GAMMA-SECRETASE MEDIATED-MODULATION OF CALCIUM SIGNALING





F. M. LaFerla and M. A. Leissring

University of California, Irvine
Department of Neurobiology and Behavior
1109 Gillespie Neuroscience Research Facility
Irvine, CA 92697-4545




Mutations in the presenilin genes (PS1 and PS2) are responsible for the majority of early-onset, autosomal dominant familial Alzheimer's disease cases. Two highly consistent and invariant consequences of presenilin mutations have been causally implicated in the pathogenesis of familial Alzheimer's disease: (1) increased gamma-secretase mediated cleavage of the beta-amyloid precursor protein which results in elevated beta-amyloid(1-42) formation, and (2) specific alterations of intracellular calcium signaling pathways. Our lab has reported that mutations in the presenilin genes lead to enhanced calcium release from intracellular stores and deficits in capacitative calcium entry. However, the relationship between the presenilin-mediated effects on gamma-secretase activity and calcium dysregulation is not well understood. To determine the relationship between beta-amyloid formation and presenilin-mediated calcium disturbances, we studied calcium signaling in cells with diminished gamma-secretase activity, achieved by either genetic or pharmacological manipulations. In genetically-modified cells in which either the PS1 gene alone, the PS2 gene alone, or both were ablated, we found that calcium responsiveness to agonist stimulation correlated very highly with gamma-secretase activity. Likewise, pharmacological inhibition of gamma-secretase activity produced a comparable diminution of calcium responsiveness. These data support a close relationship between the gamma-secretase-mediated changes in beta-amyloid formation and calcium signaling.


Supported by the American Federation of Aging Research, American Health Assistance Foundation, and NIH P50 AG16573.




Key words: Alzheimer; presenilin; calcium; gamma-secretase







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