No full admission for tau to the exclusive prion club yet

Abstract

Aggregation of the microtubule‐associated protein tau is a key feature of Alzheimer's disease and other so‐called tauopathies, yet what causes this protein to aggregate and what renders it toxic is only slowly being revealed. Because tau spreads in a stereotypical pattern through the diseased brain, it has been proposed that it possesses prion‐like properties, with aggregation‐prone tau facilitating the conversion of “naïve” tau into “toxic” forms. The current study by Wegmann et al (2015) addresses whether tau fulfils classical “prion criteria” by assessing its spreading and toxicity in the absence of endogenous tau. Using different transgenic and viral paradigms, the authors demonstrate that, although tau still propagates in this scenario, there is a decrease in its misfolding and neurotoxicity. They therefore conclude that tau is not a genuine prion, at least when the current definition of these infectious proteins is applied.

Figure 1. Comparison of the toxic principles of PrP^{S c} and tau

The present report addresses what is known about the propagation and toxicity of prions (shown on the left) and asks the question whether tau in Alzheimer's disease (on the right) displays the same characteristics. In the case of prion diseases, a form of the prion protein known as PrP^{S c} (Scrapie) propagates from cell to cell and, upon uptake by a recipient cell, leads to an infectious conversion of the endogenous, cellular form of prion (PrP^C) into the toxic PrP^{S c} form, ultimately leading to neuronal demise (as graphically illustrated by the extremely ruffled cell membrane). Importantly, both propagation and toxicity are halted, when the recipient cells lacks endogenous PrP^C expression (PrP knockout, PrP^KO). In their study, Wegmann et al (2015) use different transgenic (P301L Tau Tg) and viral paradigms, to demonstrate that, although P301L tau still propagates, there is a decrease in its misfolding and neurotoxicity in the absence of endogenous mouse tau (as visualized by the different extent of membrane ruffling under the two conditions). The assumption is that P301L tau is synonymous with tau^toxic and that endogenous mouse tau exists in a naïve form. As a possible model to explain the reduced toxicity in the absence of endogenous (naïve) tau, the authors suggest that co‐aggregation of mouse tau with human P301L tau may create more toxic “strains” of tau aggregates, with stronger effects on tau pathology in mice. The authors conclude that P301L mutant tau may not be a genuine prion.