What rendersTAU toxic

TAU is a microtubule-associated protein that under pathological conditions such asAlzheimer’s disease (AD) forms insoluble, filamentous aggregates. When 20years afterTAU’s discovery the first TAU transgenic mouse models were established, one declaredgoal that was achieved was the modeling of authentic TAU aggregate formation in theform of neurofibrillary tangles. However, as we review here, it has become increasinglyclear thatTAU causes damage much before these filamentous aggregates develop. In fact,because TAU is a scaffolding protein, increased levels and an altered subcellular localiza-tion (due to an increased insolubility and impaired clearance) result in the interaction ofTAU with cellular proteins with which it would otherwise either not interact or do so to alesser degree, thereby impairing their physiological functions. We specifically discuss thenon-axonal localization of TAU, the role phosphorylation has in TAU toxicity and how TAUimpairs mitochondrial functions. A major emphasis is on what we have learned from thefour availableTAU knock-out models in mice, and the knock-out of theTAU/MAP2 homologPTL-1 in worms. It has been proposed that in human pathological conditions such as AD,a rare toxicTAU species exists which needs to be specifically removed to abrogateTAU’stoxicity and restore neuronal functions. However, what is toxic in one context may not bein another, and simply reducing, but not fully abolishing TAU levels may be sufficient toabrogateTAU toxicity.