Strong inhibition of peptide amyloid formation by a fatty acid

Abstract

The aggregation of peptides into amyloid fibrils is associated with several diseases, including Alzheimer's and Parkinson's disease. Because hydrophobic interactions often play an important role in amyloid formation, the presence of various hydrophobic or amphiphilic molecules, such as lipids, may influence the aggregation process. We have studied the effect of a fatty acid, linoleic acid, on the fibrillation process of the amyloid-forming model peptide NACore (GAVVTGVTAVA). NACore is a peptide fragment spanning residue 68-78 of the protein a-synuclein involved in Parkinson's disease. Based primarily on circular dichroism measurements, we found that even a very small amount of linoleic acid can substantially inhibit the fibrillation of NACore. This inhibitory effect manifests itself through a prolongation of the lag phase of the peptide fibrillation. The effect is greatest when the fatty acid is present from the beginning of the process together with the monomeric peptide. Cryogenic transmission electron microscopy revealed the presence of nonfibrillar clusters among NACore fibrils formed in the presence of linoleic acid. We argue that the observed inhibitory effect on fibrillation is due to co-association of peptide oligomers and fatty acid aggregates at the early stage of the process. An important aspect of this mechanism is that it is nonmonomeric peptide structures that associate with the fatty acid aggregates. Similar mechanisms of action could be relevant in amyloid formation occurring in vivo, where the aggregation takes place in a lipid-rich environment.

Fatty acid-based polymeric micelles to ameliorate amyloidogenic disorders

“…20,21 In addition to this, linoleic acid, a polyunsaturated fatty acid, was found to inhibit the formation of amyloid aggregates by elongating the initial lag phase period. 22 The fatty acid concentration and phase transitions also modulate the amyloid aggregation pathways. 23 Even though FAs showed significant applications in the protein aggregation field, however, further biomedical applications of FAs are limited because of their poor solubility in water, which in turn results in poor bioavailability.…”

Extracellular Vesicles Slow Down Aβ(1–42) Aggregation by Interfering with the Amyloid Fibril Elongation Step

“…However, similar extremes in substoichiometric inhibition have been observed with linoleic acid and the amyloid-forming peptide NACore, and the effect is ascribed to the co-assembly of fatty acid aggregates and the amyloid species at the early stages of aggregation. 71 Moreover, whereas the EV concentrations used in this work were within the physiological range, 44,45 total Aβ(1−42) concentrations in brain fluids are generally lower 72 even though significant concentration variation likely exists. 73 This suggests that Aβ(1−42):EV ratios in the brain may be lower than those assessed here and that elongation inhibitory mechanisms could potentially be even more effective in vivo.…”

Lysophospholipids: A Potential Drug Candidates for Neurodegenerative Disorders

“…A previous report suggested that the presence of lipids inhibits NACore (GAVVTGVTAVA) fibril formation. Recently, cryogenic transmission electron microscopy (Cryo-TEM) revealed the presence of non-fibrillar clusters among NACore fibrils formed in the presence of linoleic acid [ 56 ]. This effect was additionally observed with PLs and was particularly pronounced with linoleic acid [ 57 ].…”

“…This effect was additionally observed with PLs and was particularly pronounced with linoleic acid [ 57 ]. This inhibitory effect has been attributed to a prolonged lag phase during fibril formation [ 56 ]. The α-Syn C-terminal domain contains multiple negatively charged residues, as well as a serine and three tyrosine residues that can be phosphorylated, which may impact α-Syn structure, membrane binding, aggregation, and toxicity [ 58 , 59 ].…”

“…An important aspect of this mechanism is that it is non-monomeric α-Syn structures that associate with the LPL aggregates. Similar mechanisms of action could be relevant in amyloid formation occurring in vivo, where aggregation occurs in a lipid-rich environment [ 56 ]. Under normal conditions, α-Syn adopts an α-helical secondary structure when bound to lipid interfaces, which might be important for explaining differences in how LPLs affect the amyloid formation of different proteins.…”