Cholinesterase inhibitors, beta-amyloid precursor protein and amyloid beta-peptides in Alzheimer's disease

The extracellular deposition of amyloid beta-peptide (A beta) in the form o f cerebrovascular amyloid and extracellular plaques is one of the major neu ropathological manifestations of Alzheimer's disease (AD). A beta is genera ted proteolytically from the large beta-amyloid precursor protein (APP). AP P is cleaved by a group of proteases called "secretase" to generate soluble derivatives of APP (sAPP), which are secreted in human plasma. CSF and cul tured cells. Neurochemically, there is a severe loss of cholinergic neurons and a decreased synthesis of acetylcholine in neocortex in AD. Current app roved AD drugs, such as aricept and tacrine, are based on the use of cholin esterase inhibitors (ChEIs) and have been reported to improve memory defici ts and cognitive decline in some patients with AD. To compare the effects o f ChEIs on APP processing, we have tested a series of ChEIs such as tacrine , physostigmine, metrifonate, phenserine and cymserine in cultured human ne uroblastoma cells. We analyzed levels of sAPP by immunochemical techniques with APP-specific antibodies and assayed levels of AS by a sensitive sandwi ch ELISA. Based on these results, ChEIs can be divided into three groups: t he first group of ChEIs had no effect on sAPP secretion, the second decreas ed the sAPP secretion only, and third group affected the secretion of sAPP and A beta. The difference in the action of metrifonate, physostigmine. phe nserine and tacrine on APP processing is independent of their selectivity f or the cholinesterase enzymes. This possibly is due to the different target s that are used by ChEIs. Studying the effects of ChEIs on different target s is useful to maximize the benefit of ChEIs for the treatment of AD subjec ts.