Journal
NEUROBIOLOGY OF DISEASE
Volume 18, Issue 3, Pages 638-648Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2004.10.016
Keywords
presenilin; Alzheimer's disease; Ca2+ homeostasis; capacitative Ca2+ entry; monozygotic twins; fibroblasts
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Funding
- Telethon [1226] Funding Source: Medline
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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 M2391 reduces Ca2+ release from intracellular stores [Zatti, G., Ghidoni, R., Barbiero, L., Binetti, G., Pozzan, T., Fasolato, C., Pizzo, P., 2004. The presenifin 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 Ca2+ 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. (c) 2004 Elsevier Inc. All rights reserved.
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