ºÚÁÏÍø

Abstract

Aβ accumulation is critical to the development of Alzheimer�s disease (AD). Current efforts at reducing A� 40 or 42 have focused on modulating γ-secretase to produce shorter Aβ, while attempting to spare other secretase functions. Earlier attempts at lowering total A� were unsatisfactory as they targeted the catalytic activities of β- or γ-secretase, enzymes known to also hydrolyze other substrates. New therapeutic approaches that can inhibit total Aβ without altering secretase activity are therefore of great interest. Here we demonstrate such a new, different and early approach for the treatment of AD. We previous showed that an interaction between APP and Presenilin (PS) in cell cultures is a required initial step in the ultimate production of Aβ from APP. Furthermore, if the entire NH2-terminal domain of the PS was first added to the culture, the amount of Aβ produced was significantly reduced. We exploited the potential therapeutic significance of these results to inquire whether isolated small soluble peptides within the NH2-terminal domain of PS-1 retained enough of the inhibitory activity of the whole domain, such that when added to model systems of AD, they effectively reduced Aβ production. Here we demonstrate that two small, non-over-lapping water-soluble peptides, P4 and P8 can substantially and specifically inhibit Aβ production in vitro and in the brains of APP transgenic mice. These peptide-induced reductions of total Aβ (and of Aβ 40 and 42) did not alter β- or γ-secretase activities. P4 and P8 offer new and effective potential drug candidates for the treatment of AD.

Biography

Nazneen Dewji is an Associate Professor at the University of California, San Diego. She was born in Tanzania and raised in England. She earned her B.Sc. (Hons.) in Biochemistry in 1978 and her Ph.D. in 1982 at the University of London. In 1986 she joined the department of Medicine at UCSD, where she began working on Alzheimer's disease (AD). The discoveries made in her laboratory support the development of new drug discovery targets for the treatment of AD. In 2006 she founded a company, Cenna Biosciences Inc., to further develop novel candidates for the treatment of AD.