Unveiling Ribosomal Dysfunction and Impaired Signaling Pathways in the Cortical Region of FAD5x Mice

Alzheimer's Disease represents the most significant form of neurodegenerative disease worldwide with progressive dementia and synaptic dysfunction. Though the accumulation of β-amyloid and hyperphosphorylated tau protein is the most observed pathological feature of AD, the emergence of ribosomal dysfunction and oxidative stress has recently gained interest. In this study, we conducted a comprehensive multi-omics investigation, which included transcriptomic, proteomic, and lipidomic analyses, on cortical region from FAD5x mice, a transgenic model of AD. Gene and protein expression analysis demonstrated ribosomal pathways were largely affected in the cortex. Histological and immunohistochemistry imaging showed increased amyloid-β and tau pathology leading to extensive cortical neurodegeneration. RNAseq analysis revealed increased oxidative RNA damage, indicating a potential mechanism of ribosomal stress. Elevated expression of RPL11, RPL6, and other large ribosomal subunit proteins was observed, consistent with impaired protein synthesis. This dysregulation may contribute to neurodegenerative processes in AD. Among the large subunit ribosomal proteins, RPL29 were downregulated at the gene expression level in AD, although its protein expression revealed a statistically insignificant rise. Comparison between the transcriptome and proteome demonstrated evidence of impaired translation, suggesting failed translational control. Lipidomic analyses revealed alterations in the levels of phospholipids, sphingolipids and lipid mediators in AD that is closely linked to the alterations in the neuroinflammatory pathways at the transcriptomic and proteomics levels. Multi-omics integration demonstrates that ribosomal dysregulation, oxidative stress, and protein homeostasis are affected, leading to neuronal damage in AD. According to this study, ribosomal malfunction plays a significant role in the pathophysiology of AD and serve as a potential target for therapeutic interventions.