‘Prion-Like’ Propagation of Mouse and Human Tau Aggregates in an Inducible Mouse Model of Tauopathy

Abstract

Background: Aggregates of the tau protein are a hallmark of Alzheimer’s and several other neurodegenerative diseases. Various transgenic mouse models have been generated to study the aggregation process. Since wild-type tau is highly soluble and does not aggregate readily, most models make use of tau mutations that occur in human frontotemporal dementias and are more prone to aggregate. These mouse models show neurofibrillary tangles similar to those of Alzheimer’s disease. However, since the mice contain both endogenous wild-type mouse tau and exogenous human mutant tau, the relative contribution of these components to the aggregates has been a matter of debate. Objective:Using a new set of regulatable transgenic mouse models, we sought to determine whether mouse tau coaggregates with human tau when it is switched on. Furthermore, we asked what type of tau remains in the aggregates after switching off the expression of exogenous tau. Methods: We generated doxycycline-inducible transgenic mice expressing either full-length human tau or the tau repeat domain (tau_RD). In addition, both types of human tau derivatives were expressed in a ‘proaggregant’ form (with the frontotemporal dementia with parkinsonism linked to chromosome 17 mutation ΔK280), or in an ‘antiaggregant’ form (with additional proline mutations to block β-structure and aggregation). Results:The proaggregant tau_RD mice develop tangles rapidly after induction, the antiaggregant mice do not. Analysis by biochemistry and immunohistology reveals that the tangles contain both exogenous and endogenous mouse tau. After switching off the proaggregant tau_RD, tangles persist for extended periods. However, they are composed entirely of mouse tau. Conclusions:Mouse tau and exogenous human tau can coaggregate in transgenic models of tauopathy. The aggregates are in dynamic equilibrium with their subunits, so that exogenous tau disappears when its expression is switched off. Once the seeds of aggregation are generated by the foreign tau species, they propagate in a ‘prion-like’ fashion within the cell even after the foreign tau has disappeared.