Using this model, the authors examined the appearance and progression of tau pathology in diverse areas of the brain in animals of different ages. The results show that tau pathology starts in neurons of the EC expressing the human transgene and over time progresses to cells without detectable human tau expression, first in the vicinity of the

EC and later in more distant regions located downstream in the synaptic circuit, such find more as the dentate gyrus, hippocampus, and cingulate cortex. Human tau protein appears to spread to these brain regions and to interact with and induce aggregation of endogenous mouse tau. The progressive accumulation of tau aggregates leads to synaptic degeneration and later to axonal damage and neuronal death. The exquisite regional specificity of the human transgene expression combined with the use of sophisticated techniques to analyze the brain of these animals enabled the authors to obtain a number of important conclusions, namely: (1) tau aggregates can transfer to neighboring cells and to synaptically connected neurons in distant parts of the brain, all of which do not express detectable levels

of the human protein; (2) misfolded human mutant tau recruits endogenous mouse tau into the aggregates, leading to learn more its progressive intraneuronal accumulation; (3) spreading of tau pathology induces a slow synaptic destruction, followed by axonal and later somatic degeneration of neurons. These are important findings in order to understand the progression of tau pathology and associated damage in AD, and they fit well with recent observations indicating that tau misfolding and aggregation can spread from cell to cell in a prion-like manner (Clavaguera et al., 2009, Frost et al., 2009, Guo and Lee, 2011 and Nonaka et al., 2010). However, a potential weakness of the current study is Ketanserin that, despite

all the diverse techniques used to evaluate human tau expression, the authors cannot completely rule out a low expression (below the level of detection of the methods employed) of the transgene in other brain areas. Indeed, some leakiness of expression has been reported previously for similar mouse models (Santacruz et al., 2005). In this scenario, low widespread expression of human P301L tau, and not spreading of aggregates from one site to another, may have seeded aggregation of endogenous mouse tau and triggered neurodegeneration. Although the authors provide convincing evidence that expression beyond the targeted areas must be very low (or nonexistent), it is also noticeable that because of the high efficiency of the seeding process, these minute quantities may be enough to induce tau aggregation.