Reduced levels of synaptic vesicle protein 2A in the extracellular vesicles and brain of Alzheimer′s disease- associations with Aβ, tau and synaptophysin

Background: Synaptic dysfunction plays an important role in Alzheimer′s disease (AD) and is an emerging imaging and fluid biomarker. Here, we aimed to assess the regional expression of synaptic vesicle glycoprotein 2A (SV2A) in the brain and extracellular vesicles of AD patients and its associations with the APOE e4 allele, amyloid-&#61538, tau pathologies, and other synaptic markers. Methods: Mass spectrometry-based synaptosome proteomics was performed on brain-derived extracellular vesicles (BdEVs) isolated from the frontal cortex of 17 AD patients and 4 NCs. Immunohistochemical staining for SV2A, synaptophysin, amyloid-β and phospho-tau was performed on postmortem tissue from the frontal, temporal, and entorhinal cortices and hippocampus of 40 AD patients and 44 nondemented controls (NCs). Results: Reduced levels of synaptic proteins, including synaptotagamin, GAP43, SYT1, SNAP25 and 14-3-3zeta, were positively correlated with SV2A and negatively correlated with GFAP and NEFL in BdEVs from AD patients and NCs. We detected lower levels of SV2A in the hippocampus and entorhinal cortex of AD compard to NCs, and in APOE e4 carriers than in noncarriers. SV2A levels were positively correlated with synaptophysin and negatively correlated with the levels of the amyloid-β, phospho-tau, and Braak stages. Conclusions: This study provides postmortem evidence of synaptic markers and reduced regional levels of SV2A in brain tissue slices and BdEVs from AD patients compared with NCs and in APOE e4 carriers compared to non-carriers. SV2A could serve as a valuable marker for monitoring synaptic degeneration in AD.