The effect of cholinesterase inhibitors on the secretion of APPS from rat brain cortex

In this study we examined the question whether cholinesterase inhibitors (ChEI) could alter the release of amyloid precursor protein (APP) from superfused brain cortical slices of the rat following electrical as well as pharmacological stimulation with bethanechol (BETHA). Three ChEI, both reversible and irreversible were tested for their ability to enhance the release of non-amyloidogenic soluble derivatives (APPs). These included physostigmine (PHY), heptyl-physostigmine (HEP) and 2,2-dichlorovinyldimethyl phosphate (DDVP), at the concentrations producing cholinesterase (ChE) inhibition ranging from 5% to 95%. All three ChEI elevated APPs release significantly above control levels. Electrical field stimulation significantly increased the release of APPs within 50 min. Similar increase was observed after muscarinic receptor stimulation with BETHA. Tetrodotoxin (TTX) completely blocked the effect of electrical stimulation. These findings suggest that long-term administration of ChEI to Alzheimer's disease (AD) patients may have a neuroprotective effect by activating normal APP processing and decreasing the formation of amyloidogenic APP products.