A Kinetic Map of the Influence of Biomimetic Lipid Model Membranes on Aβ42 Aggregation
Kevin N Baumann1, Greta Šneiderienė1, Michele Sanguanini1
1Yusuf Hamied Department of Chemistry, University of Cambridge, CambridgeCB2 1EW, U.K.
Abstract:
The aggregation of the amyloid β (Aβ) peptide is one of the molecular hallmarks of Alzheimer's disease (AD). Although Aβ deposits have mostly been observed extracellularly, various studies have also reported the presence of intracellular Aβ assemblies. Because these intracellular Aβ aggregates might play a role in the onset and progression of AD, it is important to investigate their possible origins at different locations of the cell along the secretory pathway of the amyloid precursor protein, from which Aβ is derived by proteolytic cleavage. Senile plaques found in AD are largely composed of the 42-residue form of Aβ (Aβ42). Intracellularly, Aβ42 is produced in the endoplasmatic reticulum (ER) and Golgi apparatus. Since lipid bilayers have been shown to promote the aggregation of Aβ, in this study, we measure the effects of the lipid membrane composition on the in vitro aggregation kinetics of Aβ42. By using large unilamellar vesicles to model cellular membranes at different locations, including the inner and outer leaflets of the plasma membrane, late endosomes, the ER, and the Golgi apparatus, we show that Aβ42 aggregation is inhibited by the ER and Golgi model membranes. These results provide a preliminary map of the possible effects of the membrane composition in different cellular locations on Aβ aggregation and suggest the presence of an evolutionary optimization of the lipid composition to prevent the intracellular aggregation of Aβ.
Insights
Amyloid beta (Aβ) aggregation in Alzheimer's disease (AD) may occur intracellularly. This study found that ER and Golgi membranes inhibit Aβ42 aggregation, suggesting cellular lipid composition prevents harmful buildup.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Amyloid beta (Aβ) peptide aggregation is a key feature of Alzheimer's disease (AD).
- While extracellular Aβ deposits (plaques) are well-known, intracellular Aβ assemblies are increasingly recognized for their potential role in AD pathogenesis.
- Aβ is derived from the amyloid precursor protein (APP) via proteolytic cleavage within the secretory pathway, including the endoplasmic reticulum (ER) and Golgi apparatus.
Purpose of the Study:
- To investigate the origins of intracellular Aβ aggregates by examining their formation in different cellular compartments.
- To determine the effect of lipid membrane composition, mimicking various cellular locations, on the in vitro aggregation kinetics of Aβ42.
- To understand how cellular membrane environments influence the aggregation of Aβ42.
Main Methods:
- Utilized large unilamellar vesicles (LUVs) to model cellular membranes.
- Modeled membranes from different cellular locations: plasma membrane (inner/outer leaflets), late endosomes, ER, and Golgi apparatus.
- Measured the in vitro aggregation kinetics of Aβ42 in the presence of these model membranes.
Main Results:
- Aβ42 aggregation was significantly inhibited by model membranes representing the ER and Golgi apparatus.
- Lipid bilayer composition influences the rate and extent of Aβ42 aggregation.
- Different cellular membrane compositions exert distinct effects on Aβ42 aggregation.
Conclusions:
- The lipid composition of ER and Golgi membranes appears to prevent or reduce intracellular Aβ42 aggregation.
- These findings provide a preliminary map of how membrane composition in various cellular locations affects Aβ aggregation.
- Suggests an evolutionary optimization of lipid composition within organelles like the ER and Golgi to mitigate intracellular Aβ aggregation.
