Benzolactam (BL) enhances sAPP secretion in fibroblasts and in PC12 cells

ACTIVATION of protein kinase C is known to favor the alpha-secretase proces sing of the Alzheimer's disease (AD) amyloid precursor protein (APP), resul ting in the generation of non-amyloidogenic soluble APP (sAPP). Consequentl y, the relative secretion of amyloidogenic A beta(1-40) and A beta(1-42(3)) is reduced. This is particularly relevant since fibroblasts and other cell s expressing APP acid presenilin AD mutations secrete increased amounts of total A beta and/or increased ratios of A beta(1-42(3))/A beta(1-40). Inter estingly, PKC defects have been found in AD brain (alpha and beta isoforms) and in fibroblasts (alpha isoform) from AD patients. Here, we use a novel PKC activator (benzolactam, BL) with improved selectivity for the alpha, be ta and gamma isoforms to enhance sAPP secretion in fibroblasts from AD pati ents and in PC12 cells. Incubation (2 h) of AD fibroblasts with BL (1 and 1 0 mu M) resulted in significant increases of sAPP secretion over basal leve ls. sAPP secretion in BL-treated AD cells was also slightly higher compared to control BL-treated fibroblasts, which only showed significant increases of sAPP secretion after treatment with 10 mu M BL. Staurosporine (a PKC in hibitor) eliminated the effects of BL in both control and AD fibroblasts. B L and a related compound (LQ12) also caused an similar to 3-fold sAPP secre tion in PC12 cells. The use of a novel and possibly non-tumorigenic PKC act ivator may prove useful to favor non-amyloidogenic APP processing and is, t herefore, of potential therapeutic value. NeuroReport 10:1035-1040 (C) 1999 Lippincott Williams & Wilkins.