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. 2011 Jan 9:2011:193618.
doi: 10.4061/2011/193618.

The pathological roles of ganglioside metabolism in Alzheimer's disease: effects of gangliosides on neurogenesis

Toshio Ariga  1 , Chandramohan Wakade, Robert K Yu
Affiliations

The pathological roles of ganglioside metabolism in Alzheimer's disease: effects of gangliosides on neurogenesis

Toshio Ariga et al. Int J Alzheimers Dis. .

Abstract

Conversion of the soluble, nontoxic amyloid β-protein (Aβ) into an aggregated, toxic form rich in β-sheets is a key step in the onset of Alzheimer's disease (AD). It has been suggested that Aβ induces changes in neuronal membrane fluidity as a result of its interactions with membrane components such as cholesterol, phospholipids, and gangliosides. Gangliosides are known to bind Aβ. A complex of GM1 and Aβ, termed "GAβ", has been identified in AD brains. Abnormal ganglioside metabolism also may occur in AD brains. We have reported an increase of Chol-1α antigens, GQ1bα and GT1aα, in the brain of transgenic mouse AD model. GQ1bα and GT1aα exhibit high affinities to Aβs. The presence of Chol-1α gangliosides represents evidence for genesis of cholinergic neurons in AD brains. We evaluated the effects of GM1 and Aβ1-40 on mouse neuroepithelial cells. Treatment of these cells simultaneously with GM1 and Aβ1-40 caused a significant reduction of cell number, suggesting that Aβ1-40 and GM1 cooperatively exert a cytotoxic effect on neuroepithelial cells. An understanding of the mechanism on the interaction of GM1 and Aβs in AD may contribute to the development of new neuroregenerative therapies for this disorder.

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Figures

Figure 1
Figure 1
Immunohistochemical localization of Aβs in the cortex of double transgenic mice coexpressing mouse/human chimeric APP with the Swedish mutation and human presenilin-1 with deletion of exon 9. The coronal brain sections are 12 μm in thickness. Nuclei (blue) and Aβ (red) were stained with Hoechst 33258 and antihuman Aβ antibody, respectively. (a) low-magnification view; (b) high-magnification view. Bar = 20 μm in (a); 5 μm in (b). (Reproduced from [85] with permission).
Figure 2
Figure 2
The content of Chol-1α antigens, GT1aα (a) and GQ1bα (b), in AD model mouse brains [85]. GT1aα and GQ1bα extracted from brains of AD model double transgenic mice coexpressing mouse/human chimeric APP with the Swedish mutation and human presenilin-1 with a deletion of exon 9 (Tg) or age-matched wild-type mice (WT) were quantified by densitometric analysis of high-performance thin-layer chromatography immunostaining. n = 3–7. (Reproduced from [85] with permission).
Scheme 1
Scheme 1
Figure 3
Figure 3
Effects of low (a) and high (b) concentrations of GM1 and Aβ1–40 on NECs. Basic fibroblast growth factor (bFGF; 0 or 5 ng/mL) was added as a mitogen of NECs. The number of NECs cultured in the presence of bFGF for 4 days was estimated by WST-8 assay with (a) GM1 (0, 1, 5 or 10 μM) and Aβ1–40 (0, 1 or 5 μM); with (b) GM1 (0 or 40 μM) and Aβ1–40 (0 or 10 μM). The spectrophotometric absorbance (Abs.) measured at the wavelength of 450 nm (reference, 650 nm) by this assay is highly correlated with the number of living NECs [113]. (Reproduced from [114] with permission).
Figure 4
Figure 4
Incorporation of exogenously added GM1 and Aβ1–40 into NECs. NECs were cultured in the presence of GM1 (0 or 40 μM) and/or fluorescein isothiocyanate-conjugated Aβ1–40 (FITC-Aβ1–40; 0 or 10 μM) for 2 days, and then stained with biotin-conjugated CTXB, a probe to detect GM1, and rhodamine-conjugated streptavidin. Nuclei were stained with Hoechst 33258. (Reproduced from [114] with permission).
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References

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