Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels.

• Abstract: Presenilin-1 and -2 (PS1 and PS2) mutations, the major cause of familial Alzheimer's disease (FAD), have been causally implicated in the pathogenesis of neuronal cell death through a perturbation of cellular Ca(2+) homeostasis. We have recently shown that, at variance with previous suggestions obtained in cells expressing other FAD-linked PS mutations, PS2-M239I and PS2-T122R cause a reduction and not an increase in cytosolic Ca(2+) rises induced by Ca(2+) release from stores. In this contribution we have used different cell models: human fibroblasts from controls and FAD patients, cell lines (SH-SY5Y, HeLa, HEK293, MEFs) and rat primary neurons expressing a number of PS mutations, e.g. P117L, M146L, L286V, and A246E in PS1 and M239I, T122R, and N141I in PS2. The effects of FAD-linked PS mutations on cytosolic Ca(2+) changes have been monitored either by using fura-2 or recombinant cytosolic aequorin as the probe. Independently of the cell model or the employed probe, the cytosolic Ca(2+) increases, caused by agonist stimulation or full store depletion by drug treatment, were reduced or unchanged in cells expressing the PS mutations. Using aequorins, targeted to the endoplasmic reticulum or the Golgi apparatus, we here show that FAD-linked PS mutants lower the Ca(2+) content of intracellular stores. The phenomenon was most prominent in cells expressing PS2 mutants, and was observed also in cells expressing the non-pathogenic, "loss-of-function" PS2-D366A mutation. Taken as a whole, our findings, while confirming the capability of presenilins to modify Ca(2+) homeostasis, suggest a re-evaluation of the "Ca(2+) overload" hypothesis in AD and a new working hypothesis is presented.
• Authors: Giancarlo Zatti, Andrea Burgo, Marta Giacomello, Laura Barbiero, Roberta Ghidoni, Giulietta Sinigaglia, Cristina Florean, Silvia Bagnoli, Giuliano Binetti, Sandro Sorbi, Paola Pizzo, Cristina Fasolato (Affiliation: Department of Biomedical Sciences, University of Padua, Italy.)
• Journal: Cell calcium (Cell Calcium) Vol. 39 Issue 6 Pg. 539-50 (Jun 2006) ISSN: 0143-4160 [Print] Scotland
• PMID: 16620965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Presenilin-1
• Presenilin-2
• Calcium
• Amyloid Precursor Protein Secretases

Topics

• Adult
• Alzheimer Disease (genetics)
• Amyloid Precursor Protein Secretases (metabolism)
• Animals
• Calcium (metabolism)
• Cells, Cultured
• Clone Cells
• Cytosol (metabolism)
• Endoplasmic Reticulum (metabolism)
• Female
• Golgi Apparatus (metabolism)
• Hela Cells
• Humans
• Male
• Mice
• Middle Aged
• Mutation (genetics)
• Neurons (cytology, metabolism)
• Presenilin-1 (deficiency, genetics)
• Presenilin-2 (deficiency, genetics)
• Rats