SYNAPTIC MIRNA DYSREGULATION IN ALZHEIMER’S DISEASE HUMAN TISSUE

Synapse loss occurs early in Alzheimer’s disease (AD) and correlates with cognitive decline. miRNAs are emerging as mediators of synaptic plasticity and may also play a role in AD pathogenesis. The aim of this study was to compare miRNA expression at AD synapses with non-pathological controls in post-mortem brain tissue and explore AD-associated changes across brain regions and compare to primary tauopathies.
Neuropathological classifications were made according to consensus criteria. We isolated synaptosomes from frozen tissue and extracted total RNA. We quantified miRNAs using the TaqMan Advanced Openarray (discovery phase) and by qPCR (validation phase). We used linear regression to identify differentially expressed miRNA, controlling the false discovery rate (FDR<0.05) and performed GO Cellular Component enrichment analysis.
Discovery: we compared the expression of 751 miRNA between 10 AD cases and 10 controls. miR-132-3p, miR-132-5p and miR-212-3p were under-expressed in temporal cortex in AD compared to controls. Validation: we confirmed the changes in the temporal cortex. Additionally, miR-132-3p and miR-212-3p were under-expressed in AD compared to controls in the prefrontal but not cingulate cortex. The same miRNAs were unaltered in 10 cases with tauopathy compared to controls. Predicted targets of miR-132-3p and miR-212-3p were enriched for proteins associated with the Schaffer collateral-CA1 synapse (CACNG2, DCC, FBXL20, KCNK2, NTNG1, SYN2), which is critical for excitatory pathways in the hippocampus.
These data support previous studies reporting a role of miR-132-3p and miR-212-3p in AD-related synapse dysfunction. Their predicted targets could be novel therapeutic targets to relieve synapse vulnerability to AD pathology.