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.