siRNA against presenilin 1 (PS1) down regulates amyloid β42 production in IMR-32 cells

In this study we used RNA interference (RNAi) technology to examine the effects of small-interfering RNA (siRNA) against PS1 on expression levels of PS1 and Aβ42 in IMR-32 Cells using RTPCR, western blotting and immunofluorescence techniques.The results of the present study showed down regulation of PS1 and Aβ42 in IMR32 cells transfected with siRNA against PS1.Our results substantiate the concept that PS1 is involved in γ-secretase activity and provides the rationale for therapeutic strategies aimed at influencing Aβ42 production.A key step in the pathogenesis of AD is proteolysis of APP that results in the formation of the amyloid-β protein (Aβ), the principle protein component of the characteristic cerebral plaques of the disease [1]. Aβ is produced from APP ？rst by the action of β- secretase, a membrane-tethered enzyme that resembles pepsin and other water-soluble aspartyl proteases [2]. This proteolysis leads to membrane shedding of the large luminal/extracellular APP domain. The 99-residue membrane-bound remnant is then cleaved in the middle of its transmembrane region by γ -secretase, releasing Aβ and again near the inner lea？et at the β site to release the APP intracellular domain (AICD) [3]. Rare mutations in the APP gene, found in and around the Aβ region cause familial early-onset Alzheimer's disease (EOAD) and these mutations alter the production of Aβ or its aggregation properties [4]. Several contemporaneous observations provided critical clues for the identi？cation of the elusive γ-secretase. First, genes encoding the multi-pass membrane proteins presenilin-1 and presenilin-2 (PS1&PS2) were discovered in a search to identify other genes associated with familial EOAD. The disease-causing missense mutations were soon found to alter how γ -secretase cuts APP leading to increased proportions of longer, more aggregation-prone forms of Aβ [5]. Second, knock out of PS-1 dramatically reduced γ -secretase cleavage of APP [6]. Third, the types of compounds that