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Comparative Study
. 2010 Oct 4;2(4):e00044.
doi: 10.1042/AN20100021.

Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1α antigens in the brain

Toshio Ariga  1 , Makoto Yanagisawa, Chandramohan Wakade, Susumu Ando, Jerry J Buccafusco, Michael P McDonald, Robert K Yu
Affiliations
Comparative Study

Ganglioside metabolism in a transgenic mouse model of Alzheimer's disease: expression of Chol-1α antigens in the brain

Toshio Ariga et al. ASN Neuro. .

Abstract

The accumulation of Aβ (amyloid β-protein) is one of the major pathological hallmarks in AD (Alzheimer's disease). Gangliosides, sialic acid-containing glycosphingolipids enriched in the nervous system and frequently used as biomarkers associated with the biochemical pathology of neurological disorders, have been suggested to be involved in the initial aggregation of Aβ. In the present study, we have examined ganglioside metabolism in the brain of a double-Tg (transgenic) mouse model of AD that co-expresses mouse/human chimaeric APP (amyloid precursor protein) with the Swedish mutation and human presenilin-1 with a deletion of exon 9. Although accumulation of Aβ was confirmed in the double-Tg mouse brains and sera, no statistically significant change was detected in the concentration and composition of major ganglio-N-tetraosyl-series gangliosides in the double-Tg brain. Most interestingly, Chol-1α antigens (cholinergic neuron-specific gangliosides), such as GT1aα and GQ1bα, which are minor species in the brain, were found to be increased in the double-Tg mouse brain. We interpret that the occurrence of these gangliosides may represent evidence for generation of cholinergic neurons in the AD brain, as a result of compensatory neurogenesis activated by the presence of Aβ.

Keywords: AD, Alzheimer's disease; APP, amyloid precursor protein; Alzheimer's disease; Aβ, amyloid β-peptide; Chol-1α antigen; HPTLC, high-performance TLC; PSEN, presenilin; PSEN1dE9, PSEN-1 with a deletion of exon 9; Tg, transgenic; WT, wild-type; amyloid β-peptide; cholinergic neuron; ganglioside; transgenic mouse.

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Figures

Figure 1
Figure 1. Immunohistochemical localization of Aβ in the cortex of double-Tg mice co-expressing APPswe and PSEN1dE9
The coronal brain sections are 12 μm thick. Nuclei (blue) and Aβ (red) were stained with Hoechst 33258 and anti-human Aβ antibody respectively. (a) Low-magnification view; (b) high-magnification view. Scale bar: (a) 20 μm and (b) 5 μm.
Figure 2
Figure 2. Serum Aβ1–42 concentration in double-Tg and age-matched WT mice
Serum Aβ1–42 concentrations were quantified using a Human β Amyloid (1–42) ELISA kit, High-Sensitive (Wako Chemicals USA); n = 3–4.
Figure 3
Figure 3. Expression of gangliosides in double-Tg and age-matched WT mouse brains
Lanes 1–3, male WT mouse brain gangliosides; lanes 4–6, female WT mouse brain gangliosides; lanes 7–11, male double-Tg mouse brain gangliosides; lanes 12–14, female double-Tg mouse brain gangliosides; lane 15, authentic GT1aα (4 ng) and GQ1bα (20 ng). Gangliosides were separated by HPTLC with a solvent system of chloroform/methanol/0.2% CaCl2 (55:45:10, by volume) and visualized by (a) orcinol/sulfuric acid staining or (b) immunostaining with an anti-Chol-1α monoclonal antibody (GGR-41).
Figure 4
Figure 4. The content of Chol-1α antigens, GT1aα (a) and GQ1bα (b), in double-Tg and age-matched WT mouse brains
GT1aα and GQ1bα were quantified by densitometric analysis of HPTLC immunostaining; n = 3–8. Statistical analyses were performed by the Student's t test. For GT1aα, P<0.01 (Tg male compared with WT male); P<0.04 (Tg female compared with WT female); P<0.05 (Tg male compared with Tg female) respectively. For GQ1bα, P<0.03 (Tg male compared with WT male); P<0.02 (Tg female compared with WT female); P<0.02 (Tg male compared with Tg female) respectively.
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