Abstract
The aggregation of the tau protein into neurofibrillary tangles is believed to correlate with cognitive decline in several neurodegenerative disorders, including Alzheimer's disease. Recent studies suggest that tau's interactions with the cell membrane could serve as a toxicity pathway and also enhance fibrillation into paired helical filaments (PHFs). Conformational changes associated with tau-membrane interactions are poorly understood, and their characterization could improve our understanding of tau pathogenicity. In this study, we investigated the molecular level structural changes associated with the interaction of the tau hexapeptide PHF6 with model lipid membranes and characterized the effects of these interactions on membrane stability and peptide fibrillation. We used two PHF6 forms, the aggregation-prone PHF6 with N-terminal acetylation (Ac-PHF6) and the non-aggregation prone PHF6 with a standard N terminus (NH3+-PHF6). We found that both PHF6 peptides are neurotoxic and exhibit similar membrane-mediated changes, consisting of: 1) favorable interactions with anionic membranes, 2) membrane destabilization through lipid extraction, and 3) membrane-mediated fibrillation. The rate at which these changes occurred was the main difference between the two peptides. NH3+-PHF6 displayed slow membrane-mediated fibrillation after 6 days of incubation, whereas Ac-PHF6 adopted a β-sheet conformation at the surface of the membrane within hours. Ac-PHF6 interactions with the membrane were also accompanied by membrane invagination and rapid membrane destabilization. Overall, our results reveal that membrane interactions could play a critical role in tau toxicity and fibrillation, and highlight that unraveling these interactions is important for significantly advancing the development of therapeutic strategies to manage tau-associated neurodegenerative diseases.
Highlights
The aggregation of the tau protein into neurofibrillary tangles is believed to correlate with cognitive decline in several neurodegenerative disorders, including Alzheimer’s disease
We investigated the lipid membrane interaction of PHF6, a hexapeptide located in the third repeat unit of the MTB domain forming the core of tau paired helical filaments (PHFs) and revealed its effect on membrane structure and peptide fibrillation
We used two PHF6 peptides, one fibrillation prone (Ac-PHF6) and another not fibrillation prone (NH3ϩ-PHF6), to study the effect of these peptides on cell toxicity, membrane interaction, and membrane-mediated fibrillation. We found that both unincubated PHF6 peptides are neurotoxic and pre-formed Ac-PHF6 fibrils exert higher toxicity with the short fibrils exhibiting highest cytotoxicity (Fig. 3)
Summary
The aggregation of the tau protein into neurofibrillary tangles is believed to correlate with cognitive decline in several neurodegenerative disorders, including Alzheimer’s disease. We investigated the molecular level structural changes associated with the interaction of the tau hexapeptide PHF6 with model lipid membranes and characterized the effects of these interactions on membrane stability and peptide fibrillation. The hexapeptide PHF6 was used as a model tau protein because of its importance in promoting tau aggregation, and the peptide on its own has been shown to recapitulate important fibril forming and toxic properties of the full-length tau [14, 15]. Insights gained about the membrane interaction, fibrillation, and toxicity of the PHF6 peptide will enhance our understanding of tau’s role in neurodegenerative diseases and could lead to significant advancement in the development of therapeutic strategies to manage tau-associated neurodegenerative diseases. Both PHF6s disrupted membrane stability and underwent membrane-mediated fibrillation
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