Integrated multi-omics analyses of synaptosomes revealed synapse-associated novel targets in Alzheimer's disease

Abstract

Synapse dysfunction is an early event in Alzheimer's disease (AD) caused by various factors, including amyloid beta, p-tau, inflammation, and aging. However, the precise molecular mechanism underlying synapse dysfunction in AD remains largely unknown. To understand this, we comprehensively analyzed the synaptosomes fraction in post-mortem brain samples from AD patients and cognitively normal individuals. We conducted high-throughput transcriptomic analyses to identify changes in microRNA (miRNA) and mRNA levels in synaptosomes extracted from the brains of unaffected individuals and those with AD. Additionally, we performed mass spectrometry analysis of synaptosomal proteins in the same sample group. These analyses revealed significant differences in the levels of miRNAs, mRNAs, and proteins between the two groups. To gain further insights into the pathways or molecules involved, we employed an integrated omics approach to study the molecular interactions of deregulated synapse miRNAs, mRNAs, and proteins in samples from individuals with AD and the control group, demonstrating the impact of deregulated miRNAs on their target mRNAs and proteins. Furthermore, the DIABLO analysis revealed complex relationships among mRNAs, miRNAs, and proteins that could be key in understanding the pathophysiology of AD. Our study identified novel synapse-associated candidates that could be critical in restoring synapse dysfunction in AD.