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

Introduction: Synaptic 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.

Methods: Here 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 discussion: We 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.