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The Journal of Neuroscience, May 15, 2002, 22(10):3963-3968

-Amyloid-Induced Synthesis of the Ganglioside Gd3 Is a Requisite for Cell Cycle Reactivation and Apoptosis in Neurons

Agata Copani¹, Daniela Melchiorri³, Andrea Caricasole³, Francesca Martini⁴, Patrizio Sale⁴, Roberto Carnevale⁴, Roberto Gradini⁴, Maria Angela Sortino², Luisa Lenti⁴, Ruggero De Maria⁵, and Ferdinando Nicoletti^{3, 6}

Departments of ¹ Pharmaceutical Sciences and ² Experimental and Clinical Pharmacology, University of Catania, 95125 Catania, Italy, Departments of ³ Human Physiology and Pharmacology and ⁴ Experimental Medicine and Pathology, University of Rome "La Sapienza," 00185 Rome, Italy, ⁵ Laboratory of Hematology and Oncology, Istituto Superiore di Sanità, 00185 Rome, Italy, and ⁶ I.N.M. Neuromed, 86077 Pozzilli, Italy

We have shown that cortical neurons challenged with toxic concentrations of -amyloid peptide (AP) 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 AP(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 AP(25-35). Confocal microscopy analysis showed that the GD3 synthesized in response to AP 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 -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 AP(25-35)-stimulated GD3 formation by ~50%, abolished the neuronal entry into the S phase and was protective against AP(25-35)-induced apoptosis.

Key words: Alzheimer's disease; -amyloid; cell cycle; ganglioside GD3; apoptosis; neurodegeneration

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22103963-06$05.00/0

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