Abstract
INTRODUCTION
Progressive supranuclear palsy (PSP) is a devastating 4R tauopathy affecting motor functions and is often misdiagnosed/underdiagnosed due to a lack of specific biomarkers. Synaptic loss is an eminent feature of tauopathies including PSP. Novel synaptic positron emission tomography tracer UCB-J holds great potential for early diagnosis; however, there is a substantial knowledge gap in terms of the mechanism and the extent and nature of synaptic loss in PSP.
METHODS
Here, we report an in-depth post mortem validation and mechanistic study of UCB-J in PSP and control brains using radioligand/autoradiography binding studies, alongside biochemical correlation analyses of synaptic markers.
RESULTS AND DISCUSSION
3H-UCB-J targeted synaptic vesicle protein 2A protein with high specificity and demonstrated a distinct interrelation with synaptic markers in PSP patients’ brain regions. The loss of UCB-J binding in the early and severely affected globus pallidus of PSP patients’ brains revealed deficits of glutamate/GABAergic synaptic terminals. Cortical and subcortical 4R tau load differentially impacted synaptic marker profiles across PSP patients, warranting further investigation.
Highlights
UCB-J targeted synaptic vesicle protein 2A with high specificity in progressive supranuclear palsy (PSP) brains and demonstrated a conserved single nM binding site across different brain regions.
UCB-J depicted prominent synaptic loss at the synaptosome levels and revealed deficits of glutamate/GABAergic synaptic terminals in the early affected globus pallidus of PSP brains as compared to the control.
Cortical and subcortical 4R tau load distinctly influenced synaptic markers profile across PSP patients and highlighted that presynaptic “ubiquitous” markers individually might not be able to represent the complete state of synaptic deficits/loss in PSP brains.
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This post is Copyright: Miriam Scarpa,
Elisavet Vallera,
Sira Ausellé‐Bosch,
Filipa M. Rocha,
Buse Esra Mercan,
Avishek Roy,
Agneta Nordberg,
Amit Kumar | December 13, 2024