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Updated: Aug 1, 2025
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In Vitro Aggregation Assays Using Hyperphosphorylated Tau Protein
Published on: January 2, 2015
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Membrane-induced tau amyloid fibrils
Nadia El Mammeri1, Olivia Gampp1, Pu Duan1
1Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
Communications Biology
|April 28, 2023
Summary
Lipid membranes, particularly small vesicles with cholesterol, promote tau protein aggregation into amyloid fibrils. Membrane curvature and cholesterol are crucial for initiating tau fibril formation, impacting neurodegenerative disease research.
Area of Science:
- Biochemistry
- Neuroscience
- Structural Biology
Background:
- The intrinsically disordered protein tau forms pathological β-sheet amyloid fibrils in Alzheimer's disease and other neurodegenerative conditions.
- Tau's interaction with lipid membranes is hypothesized to influence the formation and spread of these toxic aggregates.
Purpose of the Study:
- To investigate the conformational changes and assembly of tau protein induced by lipid membranes.
- To determine the specific roles of membrane properties like curvature and cholesterol in tau aggregation.
Main Methods:
- Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy to analyze tau conformation.
- Transmission Electron Microscopy (TEM) to visualize tau aggregate structures.
- Reconstitution of tau protein with cholesterol-containing phospholipid vesicles (SUVs, LUVs, MLVs).
Main Results:
- Tau converted from a random coil to a β-sheet conformation over weeks when incubated with membranes.
- Small unilamellar vesicles (SUVs) induced long tau fibrils, distinct from aggregates formed on large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs).
- Tau aggregates localized at the membrane-water interface, and fibril formation was dependent on both membrane curvature and cholesterol content.
Conclusions:
- Lipid membranes, specifically curved ones containing cholesterol, act as potent nucleators for pathological tau fibril formation.
- These findings highlight a potential mechanism for how cell membranes may initiate tau aggregation in neurodegenerative diseases.
- Understanding membrane-tau interactions is critical for developing therapeutic strategies targeting tauopathies.
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