Glucose directs amyloid-beta into membrane-active oligomers

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Oligomeric amyloid-β 1-42 (Aβ-42) peptides are implicated in Alzheimer's disease pathogenesis.
• The in vivo formation of toxic Aβ-42 oligomers may depend on the cellular environment.
• Neuronal membrane interaction initiates Aβ-42 aggregation and uptake.

Purpose of the Study:

• To investigate the role of extracellular molecules, specifically sugars, in Aβ-42 oligomer formation.
• To determine the characteristics and cellular effects of sugar-induced Aβ-42 oligomers.

Main Methods:

• Analysis of Aβ-42 aggregation in the presence of glucose and sucrose.
• Characterization of oligomers using dynamic light scattering, atomic force microscopy, immuno-transmission electron microscopy, and fluorescence cross-correlation spectroscopy.
• Assessment of oligomer interaction with model membranes (GUVs) and neuronal cells, and their effect on mitochondrial activity.

Main Results:

• Glucose and sucrose significantly accelerate the formation of low molecular weight Aβ-42 oligomers.
• Oligomerization is favored at slightly acidic pH (6.7-7.0).
• Aβ-42 oligomers formed in the presence of sugars do not adopt a β-sheet structure but are membrane-active, facilitate cellular uptake, and inhibit mitochondrial function.

Conclusions:

• Extracellular sugars, particularly glucose at concentrations found in diabetes, can promote the formation of toxic, membrane-active Aβ-42 oligomers.
• These findings suggest a link between metabolic conditions like diabetes and Alzheimer's disease risk.
• The study highlights the importance of the extracellular environment in modulating Aβ-42 aggregation and toxicity.