CELL-CYCLE-DEPENDENT ABNORMAL CALCIUM RESPONSE IN FIBROBLASTS FROM PATIENTS WITH FAMILIAL ALZHEIMERS-DISEASE

Change in calcium response was studied to clarify the pathological pro cess of alzheimer's disease (AD). Cultured fibroblasts from patients w ith familial Alzheimer's disease (FAD; n = 6), sporadic Alzheimer's di sease (SAD); n = 4), and age-matched healthy control subjects (n = 4) were studied with an ACAS Interactive laser cytometer (ACAS-470). Fibr oblasts from two independent families with FAD (OS-1, and OS-2 familie s) showed a suppressed calcium response after stimulation by 100 nM br adykinin (BK) 100 nM vasopressin (VP) or 10% FCS in CA(2+)-free condit ion compared with control fibroblasts at 48 h after plating. However, on the 7th day after plating, the abnormal calcium response was no lon ger observed. The height of the calcium peak showed periodic variation , indicating a relationship of calcium response with the cell cycle. W hen fibroblasts from OS-1 and OS-2 families were arrested in S phase, they showed a significantly suppressed calcium peak after BK stimulati on. However, when those fibroblasts were arrested in other phases, the y showed the same calcium peak as the other cells. The suppression of calcium response in S phase was indistinguishable from the calcium sup pression induced by A23187 administration. Since Hardy type mutation o n amyloid precursor protein gene is found in the OS-1 family, the obse rved abnormalities in calcium response might be related with pathologi cal processing of amyloid precursor protein in AD. The reported abnorm al calcium response, which is observed most obviously in fibroblasts i n S phase, may indicate participation of the cell-cycle-dependent proc ess in the pathology of AD.