ANTI-INFLAMMATORY EFFECT OF TSPO LIGAND IN MOUSE MODEL OF TAUOPATHY

Abstract

The mitochondrial translocator protein (TSPO) is a sensitive marker of neuroinflammation, becoming markedly upregulated in activated astrocytes and microglia surrounding pathological lesions in the Alzheimer‘s brain. TSPO has also been identified as a potential therapeutic target, with pleiotropic anti-inflammatory and neuroprotective benefits of TSPO ligands described in multiple models of injury and neurodegenerative disease. Recently, we have demonstrated that the well characterized TSPO ligand, Ro5–4864, reduces beta amyloid accumulation and inflammation in a transgenic mouse model of beta-amyloidosis. Here, we evaluate the potential therapeutic effects of Ro5–4864 in a transgenic mouse model of tauopathy. The effects of the TSPO ligand, Ro5–4864, were examined on AD-related neuropathy and behavioral impairment in the rTg4510 transgenic model of tauopathy (tauTg). Inflammation and tau pathogenesis were assessed in vivo by [18F]FEBMP-PET for TSPO and [11C]PBB-3-PET for tau deposits respectively, and neuronal loss was measured in living mice by volumetric MRI. In vivo findings were confirmed by immunohistochemistry of brain sections from scanned mice. Learning and memory performance was assessed in the Y-maze and anxiety-related behavior was assessed in the elevated plus maze. Ro5–4864 improved functional outcomes and attenuated markers of inflammation in TauTg mice, in the absence of any benefit on tau pathogenesis or neuronal loss. These findings suggest that TSPO is a promising target for the development of immunomodulatory strategies for the management of AD.