Critical Role of Downregulated Synaptic Vesicle Cycles in the Pathogenesis of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive loss of memory, functionality, and cognitive abilities, globally affecting 38.5 million every year. Despite its widespread prevalence, there are no cures for AD, only treatments that slow its progression. A deeper understanding of the molecular mechanisms driving this disease is critical to identify potential therapeutic targets. This study investigates differential gene expression in AD to unravel significantly dysregulated pathways associated with the pathology of this disease. High throughput Illumina® microarray analyses of the middle temporal gyrus biopsies of 97 AD patients and 98 non-disease controls were obtained from Gene Expression Omnibus (GEO) dataset GSE132903. Differential gene expression was analyzed using GEO2R, followed by pathway enrichment analysis of the top 250 significantly dysregulated genes through String-db. Using the Kyoto Encyclopedia of Genes and Genomes (KEGG), we examined the synaptic vesicle cycle (hsa04721) pathway. RStudio was used for statistical analysis and heatmap visualizations. Differential RNA analysis revealed statistically significant downregulation of the synaptic vesicle cycle (SVC) in AD samples. The SVC is essential for neuronal communication, and regulates neurotransmitter release through calcium-dependent vesicle fusion. SYT1 is a crucial calcium-binding gene in synaptic vesicle fusion, and was found to be the second most significantly dysregulated gene in the dataset. Disruption of the SVC may impair neurotransmitter release, contributing to ß-amyloid (Aß) accumulation, calcium imbalance, synaptic dysfunction, and neuronal toxicity. Each of the above imbalances are associated with impaired cognitive and motor function observed in AD patients. This study demonstrates that downregulation of the SVC may contribute significantly to AD pathology, potentially supporting the development of treatments that slow disease progression.