Gene biomarkers related to the assembly of SNARE complexes in Alzheimer’s disease: A retrospective observational study on synergistic effects and diagnostic model construction

Studies have suggested that synaptosome associated protein 25 (SNAP25) is abundantly expressed in the brain and contains two SNARE motifs, making the investigation of its role in Alzheimer’s disease particularly intriguing. This study aimed to investigate the changes of SNAP25 and STXBP1, two genes related to the assembly of SNARE complexes, in Alzheimer’s disease and their relationship with disease severity. Two human brain transcriptomic datasets, GSE5281 and GSE1297, were retrieved from the Gene Expression Omnibus database. After logarithmic transformation and Z-score normalization, a total of 161 normal and 111 Alzheimer’s disease case samples were included. Core synaptic-related genes were identified through literature review and protein-protein interaction network analysis, and a diagnostic model for Alzheimer’s disease was constructed. The gene expression of SNAP25 and STXBP1 was associated with Mini-Mental State Examination scores and neurofibrillary tangle (NFT) counts . Both SNAP25 and STXBP1 were involved in neurotransmitter transmission through the synaptic vesicle cycle mediated by the SNARE complex. The study revealed several key findings: SNAP25 and STXBP1 ranked highly in feature importance in the random forest classification predictions. Lower expression levels of SNAP25 and STXBP1 were associated with lower Mini-Mental State Examination scores, higher NFT counts, and increased severity of dementia. The correlation between SNAP25 and STXBP1 increased during the progression of the disease, showing a positive association with clinical Mini-Mental State Examination scores and NFT counts, suggesting that a stronger correlation indicates more severe dementia. Specifically, when the expression levels of both SNAP25 and STXBP1 were low, their correlation coefficient increased, leading to a higher likelihood of Alzheimer’s disease in patients, implying a synergistic relationship between SNAP25 and STXBP1. Based on these findings, we propose the following hypothesis: Downregulation of SNAP25 expression reduces the assembly efficiency of the SNARE complex, thereby leading to a decrease in STXBP1 expression levels. Furthermore, the aberrant expression of STXBP1 may trigger disordered assembly of the SNARE complex, thereby impairing neurotransmitter transmission, further causing communication deficits between neurons and a decline in synaptic function, ultimately contributing to the progression of Alzheimer’s disease. The dysregulated synergy between SNAP25 and STXBP1 leads to disordered assembly of the SNARE complex and reduces synaptic vesicle cycling efficiency, thereby impacting the progression of Alzheimer’s disease.