DHA Supplemented in Peptamen Diet Offers No Advantage in Pathways to Amyloidosis: Is It Time to Evaluate Composite Lipid Diet?

Numerous reports have documented the beneficial effects of dietary docosahexaenoic acid (DHA) on beta-amyloid production and Alzheimer's disease (AD). However, none of these studies have examined and compared DHA, in combination with other dietary nutrients, for its effects on plaque pathogenesis. Potential interactions of DHA with other dietary nutrients and fatty acids are conventionally ignored. Here we investigated DHA with two dietary regimes; peptamen (pep+DHA) and low fat diet (low fat+DHA). Peptamen base liquid diet is a standard sole-source nutrition for patients with gastrointestinal dysfunction. Here we demonstrate that a robust AD transgenic mouse model shows an increased tendency to produce beta-amyloid peptides and amyloid plaques when fed a pep+DHA diet. The increase in beta-amyloid peptides was due to an elevated trend in the levels of beta-secretase amyloid precursor protein (APP) cleaving enzyme (BACE), the proteolytic C-terminal fragment beta of APP and reduced levels of insulin degrading enzyme that endoproteolyse beta-amyloid. On the contrary, TgCRND8 mice on low fat+DHA diet (based on an approximately 18% reduction of fat intake) ameliorate the production of abeta peptides and consequently amyloid plaques. Our work not only demonstrates that DHA when taken with peptamen may have a tendency to confer a detrimental affect on the amyloid plaque build up but also reinforces the importance of studying composite lipids or nutrients rather than single lipids or nutrients for their effects on pathways important to plaque development

In Vivo Characterization of a Novel -Secretase Inhibitor SCH 697466 in Rodents and Investigation of Strategies for Managing Notch-Related Side Effects

Substantial evidence implicates -amyloid (A) peptides in the etiology of Alzheimer’s disease (AD). A is produced by the proteolytic cleavage of the amyloid precursor protein by - and -secretase suggesting that -secretase inhibition may provide therapeutic benefit for AD. Although many -secretase inhibitors have been shown to be potent at lowering A, some have also been shown to have side effects following repeated administration. All of these side effects can be attributed to altered Notch signaling, another -secretase substrate. Here we describe the in vivo characterization of the novel -secretase inhibitor SCH 697466 in rodents. Although SCH 697466 was effective at lowering A, Notch-related side effects in the intestine and thymus were observed following subchronic administration at doses that provided sustained and complete lowering of A. However, additional studies revealed that both partial but sustained lowering of Aand complete but less sustained lowering of A were successful approaches for managing Notch-related side effects. Further, changes in several Notch-related biomarkers paralleled the side effect observations. Taken together, these studies demonstrated that, by carefully varying the extent and duration of A lowering by -secretase inhibitors, it is possible to obtain robust and sustained lowering of A without evidence of Notch-related side effects