In vitro effects of metrifonate on neuronal amyloid precursor protein processing and protein kinase C level

Alteration in the processing of the amyloid precursor protein (APP) is a ce ntral event in the formation of amyloid deposits in the brains of individua ls with Alzheimer's disease (AD). It has been suggested that acetylcholines terase (AChE) inhibitors, which promote the cholinergic function and conseq uently improve the cognitive deficits, may also exert a neuroprotective eff ect by activating normal APP processing. We now report that an irreversible AChE inhibitor (metrifonate) increase the cell-associated APP level in a b asal forebrain neuronal culture and also elevate the amount of APP secreted into the medium. The alterations in APP processing were accompanied by inc reased protein kinase C (PKC) levels. The results suggest that AChE inhibit ors modulate the metabolism of APP, possibly via their stimulatory effects on PKC. Since changes in the activity and level of PE;C may be involved in the pathogenesis of AD, it is concluded that the beneficial effect of metri fonate in AD therapy may be due not only to the stimulatory cholinergic fun ction, but also to its activating effect on PKC. (C) 2000 Elsevier Science B.V. All rights reserved.