Alzheimer's disease is a prevalent and debilitating neurodegenerative condition that profoundly affects a patient's daily functioning with progressive cognitive decline, which can be partly attributed to impaired hippocampal neurogenesis. Neurogenesis in the hippocampal dentate gyrus is likely to persist throughout life but declines with aging, especially in Alzheimer's disease. Recent evidence indicated that RNA-binding protein 8A (Rbm8a) promotes the proliferation of neural progenitor cells, with lower expression levels observed in Alzheimer's disease patients compared with healthy people. This study investigated the hypothesis that Rbm8a overexpression may enhance neurogenesis by promoting the proliferation of neural progenitor cells to improve memory impairment in Alzheimer's disease. Therefore, Rbm8a overexpression was induced in the dentate gyrus of 5×FAD mice to validate this hypothesis. Elevated Rbm8a levels in the dentate gyrus triggered neurogenesis and abated pathological phenotypes (such as plaque formation, gliosis reaction, and dystrophic neurites), leading to ameliorated memory performance in 5×FAD mice. RNA sequencing data further substantiated these findings, showing the enrichment of differentially expressed genes involved in biological processes including neurogenesis, cell proliferation, and amyloid protein formation. In conclusion, overexpressing Rbm8a in the dentate gyrus of 5×FAD mouse brains improved cognitive function by ameliorating amyloid-beta-associated pathological phenotypes and enhancing neurogenesis.
Keywords: Adora2a; Alzheimer’s disease; Rbm8a; astrocyte; cAMP signaling pathway; dentate gyrus; dystrophic neurites; microglia; neurogenesis; plaque.