OO081 - BILAYER LIPIDS MODULATION OF AMYLOID BETA BIOACTIVITY: REAL-TIME SPACIO-TEMPORAL VISUAL DETECTION USING BIOMIMETIC MODEL MEMBRANES (ID 863)
Abstract
Aims
Amyloid beta (Aβ) has been strongly implicated in inducing neurotoxicity in the pathology of Alzheimer's disease. Despite much progress, the mechanisms are not fully understood.
Methods
We employ biomimetic lipid membranes to study various patho-/physiological events involving Aβ.
Results
In real-time, we (i) demonstrated species-dependent localization of Aβ, (ii) revealed membrane-transformation pathways induced by Aβ species; (iii) discovered that Aβ mediates membrane fusion (Figure). Aβ-42 has a higher fusogenicity than Aβ-40. Furthermore, we investigated the effect of cholesterol and oxidised cholesterol (7-ketocholesterol or 25-hydroxycholesterol) on Aβ activity, another aspect not yet fully understood. We have shown that (iv) oxysterols, compared to cholesterol, rendered membranes more sensitive to Aβ; (v) the oxysterols have different effects: 7-ketocholesterol has a higher association with Aβ, while 25-hydroxycholesterol mediates higher membrane morphological changes; (vi) by modulating membrane fluidity, cholesterol decreases Aβ localization in solid-ordered domains and increases that in liquid-ordered domains. 7-ketocholesterol majorly enhances fluidity and Aβ interaction within Ld phase. Last, we investigated the effect of 7-ketocholesterol on membrane-mediated aggregation of Aβ-42. We have shown that (vii) when cholesterol is present in lipid vesicles, kinetics of Aβ nuclei formation is hindered while that of fibril growth is accelerated; (viii) 7-ketocholesterol enhances the formation of Aβ-42 nuclei and decreases fibril elongation, thus maintaining the peptide in protofibrillar aggregates.
Conclusions
We have opened up the potential role of vesicular dynamics for profiling and biosensing of Aβ-induced neuro-toxicity and inhibition. Some of our current research is using this system to screen for potential nutraceuticals as inhibitors of Aβ self-assembly.
