Knock-out and transgenic mouse models of tauopathies

Abstract

Tauopathies, characterized by the dysfunction and aggregation of the microtubule-associated protein tau (MAPT), represent some of the most devastating neurodegenerative disorders afflicting the elderly, including Alzheimer's disease and progressive supranuclear palsy. Here we review the range of Mapt knock-out and MAPT transgenic mouse models which have proven successful at providing insights into the molecular mechanisms of neurodegenerative disease. In this overview we highlight several themes, including the insights such models provide into the cellular and molecular mechanisms of tauopathy, the direct relationship between neuropathology and behaviour, and the use of mouse models to help provide a platform for testing novel therapies. Mouse models have helped clarify the relationship between pathological forms of tau, cell death, and the emergence of disease, as well as the interaction between tau and other disease-associated molecules, such as the A beta peptide. Finally, we discuss potential future MAPT genomic DNA models to investigate the importance of alternative splicing of the MAPT locus and its role in sporadic tauopathies.

Fig. 1

Schematic representation of the six tau isoforms in the human CNS. Alternative splicing of exons 2 and 3 (e2 and e3, in dark and light grey) yields isoforms with two, one or no 29-amino acid inserts in the amino-terminal region of the protein (2N–0N). Alternative splicing of exon 10, which codes for the second microtubule-binding repeat (r2, with black rim) in the carboxyl-terminal part of the protein, yields isoforms with three or four microtubule-binding repeats (3R vs. 4R tau).

Fig. 2

FTDP-17 mutations and their location along human MAPT. Only the exons in which mutations have been reported are shown. Point mutations are indicated by the identity and site of the amino acid change. Splice site mutations in intron 10 are indicated by their position counting away from exon 10.