Modulation of cholinergic synaptic functions by sialylcholesterol.
The effects of sialylcholesterol, a synthetic ganglioside analogue, on cholinergic synaptic functions were investigated using synaptosomes prepared from C57BL/6 mouse brain cortices. Addition of alpha-sialylcholesterol stimulated high K (50 mM)-evoked acetylcholine (ACh) release from synaptosomes at concentrations ranging from 1 to 5 microM. The beta-anomer of the sialyl compound also increased the neurotransmitter release at 5 microM, but the effect was much smaller than that of the alpha-anomer. Beta-sialylcholesterol appeared to increase high-affinity choline uptake and Ach synthesis, resulting in an increment in the release of ACh. On the other hand, alpha-sialylcholesterol did not change the synthetic rate of ACh, and instead it increased the depolarization=induced influx of calcium ions into synaptosomes, while the beta-anomer did not affect the divalent cation influx. The enhanced calcium influx is thought to increase ACh release from synaptosomes treated with alpha-sialylcholesterol. These results imply that the two anomers of sialylcholesterol may modulate the synaptic membrane machinery differently, that is, the alpha-anomer may activate voltage-dependent calcium channels and the beta-anomer may facilitate high-affinity choline uptake. In order to evaluate the ameliorating effect of sialylcholesterol, alpha-sialylcholesterol was applied to the synaptosomes from aged mice (34 months old), which have been shown to have a decreased ACh release (Tanaka et al., 1995, J Neurosci Res, in press [1]). The reduced neurotransmitter release recovered to the levels of younger animals, suggesting that sialylcholesterol might have a potential therapeutic use for restoring synaptic function that occurs in aged brains.
Tanaka
Y
Y
Department of Membrane Biochemistry, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Japan.
Ando
S
S
D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000254:growth & development / Q000502:physiology*; D002788:Cholesterol Esters / Q000494:pharmacology*; D002794:Choline / Q000378:metabolism; D005260:Female; D005732:Gangliosides; D007536:Isomerism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D012794:Sialic Acids / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology*
D002788:Cholesterol Esters; D005732:Gangliosides; D012794:Sialic Acids; C055195:N-acetylneuraminyl cholesterol; D002794:Choline; D000109:Acetylcholine; D002118:Calcium