Abstract
It is widely accepted that the conversion of the soluble, nontoxic amyloid β-protein (Aβ) monomer to aggregated toxic Aβ rich in β-sheet structures is central to the development of Alzheimer's disease. However, the mechanism of the abnormal aggregation of Aβ in vivo is not well understood. Accumulating evidence suggests that lipid rafts (microdomains) in membranes mainly composed of sphingolipids (gangliosides and sphingomyelin) and cholesterol play a pivotal role in this process. This paper summarizes the molecular mechanisms by which Aβ aggregates on membranes containing ganglioside clusters, forming amyloid fibrils. Notably, the toxicity and physicochemical properties of the fibrils are different from those of Aβ amyloids formed in solution. Furthermore, differences between Aβ-(1–40) and Aβ-(1–42) in membrane interaction and amyloidogenesis are also emphasized.
Highlights
It is widely accepted that the amyloid β-protein (Aβ), which exists in fibrillar forms as a major component of senile plaques, is central to the development of Alzheimer’s disease (AD) [1, 2]
We have been investigating the interaction of Aβ with ganglioside-containing membranes for a dozen years and found that not the uniformly distributed but the clustered gangliosides mediate the formation of amyloid fibrils by Aβ, the toxicity and physicochemical properties of which are different from those of Aβ amyloids formed in solution
Based on the above observations, we propose a novel model for Aβ-membrane interaction as a mechanism for the abnormal aggregation of the protein (Figure 5)
Summary
It is widely accepted that the amyloid β-protein (Aβ), which exists in fibrillar forms as a major component of senile plaques, is central to the development of Alzheimer’s disease (AD) [1, 2]. Clusterin (Apo J) [6] and Zn2+ ions [7] were reported to facilitate the aggregation of Aβ more than a decade ago, their aggregation-promoting mechanisms are yet to be elucidated. In addition to these soluble factors, Jarrett and Lansbury, Jr. suggested that Aβ fibrillizes via a nucleation-dependent polymerization mechanism and lipids could act as heterogeneous seeds for the polymerization [8]. We have been investigating the interaction of Aβ with ganglioside-containing membranes for a dozen years and found that not the uniformly distributed but the clustered gangliosides mediate the formation of amyloid fibrils by Aβ, the toxicity and physicochemical properties of which are different from those of Aβ amyloids formed in solution. It will shed light on one of the initiation processes of AD
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