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Biochim Biophys Acta. 2010 Aug;1801(8):868-77. doi: 10.1016/j.bbalip.2010.01.008. Epub 2010 Feb 1.

Abeta polymerization through interaction with membrane gangliosides.

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Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.


Clarification of the molecular and cellular mechanisms underlying the assembly of amyloid beta-protein (Abeta) into insoluble fibrils in the brain has been one of the biggest challenges in the research on Alzheimer disease (AD). We previously identified a novel Abeta species, which was characterized by its tight binding to GM1 ganglioside (GM1), in the brain showing early pathological changes of AD. The ganglioside-bound Abeta (GAbeta) possessed unique characteristics, including its altered immunoreactivity, which suggests its distinct conformation from native Abeta, and its strong potency to accelerate Abeta assembly into fibrils. On the basis of these characteristics, it was hypothesized that Abeta adopts an altered conformation following interaction with GM1, leading to the generation of GAbeta, and then GAbeta acts as an endogenous seed for Alzheimer amyloid in the brain. To date, various in vitro and in vivo studies on GAbeta have revealed how Abeta binds to gangliosides, i.e., what are the favorable physicochemical and neurobiological conditions for generating GAbeta, and what is the pathological significance of ganglioside-induced Abeta assembly in the development of AD. Interestingly, GAbeta is favorably generated in the unique ganglioside-enriched (clustered), raft-like microdomains; moreover, amyloid fibrils formed in the presence of gangliosides are neurotoxic. Furthermore, the conformational change of Abeta in the presence of ganglioside has been characterized by an NMR study. In this review, we focus on the recent progress of GAbeta studies and highlight the possibility that ganglioside binding is the initial and common step in the development of a part of human misfolding-type amyloidoses, including AD.

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