A study to determine the mechanisms underlying changes in synaptic vesicle glycoprotein 2A density in Alzheimer’s disease

Abstract

AbstractBackgroundSynaptic vesicle glycoprotein 2A (SV2A) is a transmembrane synaptic vesicle protein that regulates vesicle exocytosis and neurotransmitter release. Positron emission tomography (PET) studies reveal that the levels of SV2A are decreased in the brains of patients with Alzheimer’s disease (AD) and other brain disorders. Whether changes in SV2A PET signal are caused by a loss of synapses or a loss of SV2A protein is unclear and an impediment to developing novel treatments for neurodegenerative diseases. The goal of this study is to determine the biological underpinnings of reduced SV2A signal in individuals with AD.MethodWe examined post‐mortem brain samples from the entorhinal cortex (EC) and cerebellum (CBM) in AD patients and age‐ and sex‐matched controls without neurological conditions (EC n = 19 AD, 15 controls; CBM n = 11 AD, 12 controls). We explored differences in synaptic density and synaptic ultrastructure using array tomography and electron microscopy, and analyzed data using linear mixed‐effects models (with post‐hoc Tukey comparisons) and Spearman correlations.ResultSV2A puncta density measured with array tomography in both brain regions strongly correlates with synaptophysin puncta density, the gold standard marker for synapse density in post‐mortem brain tissue (ñ = 0.87 EC, ñ = 0.72 CBM, p<0.001 both regions). We observed lower SV2A puncta density in AD cases compared to controls in EC (p = 0.001), slightly higher SV2A puncta density in AD in CBM (p = 0.02), and no difference in the proportion of synaptophysin puncta labelled with SV2A in AD vs control (p = 0.37). Electron microscopy revealed immunogold labelled SV2A protein localized specifically to presynaptic vesicles and no difference in the number of immuno‐gold labelled SV2A particles per synapse.ConclusionOur data indicate that the loss of SV2A PET signal reported in vivo in patients with AD is likely caused by a loss of synapses and not the loss of SV2A protein within remaining synapses. These findings indicate that changes in SV2A PET signal are due to synaptic loss and that strategies for reversing synaptic loss or associated neuropathophysiological effects may be important to the treatment of AD and other synaptopathies. This work is part of the SV2A PET Project, a program of the FNIH Biomarker Consortium.