along with matrixmetalloproteinases 2 and 9 (MMP-2 and MMP-9), presenilin-1, nicastrin proteins involved inAbeta production and vascular endothelial growth factor (VEGF). Pearson correlation analysis was conducted to assess relationships among Abeta, VEGF, MMP-2/9, presenilin-1, and nicastrin. Results: Confocal imaging revealed robust Abeta accumulation in blood vessels and in tumor regions with high vascularization, as well as strong Abeta accumulation in microglia and, to alesser extent, in glioma cells. Western blot analysis showed strong correlations betweenAbeta levels and factors such as VEGF, MMP-2, and presenilin-1, indicating complex regulatory interactions driving Abeta accumulation. Conclusion : These findings demonstrate that Abeta accumulation in GBM is closely linked to tumor vascularization and microglial involvement. The strong correlations with VEGF, MMP-2, and presenilin-1 suggest that both vascular remodeling and proteolytic processing contribute to Abeta buildup.This study was supported by: NIH Grants 1R15CA287203 and 1R16GM153522