Addition of the beta-hydroxy-beta-methylglutaryl-CoA (HmG-CoA) reductase inhibitor lovastatin to human HEK cells transfected with the amyloid precursor protein (APP) reduces intracellular cholesterol/protein ratios by 50%, and markedly inhibits beta-secretase cleavage of newly-synthesized APP. Exogenous water-solubilized cholesterol at 200 microg/ml concentration increases newly synthesized beta-amyloidogenic products four-fold. These intracellular changes are detectable by immunoprecipitation and immunofluorescent labelling. Analyses of the fragments captured from culture medium by an N-terminal anti-beta-amyloid antibody on ProteinChip arrays and detected using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry revealed that culture with cholesterol (200 microg/ml) increased secretion of beta-amyloid 1-40 by 1.8-fold, and increased secretion of beta-amyloid 1-42. Changes in APP processing by cholesterol may mediate the way in which the ApoE4 allele increases risk of developing Alzheimer's disease (AD) in western populations.

Worldwide, policymakers, health system managers, practitioners and researchers struggle to use evidence to improve policy and practice. There is growing recognition that this challenge relates to the complex systems in which we work. The corresponding increase in complexity-related discourse remains primarily at a theoretical level. This paper moves the discussion to a practical level, proposing actions that can be taken to implement evidence successfully in complex systems. Key to success is working with, rather than trying to simplify or control, complexity. The integrated actions relate to co-producing knowledge, establishing shared goals and measures, enabling leadership, ensuring adequate resourcing, contributing to the science of knowledge-to-action, and communicating strategically.

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