Tau and Alzheimer's disease: From structure to transgenic mice and aggregation inhibitors

Abstract

Tau pathology is a hallmark of AD, PD, and other tauopathies (FTDP17). Tau protein is changed in several ways (e.g. phosphorylation, missorting, aggregation), but the causes of neuronal degeneration are still uncertain. Several pathways of Tau-induced toxicity have been proposed: (1) Detachment of Tau from microtubules (by phosphorylation) with subsequent breakdown of microtubules, the tracks of axonal transport. (2) Aggregation of Tau into paired helical filaments. (3) Clustering of Tau on microtubules and inhibition of axonal transport, (4) Cleavage of Tau into toxic fragments. (5) Toxic functions of modified Tau. (6) Over- or understabilization of microtubules due to changes in alternative splicing or phosphorylation. We generated several inducible cell models and transgenic mouse models to distinguish between different effects of Tau and pathways of toxicity and to observe the response to switching Tau expression on and off again. Some cell models display traffic deficits upon expression of Tau, due to reduced activity of motor proteins moving along microtubules. Other cell models show that toxicity of Tau is induced by enhancing the beta-propensity of Tau (e.g. certain FTDP17 mutations), which in turn leads to proteolysis and aggregation, whereas “anti-aggregation” Tau variants are not toxic. The aggregation of Tau is reversible by inhibitor compounds or by switching off Tau expression. Analogous observations are made with inducible transgenic mice, where Tau variants with high beta-propensity lead to Tau aggregation, toxicity, and decay of neurons. The exogenous Tau species can even “poison” endogenous mouse Tau and lead to co-aggregation of both species. Here, too, the aggregation, toxicity, and even behavioral deficits are reversible after switching off the expression of exogenous Tau. The results show that the formation of Tau aggregates is remarkably dynamic, with a clear correlation to Tau-dependent toxicity, and that aggregation-induced effects are in principle reversible. Supported by MPG, DFG, ADDF, and EU/Memosad.