Endothelial cell 18kDa Translocator Protein (TSPO) as a target to improve vascular function in Alzheimer’s Disease (AD)

Alzheimer’s Disease (AD) is associated with classical vascular risk factors. In AD, reductions in cerebral vasomotor reactivity and cerebral blood flow precede symptoms by years and predict speed of cognitive decline. Neuropathological and clinical imaging studies in AD show evidence of blood brain barrier (BBB) leak. Brain endothelial cells (BECs) are enriched for AD genetic risk variants and the BEC transcriptome from AD brains shows evidence of dysregulated vascular function. I have shown that knockdown or pharmacological inhibition of TSPO protects against hypoxic, inflammatory and beta amyloid induced injury to endothelial cells (EC) in vitro and in vivo. These data suggest a novel mechanism of action mediated by a TSPO/COQ2 interaction which reduces endothelial oxidative stress and restores EC function. Here, I will test the hypothesis that the TSPO ligand XBD173 improves BBB leak in an experimental medicine study of people with AD. Rodent experiments will test whether the protective effect of TSPO ligands in AD-relevant rodent models is dependent on EC TSPO, and in vitro experiments will test the mechanistic involvement of COQ2. Positive results will provide a strong case for a Phase II study testing whether XBD173 slows cognitive decline in AD.