Efficacy of RAA7 treatment in TG4510 mouse model of Alzheimer's disease

Abstract

AbstractBackgroundTauopathies are neurodegenerative characterized by the accumulation of abnormal phosphorylated and aggregated forms of Tau protein in the brain. rTg4510 (MAPT*P301L) mouse model is a widely used tauopathy model for studying therapeutic intervention that target neurodegeneration and tau pathology.MethodIn this study rTg4510 mice (n=13‐15/group) were treated with RAA7 (10 mg/kg and 50 mg/kg) or vehicle (PBS). At 7 months of age tau pathology and neurodegeneration was characterized using cresyl fast violet staining (CFV) and NeuN for neurodegeneration, total human Tau (HT7) and phosphorylated human Tau (AT8). Sections were analyzed as % of area of positive signal. Four regions of interest were examined: cortex, CA1 and dentate gyrus regions and whole hippocampus.ResultOur results showed that RAA7 treatment diminish neurodegeneration and affect tau pathology. In CFV and NeuN staining, RAA7 10 mg/kg increased % of stained area in all analyzed brain regions, whereas RAA7 50 mg/kg in the CA1 region when compared to PBS group. In addition, high dose treatment showed neuroprotective effect in the DG regions of hippocampus as well. NeuN/CFV ratio was decreased by RAA7 10 mg/kg treatment in all analyzed areas. Assessment of tau expression revealed that RAA7 10 mg/kg decreased level of total Tau in CA1 region and phosphorylated Tau in cortex when compared to PBS group. Unexpectedly, RAA7 50 mg/kg showed significantly higher total tau level in the whole hippocampus when compared to PBS group, and no effect on the tau phosphorylation level.ConclusionIn conclusion, RAA7 treatment showed neuroprotective in Tg4510 mice demonstrated by reduced Tau accumulation and phosphorylation driven inhibition of neuronal cell death.