We have shown that cortical neurons challenged with toxic concentrations of β-amyloid peptide (βAP) enter the S phase of the cell cycle before apoptotic death. Searching for a signaling molecule that lies at the border between cell proliferation and apoptotic death, we focused on the disialoganglioside GD3. Exposure of rat cultured cortical neurons to 25 μM βAP(25-35) induced a substantial increase in the intracellular levels of GD3 after 4 hr, a time that precedes neuronal entry into S phase. GD3 levels decreased but still remained higher than in the control cultures after 16 hr of exposure to βAP(25-35). Confocal microscopy analysis showed that the GD3 synthesized in response to βAP colocalized with nuclear chromatin. The increase in GD3 was associated with a reduction of sphingomyelin (the main source of the ganglioside precursor ceramide) and with the induction of α-2,8-sialyltransferase (GD3 synthase), the enzyme that forms GD3 from the monosialoganglioside GM3. A causal relationship between GD3, cell-cycle activation, and apoptosis was demonstrated by treating the cultures with antisense oligonucleotides directed against GD3 synthase. This treatment, which reduced βAP(25-35)-stimulated GD3 formation by â¼50%, abolished the neuronal entry into the S phase and was protective against β AP(25-35)-induced apoptosis.
Copani, A., Melchiorri, D., Caricasole, A., Martini, F., Sale, P., Carnevale, R., Gradini, R., Sortino, M. A., Lenti, L., De Maria, R., Nicoletti, F., β-amyloid-Induced Synthesis of the Ganglioside Gd3 Is a Requisite for Cell Cycle Reactivation and Apoptosis in Neurons, <<THE JOURNAL OF NEUROSCIENCE>>, 2002; 22 (10): 3963-3968. [doi:10.1523/jneurosci.22-10-03963.2002] [http://hdl.handle.net/10807/113857]
β-amyloid-Induced Synthesis of the Ganglioside Gd3 Is a Requisite for Cell Cycle Reactivation and Apoptosis in Neurons
De Maria, Ruggero;
2002
Abstract
We have shown that cortical neurons challenged with toxic concentrations of β-amyloid peptide (βAP) enter the S phase of the cell cycle before apoptotic death. Searching for a signaling molecule that lies at the border between cell proliferation and apoptotic death, we focused on the disialoganglioside GD3. Exposure of rat cultured cortical neurons to 25 μM βAP(25-35) induced a substantial increase in the intracellular levels of GD3 after 4 hr, a time that precedes neuronal entry into S phase. GD3 levels decreased but still remained higher than in the control cultures after 16 hr of exposure to βAP(25-35). Confocal microscopy analysis showed that the GD3 synthesized in response to βAP colocalized with nuclear chromatin. The increase in GD3 was associated with a reduction of sphingomyelin (the main source of the ganglioside precursor ceramide) and with the induction of α-2,8-sialyltransferase (GD3 synthase), the enzyme that forms GD3 from the monosialoganglioside GM3. A causal relationship between GD3, cell-cycle activation, and apoptosis was demonstrated by treating the cultures with antisense oligonucleotides directed against GD3 synthase. This treatment, which reduced βAP(25-35)-stimulated GD3 formation by â¼50%, abolished the neuronal entry into the S phase and was protective against β AP(25-35)-induced apoptosis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.