Cholesterol‐Dependent Aggregation of Amyloid β‐Protein

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Abstract
One of the fundamental pathological processes of Alzheimer's disease (AD) is the aggregation of the amyloid β‐protein (Aβ). In the case of familial AD, the expression of genes responsible for this disease is likely to enhance aggregation of Aβ through its enhanced generation. However, there is no evidence to indicate thus far that in the case of sporadic AD, a major form of the disease, the generation of Aβ is altered. Thus, one could assume that the aggregation of Aβ in AD is induced by unknown posttranslational modification or by an altered clearance mechanism, or both. We previously identified a novel Aβ species in the human brain that exhibited early pathological changes of AD. This Aα is characterized by its tight binding to GM1 ganglioside (GM1). Based on its unique molecular characteristics, including its extremely high aggregation potential and altered immunoreactivity, we hypothesized that Aβ undergoes conformational alteration and acts as a seed for Aβ fibrillogenesis. In regard to the molecular mechanism underlying the formation of GM1‐Aβ, we recently found that binding of Aβ to GM1 was facilitated in cholesterol‐rich environments and, furthermore, it was dependent on the cholesterol‐induced clustering of GM1 in the host membranes. Recently, increasing evidence indicates that cholesterol is a risk factor for AD development. The results of our current studies may provide a new insight into the molecular mechanism underlying the cholesterol‐dependent development of AD.