Reduced expression of Brain Expressed X-linked genes in Alzheimer's disease

Background Altered expression of Brain Expressed X-linked (BEX) genes has been implicated in Alzheimer's disease (AD) with inconsistencies and a lack of experimental confirmation. Objective This study aims to characterize BEX expression patterns, examine the association of their expression with AD pathology, and investigate cellular changes induced by altered BEX expression. Methods We integrated bulk and single-cell transcriptomics datasets to characterize cortical BEX expression changes in 5xFAD mice and AD patients, which were validated by RT-qPCR in postmortem AD cortical tissue. We manipulated the expression of BEX genes in SH-SY5Y cells and examined changes in oxidative stress. Results Cortical expression of BEX genes was reduced in AD. With the dysregulation being more pronounced at a later stage of the disease, the reduction was closely related to the impairment of synaptic transmission and oxidative phosphorylation in excitatory neurons. Consistent with these, BEX3 knockdown increased oxidative stress. Conclusions Our findings suggest that reduced BEX expression in neurons appears to be a contributing factor to AD pathogenesis and BEX depletion may increase oxidative stress.