Cholesterol and Aß Aggregation

Regarding deposition of amyloid β-protein (Aβ) in brains with Alzheimer’s disease (AD), we previously identified a novel Aβ species that strongly binds to GM1 ganglioside (GM1) in human brains that exhibit early pathological changes of AD. We hypothesized that Aβ undergoes conformational alteration through its binding to GM1 and acts as a seed. We recently found that an increase in the cholesterol concentration in host membranes markedly accelerates Aβ binding to GM1. We then investigated whether the cholesterol concentration in neuronal membranes could be altered under biological conditions that are associated with risk factors for AD development. We attempted to determine the distribution of cholesterol in the synaptic plasma membranes (SPMs) of human apolipoprotein E (apoE)-knock-in mice and found that the cholesterol concentration in the exofacial leaflet of SPMs of the human apoE4-knock-in mice was approximately twice that of human apoE3-knock-in mice. The results of our studies suggest that an increase in the cholesterol concentration in the neuronal membranes accelerates Aβ aggregation through the formation of an endogenous seed.

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