Studying tau protein propagation and pathology in the mouse brain using adeno-associated viruses

The progressive spread of pathological brain lesions containing aggregated tau protein is a hallmark of Alzheimer's disease and other neurodegenerative diseases. In AD, this process follows a distinct pattern along neuronal connections from the entorhinal cortex to hippocampal areas and further on through the limbic system. In other tauopathies, the spread of tau appears less hierarchical throughout the brain, and also nonpathological tau is reported to cross-synaptic connections in the brain. To be able to study the process of cell-to-cell transport of tau and the associated neurotoxicity in the brain in vivo, adeno-associated virus-mediated expression of tau can be used to express different forms of tau in distinct brain areas in rodent models. As an example, we describe how the expression of FTD-mutant human tauP301L in the entorhinal cortex of wild-type mice can be used to study the propagation of tau to connected neurons and to determine pathological consequences such as tau hyperphosphorylation, misfolding, and gliosis. The approach described can easily be translated to study other aggregating and/or propagating proteins in the brain such as synuclein, Abeta, or SOD1.