Modulation of γ-Secretase Activity by Multiple Enzyme-Substrate Interactions: Implications in Pathogenesis of Alzheimer's Disease

BACKGROUND: We describe molecular processes that can facilitate pathogenesis of Alzheimer's disease (AD) by analyzing the catalytic cycle of a membrane-imbedded protease γ-secretase, from the initial interaction with its C99 substrate to the final release of toxic Aβ peptides. RESULTS: The C-terminal AICD fragment is cleaved first in a pre-steady-state burst. The lowest Aβ42/Aβ40 ratio is observed in pre-steady-state when Aβ40 is the dominant product. Aβ42 is produced after Aβ40, and therefore Aβ42 is not a precursor for Aβ40. The longer more hydrophobic Aβ products gradually accumulate with multiple catalytic turnovers as a result of interrupted catalytic cycles. Saturation of γ-secretase with its C99 substrate leads to 30% decrease in Aβ40 with concomitant increase in the longer Aβ products and Aβ42/Aβ40 ratio. To different degree the same changes in Aβ products can be observed with two mutations that lead to an early onset of AD, ΔE9 and G384A. Four different lines of evidence show that γ-secretase can bind and cleave multiple substrate molecules in one catalytic turnover. Consequently depending on its concentration, NotchΔE substrate can activate or inhibit γ-secretase activity on C99 substrate. Multiple C99 molecules bound to γ-secretase can affect processive cleavages of the nascent Aβ catalytic intermediates and facilitate their premature release as the toxic membrane-imbedded Aβ-bundles. CONCLUSIONS: Gradual saturation of γ-secretase with its substrate can be the pathogenic process in different alleged causes of AD. Thus, competitive inhibitors of γ-secretase offer the best chance for a successful therapy, while the noncompetitive inhibitors could even facilitate development of the disease by inducing enzyme saturation at otherwise sub-saturating substrate. Membrane-imbedded Aβ-bundles generated by γ-secretase could be neurotoxic and thus crucial for our understanding of the amyloid hypothesis and AD pathogenesis

Colloidal Lithography

This chapter is a visual guide to the numerous approaches to nanolithography nanofabrication on large area based on supramolecular self-assembly. A short history of this recent scientific and technological field, an outline of the most-cited methods of self-assembly, and tables reporting different nanofabrication methods are reported. Indications on requirements, advantages, and drawbacks of the various approaches are also listed in the table. Thanks to the recently developed metal-assisted catalytic etching (MACE), the colloidal patterns can be easily propagated to silicon and other semiconductors opening a wide field of morphology, nanostructures, and applications

Multisession Cognitive Bias Modification Targeting Multiple Biases in Adolescents with Elevated Social Anxiety

Research studies applying cognitive bias modification of attention (CBM-A) and interpretations (CBM-I) training to reduce adolescent anxiety by targeting associated cognitive biases have found mixed results. This study presents a new multi-session, combined bias CBM package, which uses a mix of training techniques and stimuli to enhance user-engagement. We present preliminary data on its viability, acceptability and effectiveness on reducing symptoms and biases using an A–B case series design. 19 adolescents with elevated social anxiety reported on their social anxiety, real-life social behaviours, general anxiety, depression, and cognitive biases at pre/post time-points during a 2-week baseline phase and a 2-week intervention phase. Retention rate was high. Adolescents also reported finding the CBM training helpful, particularly CBM-I. Greater reductions in social anxiety, negative social behaviour, and general anxiety and depression, characterised the intervention but not baseline phase. There was a significant correlation between interpretation bias change and social anxiety symptom change. Our enhanced multi-session CBM programme delivered in a school-setting appeared viable and acceptable. Training-associated improvements in social anxiety will require further verification in a study with an active control condition/group.Medical Research Counci