Tracing synaptic loss in Alzheimer's brain with SV2A PET‐tracer UCB‐J

Abstract

AbstractINTRODUCTIONSynaptic loss is an early prominent feature of Alzheimer's disease (AD). The recently developed novel synaptic vesicle 2A protein (SV2A) PET‐tracer UCB‐J has shown great promise in tracking synaptic loss in AD. However, there have been discrepancies between the findings and a lack of mechanistic insight.METHODSHere we report the first extensive pre‐clinical validation studies for UCB‐J in control (CN; n = 11) and AD (n = 11) brains using a multidimensional approach of post‐mortem brain imaging techniques, radioligand binding, and biochemical studies.RESULTS AND DISCUSSIONWe demonstrate that UCB‐J could target SV2A protein with high specificity and depict synaptic loss at synaptosome levels in AD brain regions compared to CNs. UCB‐J showed highest synaptic loss in AD hippocampus followed in descending order by frontal cortex, temporal cortex, parietal cortex, and cerebellum. 3H‐UCB‐J large brain‐section autoradiography and cellular/subcellular fractions binding studies indicated potential off‐target interaction with phosphorylated tau (p‐tau) species in AD brains, which could have subsequent clinical implications for imaging studies.Highlights Synaptic positron emission tomography (PET)–tracer UCB‐J could target synaptic vesicle 2A protein (SV2A) with high specificity in Alzheimer's disease (AD) and control brains. Synaptic PET‐tracer UCB‐J could depict synaptic loss at synaptosome levels in AD brain regions compared to control. Potential off‐target interaction of UCB‐J with phosphorylated tau (p‐tau) species at cellular/subcellular levels could have subsequent clinical implications for imaging studies, warranting further investigations.