Therapeutic and immunomodulatory functions of the translocator protein in Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is an age-associated neurodegenerative disease with no effective treatments. The translocator protein (TSPO) has been identified as a promising therapeutic target in AD, as TSPO ligands reduce the accumulation of beta-amyloid. However, the role of TSPO in other aspects of AD pathology, such as tauopathy, neuroinflammation, and mitochondrial dysfunction has not been explored. In this study, we report that treatment with TSPO ligands attenuates brain atrophy and neuroinflammation, but does not effect phosphorylated tau in the rTg4510 mouse model of tauopathy. Using the APP-KI nl-g-f mouse model with TSPO-KO, we show that TSPO-KO increases amyloid load, reduces phagocytic microglia, and protective microglial subpopulations. Lastly, treatment with TSPO ligands attenuates mitophagy impairments and modulates mitochondrial dynamics in neuroblastoma cells expressing mutant tau and APP. Taken together, these findings suggest that TSPO plays a neuroprotective role in AD pathology and highlights its therapeutic potential as a drug target for AD.