Phenserine

    Impairment of the cholinergic system is one of the most important clinical featured symptoms of AD. This process can be partially reversed by acetylcholinesterase inhibitors, including phenserine. Coincidentally, we have discovered that phenserine is a member of a class of preexisting medicinal compounds that also block APP translation by targeting the unique stemloop formed from 5'UTR sequences in APP mRNA.

       Indeed, studies of rats with forebrain cholinergic lesions have shown that phenserine decreases the level of APP production, unlike some other acetylcholinesterase inhibitors that increase the production of APP. Phenserine is an example of a small molecule (Mw = 487) that acts, at least in part, by blocking translation of APP mRNA through the regulation of the 5'UTR, to suppress APP synthesis, thus inhibiting A(3-peptide output (Dr. N. Greig, NIA, Baltimore, MD).

       We have tested the capacity of the lead compound phenserine (and other related RNA-targeting compounds) to block APP gene expression through 5'UTR sequences in APP mRNA. The iron chelator, Df, was used as a positive control, representing a small molecule that markedly suppressed APP mRNA translation via 5'UTR sequences (Molecular weight of Df = 656.8).