Work

Altered gene expression in excitatory neurons is associated with Alzheimer's disease and its higher incidence in women

Year: 2023

Type: article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative disorder involving interactions between different cell types in the brain. Previous single-cell and bulk expression Alzheimer’s studies have reported conflicting findings about the key cell types and cellular pathways whose expression is primarily altered in this disease. We reanalyze these data in a uniform, coherent manner aiming to resolve and extend past findings. We further examine if this reanalysis may shed light on the observation that females have substantially higher AD incidence than males.Methods: We reanalyzed three published single-cell transcriptomics datasets including redoing some of their preprocessing. We used the software method MAST within the Seurat package to look for differentially expressed genes comparing AD cases to matched controls for both sexes together and for each sex separately. We used the GOrilla software to search for enriched pathways and other gene sets among the differentially expressed genes. Motivated by the male/female difference in incidence, we studied genes on the X-chromosome, focusing on genes in the pseudoautosomal region and on genes that are heterogeneous across either individuals or tissues for X-inactivation. We additionally obtained bulk AD datasets from the cortex from the Gene Expression Omnibus and used voom-limma for differential expression analysis.Results: Our results resolve the apparent contradiction in the literature, showing that comparing AD patients to unaffected controls, excitatory neurons have more differentially expressed genes than do astrocytes and other cell types. Altered pathways between males and females in excitatory neurons involve synaptic transmission and related pathways. Further analysis suggests that numerous pseudoautosomal region (PAR) genes and X-chromosome heterogeneous genes, including such as BEX1 and ELK1, may contribute to the difference in sex incidence of Alzheimer’s disease. Among autosomal genes, GRIN1, stood out as an overexpressed gene in cases vs. controls in all three single-cell data sets and as a functional candidate gene contributing to several important pathways upregulated in cases.Conclusions: Taken together, these results point to a potential linkage between two longstanding questions concerning AD pathogenesis, involving which cell type is the most important and why females have higher incidence than males.

Source: Alzheimer s & Dementia Translational Research & Clinical Interventions

DOI: 10.1002/trc2.12373

Authors: A. Xavier Garcia, Jielin Xu, Feixiong Cheng, Eytan Ruppin, Alejandro A. Schäffer