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

Ruggero De Maria Marchiano, Agata Copani, Daniela Melchiorri, Andrea Caricasole, Francesca Martini, Patrizio Sale, Roberto Carnevale, Roberto Gradini, Maria Angela Sortino, Luisa Lenti, Ferdinando Nicoletti

Risultato della ricerca: Contributo in rivistaArticolo in rivista

83 Citazioni (Scopus)

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 ∼50%, abolished the neuronal entry into the S phase and was protective against β AP(25-35)-induced apoptosis.
Lingua originaleEnglish
pagine (da-a)3963-3968
Numero di pagine6
RivistaTHE JOURNAL OF NEUROSCIENCE
Volume22
Stato di pubblicazionePubblicato - 2002

Keywords

  • Alzheimer's disease
  • Apoptosis
  • Cell cycle
  • Ganglioside GD3
  • Neurodegeneration
  • Neuroscience (all)
  • β-amyloid

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