Membrane Anchored Polymers Modulate Amyloid Fibrillation.

Area of Science:

• Biochemistry
• Polymer Chemistry
• Neuroscience

Background:

• Cellular membrane components, particularly lipid moieties, are known to nucleate amyloid beta (Aβ) fibrillation.
• Understanding factors that modulate Aβ aggregation is crucial for developing therapeutic strategies against amyloid-related diseases.

Purpose of the Study:

• To investigate the impact of novel lipid-polymer conjugates on Aβ$_{1-40}$ fibrillation.
• To elucidate the influence of polymer cloud point temperature (Tcp) and hydrophobic tail characteristics on amyloid aggregation.

Main Methods:

• Synthesis of novel lipid-polymer conjugates using reversible addition-fragmentation chain transfer (RAFT) polymerization.
• Tuning the hydrophilic-hydrophobic balance of conjugates by varying polymer degree of polymerization (n) and ethylene glycol units (m).
• In vitro kinetic studies and transmission electron microscopy (TEM) to assess Aβ$_{1-40}$ fibrillation.

Main Results:

• Hydrophobic lipid anchors (cholesterol, diacylglycerol) significantly delayed both the lag phase and half-time of Aβ$_{1-40}$ fibrillation.
• TEM analysis revealed similar fibrillar structures for Aβ$_{1-40}$ in the presence of hydrophobic anchors compared to native Aβ$_{1-40}$ alone.
• Other hydrophobic end groups also delayed fibrillation, irrespective of polymer chain length (n) or ethylene glycol units (m).
• More hydrophilic polymers, particularly those with longer ethylene glycol side chains (m=3 or m=5), showed only marginal inhibition of Aβ$_{1-40}$ fibrillation.

Conclusions:

• Lipid-polymer conjugates, especially those with hydrophobic anchors, are effective inhibitors of Aβ$_{1-40}$ fibrillation.
• The hydrophobic character of the lipid anchor plays a critical role in modulating amyloid aggregation.
• These findings offer insights into designing targeted inhibitors for amyloid-related pathologies.