Phenserine Regulates Translation of ß—Amyloid Precursor Protein Message

One of the major hallmarks of Alzheimer’s disease (AD) is the appearance of senile plaques primarily composed of amyloid s-peptide (As), which is derived from a larger protein called s-amyloid precursor protein, sAPP1. sAPP is cleaved by three enzymes, a-, s- and γ-secretases, to different protein fragments, including the toxic As and other C-terminal fragments implicated in the pathogenesis of AD.1 Our goal is to study agents that reduce sAPP expression, as this is the precursor to all the toxic fragments. Recently, we have synthesized a family of novel cholinesterase inhibitors (ChEIs), phenserine and analogues.2 Phenserine improves cognitive performance in rodents.3 Studies of rats with forebrain cholinergic lesions, known to increase sAPP in cholinergic projection areas, have shown that phenserine can prevent this rise and, additionally, reduce sAPP production in naive animals.4 As both sAPP processing and cholinesterase activity are affected in the AD brain, our current studies have focused on the molecular changes induced by ChEIs.5–7 We have reported that tacrine, a first generation of ChEIs for treatment of AD, could reduce the levels of secreted sAPP and As.7 We report herein, the mechanism through which phenserine interacts with the cellular processing of sAPP.