Imagine Alzheimer’s disease as a stage performance. The cast of characters includes the immune hub genes and peripheral immune cells, and their interaction determines the progression of the disease. Just like a choreographer, scientists have identified the key players – GRB2, HSP90AA1, HSPA4, IGF1, KRAS, PIK3R1, and PTPN11 – that take center stage in the Alzheimer’s molecular dance. Among them, KRAS and PIK3R1 steal the spotlight as they closely influence Tau and Aβ pathology. As the performance intensifies (represented by increasing Braak stages), immune infiltration becomes more prominent and five immune cell types join the ensemble: plasma cells, T follicular helper cells, M2 macrophages, activated NK cells, and eosinophils. Together, KRAS and PIK3R1 guide this intricate choreography through various molecular pathways such as axon guidance and cytokine signaling. These findings shed light on new therapeutic targets and open new avenues for understanding the complex tango between the immune system and Alzheimer’s disease. Put on your dancing shoes and follow the research to unravel the secrets of this molecular dance!

BackgroundAlzheimer’s disease (AD) is the most common type of neurodegenerative disease. Tau pathology is one of the pathological features of AD, and its progression is closely related to the progress of AD. Immune system dysfunction is an important mediator of Tau pathological progression, but the specific molecular mechanism is still unclear. The purpose of this study is to determine the immune hub genes and peripheral immune cell infiltration associated with the Braak stages, and the molecular mechanisms between them.MethodsIn this study, 60 samples with different Braak stages in the GSE106241 dataset were used to screen Braak stages-related immune hub genes by using the WGCNA package in R and cytoHubba plugin. The temporal lobe expression data in the Alzdata database were used to verify the results. The correlation between the expression level of immune core genes and the pathological features of AD was analyzed to evaluate the abundance of peripheral immune cell infiltration and screened Braak stages-related cells. Finally, we used correlation analysis of immune hub genes and immune cells and Gene Set Enrichment Analysis (GSEA) of them.ResultsSeven genes (GRB2, HSP90AA1, HSPA4, IGF1, KRAS, PIK3R1, and PTPN11) were identified as immune core genes after the screening of the test datasets and validation of independent data. Among them, Kirsten rat sarcoma viral oncogene homolog (KRAS) and Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1) were the most closely related to Tau and Aβ pathology in AD. In addition, the ImmuneScore increased gradually with the increase of Braak stages. Five types of immune cells (plasma cells, T follicular helper cells, M2 macrophage, activated NK cells, and eosinophils) were correlated with Braak stages. KRAS and PIK3R1 were the immune core genes most related to the abnormal infiltration of peripheral immune cells. They participated in the regulation of the pathological process of AD through axon guidance, long-term potentiation, cytokine–cytokine receptor interaction, RNA polymerase, etc.ConclusionThe KRAS and PIK3R1 genes were identified as the immune hub genes most associated with Tau pathological progress in AD. The abnormal infiltration of peripheral immune cells mediated by these cells was involved in the Tau pathological process. This provides new insights for AD.

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