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Review
. 2008 Jun;49(6):1157-75.
doi: 10.1194/jlr.R800007-JLR200. Epub 2008 Mar 11.

Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease--a review

Toshio Ariga  1 , Michael P McDonald, Robert K Yu
Affiliations
Review

Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease--a review

Toshio Ariga et al. J Lipid Res. 2008 Jun.

Abstract

Gangliosides are expressed in the outer leaflet of the plasma membrane of the cells of all vertebrates and are particularly abundant in the nervous system. Ganglioside metabolism is closely associated with the pathology of Alzheimer's disease (AD). AD, the most common form of dementia, is a progressive degenerative disease of the brain characterized clinically by progressive loss of memory and cognitive function and eventually death. Neuropathologically, AD is characterized by amyloid deposits or "senile plaques," which consist mainly of aggregated variants of amyloid beta-protein (Abeta). Abeta undergoes a conformational transition from random coil to ordered structure rich in beta-sheets, especially after addition of lipid vesicles containing GM1 ganglioside. In AD brain, a complex of GM1 and Abeta, termed "GAbeta," has been found to accumulate. In recent years, Abeta and GM1 have been identified in microdomains or lipid rafts. The functional roles of these microdomains in cellular processes are now beginning to unfold. Several articles also have documented the involvement of these microdomains in the pathogenesis of certain neurodegenerative diseases, such as AD. A pivotal neuroprotective role of gangliosides has been reported in in vivo and in vitro models of neuronal injury, Parkinsonism, and related diseases. Here we describe the possible involvement of gangliosides in the development of AD and the therapeutic potentials of gangliosides in this disorder.

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Figures

Fig. 1.
Fig. 1.
Structure and metabolism of gangliosides in mammalian brain. The nomenclature of gangliosides follows the system of Svennerholm (183).
Fig. 2.
Fig. 2.
Expression of GQ1bα in brains of transgenic (TG) mice induced with AP-1 and Aβ1-42. Lane 1: bovine brain ganglioside mixtures; lanes 2–4: TG (2 weeks); lanes 5–7: TG (4 weeks); lanes 8 and 9: wild-type; lane 10: GQ1bα standard, 10 ng. A: resorcinol-HCL reagent staining; B: immunostaining with anti-Chol-1 monoclonal antibody (CGR-41). The plates were developed with the solvent system of chloroform-methanol-0.2% CaCl2; 55:45:10; v/v/v.
Fig. 3.
Fig. 3.
Expression of GQ1bα in developing mouse brain. Gangliosides isolated from the developing mouse brains were subjected to high-performance thin-layer chromatography (HPTLC) immunostaining with GGR-41 anti-Chol-1α (GT1aα and GQ1bα) antibody (A), and then visualized with the resorcinol-HCl reagent (B) (5).
Fig. 4.
Fig. 4.
Representative thin-layer chromatographs from wild-type, double-transgenic, and triple-mutant mice. The plate was developed with the solvent system of chloroform-methanol-0.2%CaCl2; 55:45:10; v/v/v). Triple-mutant mice lack two of the four major brain gangliosides, and have increased levels of a-series gangliosides GM1 and GD1a, compared with wild-type mice. Differences between double-transgenic and wild-type mice were not significant.
Fig. 5.
Fig. 5.
Accumulation of Aβ in PC12 cells expressing no GM1. PC12 cells were cultured in the presence or absence of Aβ1-40 (2.5 μg) or FL-Aβ (1-40 or 1-42) (2.5 μg) for 48 h. The nuclei were stained with Hoechs 33258 (2 μg/ml) (101).
Fig. 6.
Fig. 6.
Reactivity of cholera toxin B-subunit (Ctxb) in PC12 cells. PC12 cells did not express GM1 (A), but expressed FucGM1 that reacted with Ctxb (B). Total lipids extracted from the PC12 cells were subjected to HPTLC-overlay assay with biotin-conjugated Ctxb (2.5 μg/ml). Resorcinol-HCl reagent was used for ganglioside detection. Lane 1: human brain ganglioside mixture; lane 2: authentic sample of fucosyl-GM1 (FucGM1); lane 3: total lipids extracted from PC12 cells (101).
Fig. 7.
Fig. 7.
Interactions of gangliosides and amyloid β-proteins in lipid rafts.
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