Neurobiology of Disease (Mar 2004)
The presenilin 2 M239I mutation associated with familial Alzheimer's disease reduces Ca2+ release from intracellular stores
Abstract
Mutations in presenilin (PS) genes account for the majority of the cases of the familial form of Alzheimer's disease (FAD). PS mutations have been correlated with both over-production of the amyloid-β-42 (Aβ42) peptide and alterations of cellular Ca2+ homeostasis.We here show, for the first time, the effect of the recently described PS2 FAD-associated M239I mutation on two major parameters of intracellular Ca2+ homeostasis: the Ca2+ storing capacity of the endoplasmic reticulum (ER) and the activation level of capacitative Ca2+ entry (CCE), the Ca2+ influx pathway activated by depletion of intracellular stores.Ca2+ release from intracellular stores was significantly reduced in fibroblasts from FAD patients, compared to that found in cells from healthy individuals or patients affected by sporadic forms of Alzheimer's Disease (AD). No significant difference was however found in CCE between FAD and control fibroblasts. Similar results were obtained in two cell lines (HEK293 and HeLa) stably or transiently expressing the PS2 M239I mutation.
