Increased Expression of PS1 Is Sufficient to Elevate the Level and Activity of γ-Secretase In Vivo

Increase in the generation and deposition of amyloid-β (Aβ) plays a central role in the development of Alzheimer's Disease (AD). Elevation of the activity of γ-secretase, a key enzyme required for the generation for Aβ, can thus be a potential risk factor in AD. However, it is not known whether γ-secretase can be upregulated in vivo. While in vitro studies showed that expression of all four components of γ-secretase (Nicastrin, Presenilin, Pen-2 and Aph-1) are required for upregulation of γ-secretase, it remains to be established as to whether this is true in vivo. To investigate whether overexpressing a single component of the γ-secretase complex is sufficient to elevate its level and activity in the brain, we analyzed transgenic mice expressing either wild type or familial AD (fAD) associated mutant PS1. In contrast to cell culture studies, overexpression of either wild type or mutant PS1 is sufficient to increase levels of Nicastrin and Pen-2, and elevate the level of active γ-secretase complex, enzymatic activity of γ-secretase and the deposition of Aβ in brains of mice. Importantly, γ-secretase comprised of mutant PS1 is less active than that of wild type PS1-containing γ-secretase; however, γ-secretase comprised of mutant PS1 cleaves at the Aβ42 site of APP-CTFs more efficiently than at the Aβ40 site, resulting in greater accumulation of Aβ deposits in the brain. Our data suggest that whereas fAD-linked PS1 mutants cause early onset disease, upregulation of PS1/γ-secretase activity may be a risk factor for late onset sporadic AD

Naturalness as a basis for incorporating marine biodiversity into life cycle assessment of seafood

PurposeMethods to quantify biodiversity impacts through life cycle assessment (LCA) are evolving for both land- and marine-based production systems, although typically independently from each other. An indicator for terrestrial food production systems that may be suitable to assess marine biodiversity, and is applicable across all food production systems, is a measure of hemeroby or distance from the natural state. We explore the possibility of adapting this approach to marine systems to assess the impact of fishing on seawater column and seafloor systems.MethodsThe terrestrial hemeroby concept is adapted here for marine ecosystems. Two commercial fishery case studies are used to trial the effectiveness of hemeroby in measuring the influence exerted by fishing practices on marine biodiversity. Available inventory data are used to score areas to a hemeroby class, following a semi-quantitative scoring matrix and a seven-point scale, to determine how far the seafloor and seawater column are from their natural state. Assessment can progress to the impact assessment stage involving characterisation of the hemeroby score, to determine the Naturalness Degradation Potential (NDP) for use in calculating the Naturalness Degradation Indicator (NDI). The method builds on well-established processes for assessing fisheries within the ecosystem-based fisheries management framework and is designed to enhance assessment of fishing impacts within LCA.Results and discussionAustralian fisheries case studies were used to demonstrate the application of this method. The naturalness of these fisheries was scored to a hemeroby level using the scoring matrix. The seafloor of the Northern Prawn Fishery and the seawater column of the South Australian Sardine Fishery were both classified as partially close to nature. Impact assessment was carried out following the process outlined for the NDI. The naturalness degradation results were highly sensitive to area calculation method and data. There was also variation in results when using annual or averaged data for catch. Results should therefore be interpreted in the context of these sensitivities.ConclusionsAdaptation of the hemeroby concept to marine habitats may present an opportunity for more informed comparison of impacts between terrestrial and marine systems. Incorporating a measure of naturalness into assessments of food production can be useful to better understand the cost, in terms of transforming ecosystems from natural to more artificial, of meeting growing food demand. Biodiversity is a broad concept not easily captured through one indicator, and this method can complement emerging biotic LCA indicators, to provide a suite of indicators capable of capturing the full impact of fishing on marine biodiversity