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 trisphosphatemediated release of intracellular Ca2+.A number of cellular changes have been observed in fibroblasts from patients with Alzheimer disease (AD). These include abnormality of glucose and energy-related metabolism (1), defective release of a cholinergic factor (2), abnormal f8-amyloid expression and processing (3), changes in Ca2+ metabolism (30-34), and altered p-adrenergic-induced cAMP formation (4). The recent demonstration of K+ channel dysfunction in AD fibroblasts (5, 6) and past observations of Ca2+-mediated K+ channel modulation during memory storage (7) suggested that AD, which is characterized by memory loss and other cognitive deficits (8, 9), might also involve dysfunction of intracellular Ca2+ mobilization. Bombesin (10-12), an agent that activates phospholipase C (PLC) to generate inositol 1,4,5-trisphosphate (1P3) (13)(14)(15) different for AD and control fibroblasts. f-Amyloid protein (23-25) itself, while causing the previously observed inactivation of K+ channels in AD fibroblasts, had no effect on the bombesin-elicited Ca2+ signals. These and other findings, together with measurements of bombesin receptor number, suggest that PLC/G-protein coupling and/or IP3 receptors are responsible for differences in Ca2+ responses between AD and non-AD fibroblasts. METHODSCell Lines. Human skin fibroblasts (Table 1) were purchased from the Coriell Cell Repositories (Camden, NJ). Cells were seeded and maintained as described (5). The number of passages was not significantly different between groups [AD, 10.9 ± 1.3 (mean ± SEM), n = 10; AC, 11.5 + 0.8, n = 8;...

Activation of protein kinase C (PKC) can mimic the biophysical effects of associative learning on neurons. Furthermore, classical conditioning of the rabbit nictitating membrane (a form of associative learning) produces translocation of PKC activity from the cytosolic to the membrane compartments of the CA1 region of the hippocampus. Evidence is provided here for a significant change in the amount and distribution of PKC within the CA1 cell field of the rabbit hippocampus that is specific to learning. This change is seen at 1 day after learning as focal increments of [3H]phorbol-12,13-dibutyrate binding to PKC in computer-generated images produced from coronal autoradiographs of rabbit brain. In addition, 3 days after learning, the autoradiographs suggest a redistribution of PKC within CA1 from the cell soma to the dendrites.

Postmortem, genetic, brain imaging, and peripheral cell studies all support decreased mitochondrial activity as a factor in the manifestation of Bipolar Disorder (BD). Because abnormal mitochondrial morphology is often linked to altered energy metabolism, we investigated whether changes in mitochondrial structure were present in brain and peripheral cells of patients with BD. Mitochondria from patients with BD exhibited size and distributional abnormalities compared with psychiatrically-healthy age-matched controls. Specifically, in brain, individual mitochondria profiles had significantly smaller areas, on average, in BD samples (P = 0.03). In peripheral cells, mitochondria in BD samples were concentrated proportionately more within the perinuclear region than in distal processes (P = 0.0008). These mitochondrial changes did not appear to be correlated with exposure to lithium. Also, these abnormalities in brain and peripheral cells were independent of substantial changes in the actin or tubulin cytoskeleton with which mitochondria interact. The observed changes in mitochondrial size and distribution may be linked to energy deficits and, therefore, may have consequences for cell plasticity, resilience, and survival in patients with BD, especially in brain, which has a high-energy requirement. The findings may have implications for diagnosis, if they are specific to BD, and for treatment, if they provide clues as to the underlying pathophysiology of BD.