Investigation of the temporal development of Tau pathology in TAU58/2 transgenic mice

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which is a major public health burden in the world. Despite recent progress has been made in understanding the pathology of AD, the exact causes of AD are still unclear. Two of the hallmark pathologies of AD are the formation of β-amyloid plaques and neurofibrillary tangles (NFTs). NFTs are composed of hyperphosphorylated Tau protein which aggregates and forms insoluble Tau. Several transgenic mouse models for AD have been developed to identify the underlying molecular mechanisms by demonstrating tauopathy such as TAU58/2, a P301S mutant Tau transgenic mouse line. Current study has investigated the expression profile of Tau regarding different phosphorylation sites, and isoforms in TAU58/2 mouse model in hippocampus during different stages of disease progression by Western blot, and in comparison with their wild type littermates. Also, abnormal Tau distribution, morphology, and its correlation with neuronal loss as well as neuroinflammation in TAU58/2 mouse model has been studied by immunohistochemistry. Data provided by this MRes project will define the time points for future experiments that will seek to downregulate these proteins. Tau phosphorylation at Ser202/Thr205 and Thr231 sites as well as total Tau levels were increased in hippocampus both in three and twelve months old, whereas insoluble Tau formation only occurred in 12 months and at Ser202/Thr205 phosphorylation site. Results obtained from Western blot were confirmed by IHC; in addition, it uncovered the distribution and morphology of Phospho-Tau, as well as Astrogliosis. These results provide important insights into Tauopathy in TAU58/2 mouse model at two timepoints. Given the fact that reported changes begin as soon as 3 months of age, additional studies to assess neuronal loss and neuroinflammation are needed to gain a comprehensive understanding of the best timepoint to apply nanoparticle-based therapies in the future.