Internal Ca²⁺ mobilization is altered in fibroblasts from patients with Alzheimer disease

The recent demonstration of K⁺ channel dysfunction in fibroblasts from Alzheimer disease (AD) patients and past observations of Ca²⁺-mediated K⁺ channel modulation during memory storage suggested that AD, which is characterized by memory loss and other cognitive deficits, might also involve dysfunction of intracellular Ca²⁺ mobilization. Bombesin-induced Ca²⁺ release, which is inositol trisphosphate-mediated, is shown here to be greatly enhanced in AD fibroblasts compared with fibroblasts from control groups. Bradykinin, another activator of phospholipase C, elicits similar enhancement of Ca²⁺ signaling in AD fibroblasts. By contrast, thapsigargin, an agent that releases Ca²⁺ by direct action on the endoplasmic reticulum, produced no differences in Ca²⁺ increase between AD and control fibroblasts. Depolarization-induced Ca²⁺ influx data previously demonstrated the absence of between-group differences of Ca²⁺ pumping and/or buffering. There was no correlation between the number of passages in tissue culture and the observed Ca²⁺ responses. Furthermore, cells of all groups were seeded and analyzed at the same densities. Radioligand binding experiments indicated that the number and affinity of bombesin receptors cannot explain the observed differences. These and previous observations suggest that the differences in bombesin and bradykinin responses in fibroblasts and perhaps other cell types are likely to be due to alteration of inositol trisphosphate-mediated release of intracellular Ca²⁺.