Reduction of Ca2+ stores and capacitative Ca2+ entry is associated with the familial Alzheimer's disease presenilin-2 T122R mutation and anticipates the onset of dementia

Marta Giacomello, Laura Barbiero, Giancarlo Zatti, Rosanna Squitti, Giuliano Binetti, Tullio Pozzan, Cristina Fasolato, Roberta Ghidoni, Paola Pizzo

Research output: Contribution to journalArticle


Mutations in the presenilin genes PS1 and PS2, the major cause of familial Alzheimer's disease (FAD), are associated with alterations in Ca2+ signalling. In contrast to the majority of FAD-linked PS1 mutations, which cause an overload of intracellular Ca2+ pools, the FAD-linked PS2 mutation M239I reduces Ca2+ release from intracellular stores [Zatti, G., Ghidoni, R., Barbiero, L., Binetti, G., Pozzan, T., Fasolato, C., Pizzo, P., 2004. The presenilin 2 M239I mutation associated with Familial Alzheimer's Disease reduces Ca2+ release from intracellular stores. Neurobiol. Dis. 15/2, 269-278]. We here show that in human FAD fibroblasts another PS2 mutation (T122R) reduces both Ca2+ release and capacitative Ca 2+ entry. The observation, done in two monozygotic twins, is of note since only one of the subjects showed overt signs of disease at the time of biopsy whereas the other one developed the disease 3 years later. This finding indicates that Ca2+ dysregulation anticipates the onset of dementia. A similar Ca2+ alteration occurred in HeLa and HEK293 cells transiently expressing PS2-T122R. Based on these data, the "Ca2+ overload" hypothesis in AD pathogenesis is here discussed and reformulated.

Original languageEnglish
Pages (from-to)638-648
Number of pages11
JournalNeurobiology of Disease
Issue number3
Publication statusPublished - Apr 2005



  • Alzheimer's disease
  • Ca homeostasis
  • Capacitative Ca entry
  • Fibroblasts
  • Monozygotic twins
  • Presenilin

ASJC Scopus subject areas

  • Neurology

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