Structural Analysis of Tau Peptide Interactions with Lipid Membranes using Fourier Transform Infrared Spectroscopy

Alzheimer's disease is a common form of dementia that is characterized by the formation of neurofibrillary tangles formed by the protein tau. The neurofibrillary tangles are formed when tau protein delocalizes from the microtubule binding domain and misfolds. This misfolding occurs primarily at four repeat segments: R1, R2, R3, and R4. Previous studies indicate that lipid membranes may be involved during this aggregation; particularly those with negative charge were shown to localize the aggregates of tau. In this study, we analyzed the four repeat segments using FTIR spectroscopy to monitor structural changes under various membrane conditions to investigate this phenomenon. The Amide I peak was used as a proxy for secondary structure in the presence of neutral DOPC lipid vesicles (a model of the plasma membrane) and negatively charged DOPC/DOPG (80:20) lipid vesicles (a model of the Golgi membrane). We show that the repeat segments are largely random coil in aqueous solution and that the introduction of negatively charged vesicles increases β-sheet and α-helix secondary structure by up to 50%. On the other hand, neutral membranes induced secondary structure changes by up to 20%. Further studies that correlate the aggregation rate of these peptides under these conditions will be presented. Taken together, these data suggest that tau mislocalization to different compartments may expose the repeat segments to membranes that increase the propensity for misfolding and subsequent aggregation.