ACTIVATION OF PROTEIN-KINASE-C INHIBITS CELLULAR PRODUCTION OF THE AMYLOID BETA-PROTEIN

The 39-43-amino acid amyloid beta-protein (Abeta), which is progressiv ely deposited in cerebral plaques and blood vessels in Alzheimer's dis ease (AD), is released by cultured human cells during normal metabolis m. Here we show that agents which activate protein kinase C or otherwi se enhance protein phosphorylation caused a substantial decrease in Ab eta production in vitro. Protein kinase C activation also markedly dec reased Abeta release from cells that express mutant forms of the beta- amyloid precursor protein genetically linked to familial AD. Inhibitio n of Abeta secretion could also be effected by direct stimulation of m 1 muscarinic acetylcholine receptors with carbachol. These results dem onstrate that activation of the protein kinase C signal transduction p athways down-regulates the generation of the amyloidogenic Abeta pepti de. Pharmacologic agents that activate this system, including a variet y of first messengers, could potentially slow the development or growt h of some Abeta plaques during the early stages of AD.