P4‐342: Intracerebral injection of tau aggregates initiates widespread tauopathy in the transgenic mouse brain

An important hallmark of Alzheimer's disease (AD) is the accumulation of hyperphosphorylated tau in neurofibrillary tangles (NFTs). Since there is a clear correlation of NFT density with cognitive decline, misfolded tau is likely a key pathological agent in AD. The events leading to tau aggregate formation are not completely understood and were long thought to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. Recent studies have shown, however, that prion-like spreading mechanisms might be important in the propagation of tau pathology. In vitro studies indicated that extracellular tau aggregates can act as a seed to induce aggregation of intracellular tau. Furthermore an in vivo study by Clavaguera et al. showed tau aggregation and spreading of pathology in transgenic wild-type tau-expressing animals 15 months after injection of brain extracts from mice with filamentous tau pathology. The goal of our study was to make an accelerated, robust in vivo tau aggregation mouse model which can be used to investigate the molecular mechanism of spreading and to validate new therapeutic strategies for AD. In this study in vitro aggregated K18P301L fragments were unilaterally injected in the hippocampus or frontal cortex of P301L tau transgenic mice six months before they develop intrinsic tau pathology. Left and right hemispheres were dissected at different time points after seed injection. Phosphorylation and aggregation of transgenic tau was analyzed by immunohistochemisty and biochemical assays. Already one month after injection of in vitro aggregated tau fragments clear hyperphosphorylation and aggregation of transgenic tau was observed at the injection site, but also at more distant brain areas. These results indicate that injection of in vitro aggregated tau fragments is able to induce misfolding of transgenic tau in distinct brain areas of the recipient mouse, which suggests spreading and points to a prion-like mechanism. However, diffusion of the injected material cannot be ruled out and the apparent propagation of misfolded tau should be further investigated. Because of the fast induction and widespread appearance of tau pathology, this mouse model also offers a good in vivo model to investigate new therapeutic strategies based on interfering with non-cell autonomous effects. References: 1. Guo JL and Lee VM. Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Bio Chem 286: 15317–15331 (2011) 2. Clavaguera F et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Bio 11, 909–914 (2009) 3. Liu L et al. Trans-synaptic spread of tau pathology in vivo. Plos One 7: e31302 (2012).