The β-Propensity of Tau Determines Aggregation and Synaptic Loss in Inducible Mouse Models of Tauopathy
Katrin Eckermann, Maria-Magdalena Mocanu, Inna Khlistunova, Jacek Biernat, Astrid Nissen, Anne Hofmann, Kai Schönig, Hermann Bujard, Andreas Haemisch, Eckhard Mandelkow, Lepu Zhou, Gabriele Rune
Journal of Biological Chemistry
Neurofibrillary lesions are characteristic for a group of human diseases, named tauopathies, which are characterized by prominent intracellular accumulations of abnormal filaments formed by the microtubule-associated protein Tau. The tauopathies are accompanied by abnormal changes in Tau protein, including pathological conformation, somatodendritic mislocalization, hyperphosphorylation, and aggregation, whose interdependence is not well understood. To address these issues we have created
... nic mouse lines in which different variants of full-length Tau are expressed in a regulatable fashion, allowing one to switch the expression on and off at defined time points. The Tau variants differ by small mutations in the hexapeptide motifs that control the ability of Tau to adopt a ␤-structure conformation and hence to aggregate. The "pro-aggregation" mutant ⌬K280, derived from one of the mutations observed in frontotemporal dementias, aggregates avidly in vitro, whereas the "anti-aggregation" mutant ⌬K280/PP cannot aggregate because of two ␤-breaking prolines. In the transgenic mice, the pro-aggregation Tau induces a pathological conformation and pre-tangle aggregation, even at low expression levels, the antiaggregation mutant does not. This illustrates that abnormal aggregation is primarily controlled by the molecular structure of Tau in vitro and in the organism. Both variants of Tau become mislocalized and hyperphosphorylated independently of aggregation, suggesting that localization and phosphorylation are mainly a consequence of increased concentration. These pathological changes are reversible when the expression of Tau is switched off. The pro-aggregation Tau causes a strong reduction in spine synapses. . 2 The abbreviations used are: MT, microtubule; AD, Alzheimer disease; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; PHF, paired helical filament; MES, 4-morpholineethanesulfonic acid; PIPES, 1,4-piperazinediethanesulfonic acid; tTA, tetracycline transactivator; Ca/CMKII␣, calcium/calmodulin kinase II␣.