Membrane-mediated fibrillation and toxicity of the tau hexapeptide PHF6

Abstract

Edited by Wolfgang PetiThe 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 nonaggregation prone PHF6 with a standard N terminus (NH 3 ؉ -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. NH 3 ؉ -PHF6 displayed slow membrane-mediated fibrillation after 6 days of incubation, whereas Ac-PHF6 adopted a ␤-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.

Role of the Lipid Membrane and Membrane Proteins in Tau Pathology

“…Fulllength 2N4R tau, K18, and K19 are all able to bind to lipid vesicles in vitro with an 2N4R tau > K18 > K19 rank potency order, suggesting that in addition to MTBD domain, additional regions may participate in the tau-membrane interaction and within MTBD domain, 2R region is important for the taumembrane affinity (Barre and Eliezer, 2006;Kunze et al, 2012;Georgieva et al, 2014;. In particular, two hexapeptide motifs were demonstrated to play an important role in the formation of the tau-phospholipid complexes, which are easily converted to elongated fibrils in acidic pH and toxic to primary hippocampal neurons Fanni et al, 2019). Another study showed that the N-terminal projection domain of tau is also involved in the interaction of tau with the cytoplasmic face of the axonal membrane (Brandt et al, 1995;Arrasate et al, 2000).…”

“…In the MTBD, two hydrophobic hexapeptides motifs, PHF6 * -and PHF6-motif, are reported to be a core of K18/phospholipid complex and PHF6 motif has a higher propensity to form β-strand-like structure than PHF6 * motif (Barre and Eliezer, 2013;. In addition, a study using CD spectra and X-ray reflection revealed that acetylation of PHF6 motif facilitates membrane-templated fibrillization and membrane destabilization at the DMPG monolayer and LUV of POPC/POPG (Fanni et al, 2019). So far, it is not clear what factors regulate the tau-membrane interaction and fibrillization on the membrane.…”

Oligomerization and Conformational Change Turn Monomeric β-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer’s Pathogenesis

“…The exact mechanism of TauO formation is not yet known [178]. Model peptide experiments emphasize the role of membranes in oligomerization [179]. There is an assumption that granular tau oligomers (gTauO) might be the most toxic species, this type of tau could be isolated from AD brain [139].…”

The broad‐spectrum antibiofilm activity of amyloid‐forming hexapeptides

“…Although the sequences of AFhPs in our study did not satisfy the regularity of XBBXBX, cell wall carbohydrates (PGN, LTA, glucan, and zymosan A) still significantly impeded AFhPs’ antibiofilm activities, suggesting that microbial cell wall carbohydrates are the binding targets. In the amyloid hypothesis of Alzheimer’s disease, the cytotoxicity of Aβ was supposed to be the result of interactions between Aβ fibrillation and cell lipid membranes (Niu et al ., 2018; Fanni et al ., 2019). Studies have verified that lipid membranes play a pivotal role in triggering and accelerating Aβ fibrillation (Lindberg et al ., 2017).…”