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The use of statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that block the synthesis of mevalonate (and downstream products such as cholesterol and nonsterol isoprenoids), as a therapy for Alzheimer disease is currently the subject of intense debate. It has been reported that statins reduce the risk of developing the disorder, and a link between cholesterol and Alzheimer disease pathophysiology has been proposed. Moreover, experimental studies focusing on the cholesterol-dependent effects of statins have demonstrated a close association between cellular cholesterol levels and amyloid production. However, evidence suggests that statins are pleiotropic, and the potential cholesterol-independent effects of statins on amyloid precursor protein (APP) metabolism and amyloid ␤-peptide (A␤) genesis are unknown. In this study, we developed a novel in vitro system that enabled the discrete analysis of cholesterol-dependent and -independent (i.e. isoprenoid-dependent) statin effects on APP cleavage and A␤ formation. Given the recent interest in the role that intracellular A␤ may play in Alzheimer disease, we analyzed statin effects on both secreted and cell-associated A␤. As reported previously, low cellular cholesterol levels favored the ␣-secretase pathway and decreased A␤ secretion presumably within the endocytic pathway. In contrast, low isoprenoid levels resulted in the accumulation of APP, amyloidogenic fragments, and A␤ likely within biosynthetic compartments. Importantly, low cholesterol and low isoprenoid levels appeared to have completely independent effects on APP metabolism and A␤ formation. Although the implications of these effects for Alzheimer disease pathophysiology have yet to be investigated, to our knowledge, these results provide the first evidence that isoprenylation is involved in determining levels of intracellular A␤.A growing body of evidence suggests that the amyloid ␤-peptide (A␤) 1 plays a critical and early role in Alzheimer disease (AD) pathogenesis. AD is characterized by cerebral amyloid plaques, which are extracellular deposits of A␤ (1, 2). Overproduction of the 42-amino acid form of A␤ (A␤42) is associated with early onset familial AD, and A␤42 appears toxic to neurons in vitro and in vivo (reviewed in Refs. 3 and 4). Moreover, recent reports suggest that, in addition to extracellular A␤, the accumulation of intracellular A␤ may be involved in AD (5-15). Thus, much research has been devoted to understanding the role of A␤ in AD and to developing therapeutic strategies for reducing A␤ levels or toxicity. A␤ is cleaved from amyloid precursor protein (APP) by two proteases, the ␤-and ␥-secretases (reviewed in Refs. 4, 16, and 17). Initially, ␤-secretase (also known as BACE1) cuts APP at the N terminus of the A␤ domain to produce the membranebound APP C-terminal fragment (CTF) C99 and the secreted APP ectodomain APPs␤. C99 is the substrate of ␥-secretase, which cleaves to generate the C terminus of A␤. ␥-Secretase cleavage is heterogeneous and produces A␤ peptides of different le...

IntroductionThis study evaluated the impact of a waiting room-administered, low-literacy, computer multimedia diabetes education program on patient self-management and provider intensification of therapy.MethodsIn this randomized, controlled trial, 129 participants either viewed a computer multimedia education program (intervention group) or read an educational brochure (control group) while in the waiting room. Participants were uninsured, primarily ethnic minority adults with type 2 diabetes receiving care from a county clinic in Chicago, Illinois. Wilcoxon test, t-test, and linear mixed model analyses evaluated changes in diabetes knowledge, self-efficacy, behaviors, medications prescribed, hemoglobin A1c (HbA1c), and blood pressure levels over 3 months.ResultsDuring the study period, there was an increase in the number of oral diabetes medications prescribed over three months to multimedia users compared with those in the control group (P=0.017). HbA1c declined by 1.5 in the multimedia group versus 0.8 in the control group (P=0.06). There were no differences between groups in changes in blood pressure levels, self-efficacy, and most diabetes-related behaviors. Self-reported exercise increased in the control group compared with the multimedia group (0.9 days/week vs. 0.1 days/week, P=0.016).ConclusionMultimedia users received a greater intensification of diabetes therapy, but demonstrated no difference in self-management in comparison with those receiving educational brochures. The availability of a computer multimedia program in the waiting room appears to be a novel and acceptable approach in providing diabetes education for underserved populations.

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