Abnormal changes in the properties of Tau protein are closely correlated with the progression of Alzheimer disease. They include aggregation into neurofibrillary tangles, hyperphosphorylation, missorting from the axons into the somatodendritic compartments of neurons. It is currently not well understood what causes the abnormal changes, and how they are related to the toxicity of Abeta, the decay of synapses, and the death of neurons. We have used different modes of live cell microscopy of primary neurons, adenoviral transfection of neurons with different variants of tau, and inducible transgenic mouse models of tauopathy. The study mainly focussed on three facets of Tau: (1) By obstructing the surface of microtubules, Tau is capable, in principle, of slowing down axonal transport by inhibiting the attachment of motor proteins. This is particularly visible in the form of reduced mitochondrial movement, which in turn causes an energy crisis in the neuron by reducing the ATP level. As a result, synapses disintegrate, and synaptic markers disappear. (2) Although Tau is mostly a “microtubule-associated protein” (MAP), its residence time on microtubules is only a few seconds, and thus Tau is able to move through cytosolic space by diffusion with surprising speed. This may be one of the factors that enables Tau to enter the somatodendritic compartment, once the normal sorting mechanisms break down during Alzheimer disease. (3) There is a debate on whether the aggregation of Tau as such is toxic to neurons, or whether tau-induced toxicity depends on other factors. Using inducible cell and transgenic mouse models we find that the toxicity of Tau to neurons is tightly correlated with its ability to form beta-structure and to aggregate. Thus mutants of Tau that have a high beta-propensity show rapid aggregation and high toxicity, whereas mutants that are unable to aggregate are not toxic. The findings argue that the toxicity of Tau to neurons requires a particular pathological conformation which promotes beta-structure and tau-tau interactions. Using small molecule inhibitors it may be possible to prevent the pathological conformation and thus to keep Tau functional in the neuron without aggregation.