Modeling of Tau-Mediated Synaptic and Neuronal Degeneration in Alzheimer's Disease

Figure 4

Model for Tau-mediated neurodegeneration. In normal conditions, protein Tau is regulated tightly at different levels: isoform expression, phosphorylation, microtubule binding, turnover, all needed to ensure normal transport along microtubules in axons and dendrites (upper panel). Increased expression of protein Tau, either genetically or pathologically in humans or experimentally in animal models will increase the amount of protein Tau bound to microtubules, thereby competing for and blocking the binding-sites needed for the motor proteins that carry out transport (middle panel). The resulting impairment in transport of any cargo, from synaptic vesicles and mitochondria to proteins, will impair any transport and energy-dependent processes at the synapses, which will extend and evolve into degenerating neuronal processes, and eventually lead to neuronal death. Defective synaptic transmission is then expected to be an early indication or symptom. Initially, small and loose aggregates or oligomers of protein Tau collect onto the microtubules, causing them to disintegrate or collapse. We also propose that the injured neuronal processes release proteins and factors, purposely or accidental that contribute to the activation of microglia and astroglia. The activated inflammatory cells secrete then factors that affect not only neurons but also other cells that constitute the unit blood-brain-barrier, provoking higher permeability, which further negatively affects neurons [11, 30]. Interesting is the connection to increased activity of GSK3, which rescued the axonopathy of Tau4R mice and the premature death of Tau.P301L mice by phosphorylating protein Tau and thereby detach it from the microtubuli to restore normal transport by motor proteins (lower panel) [26, 37]. Likewise, neither cell-death nor inflammation is provoked by AAV-Tau.255, devoid of the microtubule binding domain. The transgenic and viral models thereby underscore the microtubule binding of protein Tau as the common mechanism of action whereby protein Tau is causing neuronal demise and eventually neurodegeneration.