RESTORATION OF TEA-INDUCED CALCIUM RESPONSES IN FIBROBLASTS FROM ALZHEIMERS-DISEASE PATIENTS BY A PKC ACTIVATOR

Several alterations in fibroblasts of Alzheimer's disease (AD) patient s have been described, including alterations in calcium regulation, pr otein kinase C (PKC), and potassium (K+) channels. Studies have also f ound reduced levels of the or isoform of PKC in brains and fibroblasts of AD patients. Since PKC is known to regulate ion channels, we studi ed K+ channel activity in fibroblasts from AD patients in the presence of (2S, 5S)-8-(1-decynyl)benzolactam (BL), a novel activator of PKC w ith improved selectivity for the alpha, beta, and gamma isoforms. We p resent evidence for restoration of normal K+ channel function, as meas ured by TEA-induced [Ca2+](i) elevations, due to activation of PKC by BL. Representative patch-clamp data further substantiate the effect of BL on restoration of 113pS K+ channel activity. Immunoblotting analys es using an alpha-isozyme-specific PKC antibody confirm that BL-treate d fibroblasts of AD patients show increased PKC activation. The presen t study suggests that PKC activator-based restoration of K+ channels m ay offer another approach to the investigation of AD pathophysiology, which in turn could lead to the development of a useful model for AD t herapeutics, (C) 1998 Academic Press.