Accelerated Aβ aggregation in the presence of GM1‐ganglioside‐accumulated synaptosomes of aged apoE4‐knock‐in mouse brain

Abstract

Aging and apolipoprotein E4 (apoE4) expression are strong risk factors for the development of Alzheimer's disease (AD); however, their pathological roles remain to be clarified. In the process of AD development, the conversion of the nontoxic amyloid -protein (A) monomer to its toxic aggregates is a fundamental process. We previously hypothesized that A aggregation is accelerated through the generation of GM1 ganglioside (GM1)-bound A which acts as a seed for A fibril formation. Here we report that GM1 level in detergent-resistant membrane microdomains (DRMs) of synaptosomes increased with age and that this increase was significantly pronounced in the apoE4-than the apoE3-knock-in mouse brain. Furthermore, we show that A aggregation is markedly accelerated in the presence of the synaptosomes of the aged apoE4-knock-in mouse brain. These observations suggest that aging and apoE4 expression cooperatively accelerate A aggregation in the brain through an increase in the level of GM1 in neuronal membranes.

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

“…In this case, they suggested that aging and apoE4 expression cooperatively accelerated Ab aggregation in the brain through an increase in the level of GM1 in particular microdomains of neuronal membranes. These results suggest that Ab accumulation in these microdomains is an early event in the process of AD development (42).…”

“…In this case, the level of sphingomyelin decreased significantly, but not the level of gangliosides. Yamamoto et al (42) reported that the concentration of GM1 in DRMs of synaptosomes increased with age and that this increase was more pronounced in brains of knock-in mice homozygous for the human apoE e4 allele, compared with those harboring two e3 alleles. In this case, they suggested that aging and apoE4 expression cooperatively accelerated Ab aggregation in the brain through an increase in the level of GM1 in particular microdomains of neuronal membranes.…”

“…Although the amount of gangliosides and their patterns are similar in control and in AD cases (37), an observation was made that the A2B5 antibody reacted with human brain c-series gangliosides and, unexpectedly, sulfatides (38). The brain gangliosides of different transgenic mouse models of AD have been analyzed and compared with those of age-matched wild-type mice (39)(40)(41)(42). Barrier et al (39) observed a marked increase in the simple gangliosides GM2 and GM3 in the cortex of 2-year-old APP SL mice expressing the Swedish (K670N/M671L) and London (V717I) mutations of human APP.…”

“…Surface-associated, b-sheet-rich, peptide micro-aggregates could then act as a specific template ("seed") to recruit additional peptide molecules from solution and promote fibril formation by a b-sheet augmentation mechanism (54). Ab aggregation in brain is accelerated through an increase in the level of GM1 in neuronal membranes (42). Further studies have demonstrated that GM1 and GT1b promote the aggregation and cytotoxicity of Ab1-40, and these gangliosides, especially GM1, catalyze the formation of neurotoxic fibrils (74).…”

A Ganglioside-induced Toxic Soluble Aβ Assembly

“…Dutch-type, Italian-type, and Flemish-type A␤s), preferably assembles in the presence of GM1 ganglioside, as does wild-type A␤ (35,36). We also reported that GM1 ganglioside level increases in synaptosomes prepared from aged, human apolipoprotein E4 knock-in mice (37). Thus, it is possible that an alteration in the expression or distribution of GM1 ganglioside is the background to the assembly and deposition of A␤ in the brain parenchyma.…”