(230b) Lipid-Membrane Mediated Tau Misfolding and Aggregation

Authors: 
Camp, P., University of New Mexico
Majewski, J., Los Alamos National Laboratory
Biernat, J., Max Planck Unit for Structural Biology
Mandelkow, E., Max Planck Unit for Structural Biology
Chi, E., University of New Mexico


Aside from amyloid plaques, tau neurofibrillary tangles (NFTs) comprise another pathological hallmark of Alzheimer's disease (AD). The discovery that a number of tau mutations cause frontotemporal dementia and a recent finding that reducing tau levels can block cognitive impairments in AD mouse models pivotally established that tau abnormalities can directly cause neurodegeneration, strengthening the hypothesis that tau plays a critical role in AD pathogenesis. However, the molecular basis of the early tau aggregation events, such as the nature of the structural fluctuations that trigger the cascade of misfolding and aggregation events, are unknown. Several lines of evidence suggest that tau in AD brains may exhibit abnormal interactions with the neuronal cell membrane. We hypothesize that the lipid membrane can mediate tau pathology by templating the natively unstructured tau to misfold into an assembly-competent conformation and subsequently nucleating tau to aggregate into oligomers and fibrils. To test our hypothesis, we used lipid monolayers at the air/water interface as a model membrane to probe tau-membrane interactions. Our data show that although the full length human tau (hTau40, 441 amino acids) is highly soluble and charged, it is also highly surface active. At a lipid monolayer surface, hTau40 exhibits strong association with negative DMPG lipids, while exhibiting weaker and no interactions with the positive DMTAP and neutral DMPC lipids. Thus, tau-membrane interactions are strongly mediated by electrostatic interactions. To identify the specific domain on hTau40 that is responsible for its interaction with lipid membranes, the interaction between different tau constructs (K18 and K32) and lipid monolayers were measured. Additionally, x-ray scattering experiments were carried out to elucidate the Angstrom scale, structural details of tau associated with lipid membranes. Our data show that tau's C-terminal, microtubule binding domain is responsible for tau's binding to the negatively charged membranes and that these binding events induces global changes to the ordering and structure of membrane lipids. Our study suggests that the ?soft? nature of tau can give rise to rich dynamic behaviors at interfaces, such as the physiological lipid membrane interface. Our data implicate that the inner leaflet of the cell membrane, enriched in negatively charged lipids, can potentially recruit tau in the cytoplasm, which may be critical in initiating the cascade of pathogenic misfolding and aggregation events in AD.