Modulation of tau pathology propagation

Korte inhoud:Accumulation of insoluble Tau protein aggregates and stereotypical propagation of Tau pathology through the brain are common hallmarks of Tauopathies, including Alzheimer’s disease (AD). Propagation of Tau pathology appears to occur along connected neurons, but whether synaptic contacts between neurons are facilitating propagation has not been demonstrated. Using quantitative in vitro models, we demonstrate that in parallel to non-synaptic mechanisms, synapses, but not merely the close distance between the cells, enhance the propagation of Tau pathology between acceptor hippocampal neurons and Tau donor cells. Similarly, in an artificial neuronal network using microfluidic devices, synapses and synaptic activity are promoting neuronal Tau pathology propagation in parallel to the non-synaptic mechanisms. Our work indicates that the physical presence of synaptic contacts between neurons facilitate Tau pathology propagation which can have implications for "synaptic repair" therapies which may turn out to have adverse effects by promoting propagation of Tau pathology. Mechanisms underlying the release and internalization of Tau aggregates are unclear. Some evidences suggest that internalization step relies on endocytic mechanisms. BIN1 is a late-onset AD risk factor involved in endocytosis and membrane trafficking. Therefore we investigated if myc box-dependent-interacting protein 1 (BIN1) influences endocytosis and modulates Tau pathology propagation. We first found a link between BIN1 levels and Tau pathology propagation. BIN1 levels inversely correlated with Tau pathology propagation in two in vitro models. We further analysed the biological role of this protein and found that changes in BIN1 neuronal levels profoundly impairs endocytic flux. Moreover our work suggests that the involvement of BIN1 in Tau pathology propagation is by mediating the endocytosis of Tau aggregates. We show that when Tau aggregates hijack endocytic routes induce membrane damaging, suggesting that they escape from endocytic compartments to the cytosol. Taken together our work suggests that modulating endocytic flux, through BIN1 levels, halts or enhances Tau aggregates uptake and further Tau pathology propagation between cells

Jaar van publicatie:2016

Toegankelijkheid:Closed