HAI Book 2025 - Flipbook - Page 447
Lemoine, Laetitia
Understanding the mechanisms of synaptic vesicle glycoprotein 2A change
in Alzheimer's disease
Declan King1, David Bonsall2, Scott Gladstein3, Laetitia Lemoine2, Amanda Bevis4, Sjoerd J
Finnema3, Tara L Spires-Jones1, FNIH SV2A Project Team4
1
University of Edinburgh, Edinburgh, GB
Perceptive, London, GB
3
AbbVie, Chicago, IL, US
4
Foundation for the National Institutes of Health, Rockville, MD, US
2
Background & Methods: Synaptic vesicle glycoprotein 2A (SV2A) levels are decreased in Alzheimer's disease (AD)
brains, as revealed by Positron Emission Tomography (PET). Whether this decrease is due to synapse loss or SV2A
protein loss remains unclear, hindering treatment development and interpretation of SV2A PET as a biomarker for
neurodegenerative diseases. Radioligand binding, array tomography, and electron microscopy were each applied
to post-mortem entorhinal cortex (EC) and cerebellum from control (BS 0-II; n=23), early-AD (BS III-VI; n=21) and
AD (BS V-VI; n=25) cases to understand how changes in binding signal may relate to structural changes and PET
signal.
Results: All samples showed similar binding affinity using [3H]SynVesT-1 (KD range 3-7 nM). In the EC
synaptoneurosomes, the E-AD group showed a higher BMAX compared to the other groups (5380 ± 319 fmol/mg
protein). Array tomography of a sub-population of AD vs Control cases showed SV2A puncta density strongly
correlated with synaptophysin puncta density in both brain regions (p
