Capacitative calcium entry deficits and elevated luminal calcium content in mutant presenilin-1 knockin mice.
Dysregulation of calcium signaling has been causally implicated in brain aging and Alzheimer's disease. Mutations in the presenilin genes (PS1, PS2), the leading cause of autosomal dominant familial Alzheimer's disease (FAD), cause highly specific alterations in intracellular calcium signaling pathways that may contribute to the neurodegenerative and pathological lesions of the disease. To elucidate the cellular mechanisms underlying these disturbances, we studied calcium signaling in fibroblasts isolated from mutant PS1 knockin mice. Mutant PS1 knockin cells exhibited a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation. These cells also showed significant impairments in capacitative calcium entry (CCE, also known as store-operated calcium entry), an important cellular signaling pathway wherein depletion of intracellular calcium stores triggers influx of extracellular calcium into the cytosol. Notably, deficits in CCE were evident after agonist stimulation, but not if intracellular calcium stores were completely depleted with thapsigargin. Treatment with ionomycin and thapsigargin revealed that calcium levels within the ER were significantly increased in mutant PS1 knockin cells. Collectively, our findings suggest that the overfilling of calcium stores represents the fundamental cellular defect underlying the alterations in calcium signaling conferred by presenilin mutations.
Leissring
M A
MA
Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory and Institute for Brain Aging and Dementia, University of California Irvine 92697-4561, USA.
Akbari
Y
Y
Fanger
C M
CM
Cahalan
M D
MD
Mattson
M P
MP
LaFerla
F M
FM
D000544:Alzheimer Disease / Q000209:etiology; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010716:Phosphatidylinositols / Q000378:metabolism; D053764:Presenilin-1
D008565:Membrane Proteins; D010716:Phosphatidylinositols; D053764:Presenilin-1; D001839:Bombesin; D001920:Bradykinin; D002118:Calcium