Interaction of Tau construct K18 with model lipid membranes.

One of the hallmarks of Alzheimer's disease (AD) is the formation of neurofibrillary tangles, resulting from the aggregation of the tubulin associated unit protein (Tau), which holds a vital role in maintaining neuron integrity in a healthy brain. The development of such aggregates and their deposition in the brain seem to correlate with the onset of neurodegeneration processes. The misfolding and subsequent aggregation of the protein into paired helical filaments that further form the tangles, lead to dysfunction of the protein with neuronal loss and cognitive decline. The aggregation of the protein then seems to be a causative factor of the neurodegeneration associated with AD. The hypothesis of an involvement of the membrane in modulating the misfolding and assembly of Tau into paired helical filaments attracts increasing interests. To provide more insight about how lipids can modulate the interactions with Tau, we have conducted a comprehensive Atomic Force Microscopy (AFM) study involving supported lipid bilayers of controlled compositions with the Tau microtubule-binding construct K18. Particularly, the effects of zwitterionic and negatively charged phospholipids on the interaction have been investigated. Deleterious solubilization effects have been evidenced on fluid zwitterionic membranes as well as an inability of K18 to fragment gel phases. The role of negative lipids in the aggregation of the peptide and the particular ability of phosphatidylinositol-4,5-bisphosphate (PIP