Interaction of Tau construct K18 with model lipid membranes

Area of Science:

• Neuroscience
• Biochemistry
• Biophysics

Background:

• Alzheimer's disease (AD) is characterized by neurofibrillary tangles formed by Tau protein aggregation.
• Tau protein misfolding and aggregation into paired helical filaments lead to neuronal dysfunction and cognitive decline.
• The role of cellular membranes in modulating Tau aggregation is an emerging area of interest.

Purpose of the Study:

• To investigate how lipids modulate the interaction and aggregation of the Tau protein.
• To explore the effects of different phospholipid compositions on Tau aggregation using Atomic Force Microscopy (AFM).

Main Methods:

• Utilized Atomic Force Microscopy (AFM) to study the interaction of Tau's microtubule-binding construct (K18) with supported lipid bilayers.
• Investigated the effects of zwitterionic and negatively charged phospholipids on K18 aggregation and membrane interaction.

Main Results:

• Observed detrimental solubilization effects of K18 on fluid zwitterionic membranes.
• Found that K18 could not fragment gel phases of zwitterionic membranes.
• Demonstrated the role of negatively charged lipids in promoting K18 aggregation.
• Identified phosphatidylinositol-4,5-bisphosphate (PIP2) as a potent inducer of K18 fibrillization on membranes.

Conclusions:

• Lipid composition significantly influences Tau protein aggregation pathways.
• Negatively charged lipids, particularly PIP2, play a critical role in promoting Tau fibril formation on cellular membranes.
• These findings provide insights into the membrane's role in Alzheimer's disease pathogenesis.