Synaptosome microRNAs regulate synapse functions in Alzheimer's disease

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• MicroRNAs (miRNAs) are present in nerve terminals, but their specific roles in Alzheimer's disease (AD) synapses remain unclear.
• Investigating differences between synaptic and cytosolic miRNA populations in AD is crucial for understanding disease mechanisms.

Purpose of the Study:

• To determine if synaptic and cytosolic miRNA populations differ in Alzheimer's disease (AD).
• To investigate the impact of synaptosomal miRNAs on AD synapse activity.
• To identify specific miRNAs associated with AD progression and synapse function.

Main Methods:

• Analysis of synaptosomes and cytosolic fractions from postmortem brains of AD and unaffected control (UC) samples using miRNA microarrays.
• Validation of differentially expressed miRNAs in AD postmortem brains and transgenic mouse models (APP Tg2576, P301L Tau).
• Gene Ontology and Ingenuity Pathway Analysis to determine the functional roles of identified miRNAs.

Main Results:

• Significant differences in miRNA expression were observed between synaptosome and cytosol fractions, and between AD and UC samples.
• Specific miRNAs, including miR-501-3p, miR-502-3p, and miR-877-5p, were upregulated in synaptosomes with AD progression (Braak stages).
• Enrichment analysis indicated involvement of these miRNAs in nervous system development, synapse organization, and GABAergic synapse function.

Conclusions:

• This study provides the first description of distinct synaptic versus cytosolic miRNA populations in AD.
• Identified synaptosomal miRNAs are significantly altered in AD and associated with disease progression and synapse function.
• These findings highlight the potential of synaptosomal miRNAs as biomarkers and therapeutic targets for Alzheimer's disease.