Ectodomain shedding of the amyloid precursor protein: Cellular control mechanisms and novel modifiers

Proteolytic cleavage in the ectodomain of the amyloid precursor protein (APP) is a key regulatory step in the generation of the Alzheimer's disease amyloid-beta (A beta) pepticle and occurs through two different protease activities termed alpha- and beta-secretase. Both proteases compete for APP cleavage, but have opposite effects on A beta generation. At present, little is known about the cellular pathways that control APP alpha- or beta-secretase cleavage and thus A beta generation. To explore the contributory pathways in more detail we have recently employed an expression cloning screen and identified several activators of APP cleavage by alpha- or beta-secretase. Among them were known activators of APP cleavage, for example protein kinase A, and novel activators, such as endophilin and the APP homolog amyloid precursor-like protein 1 (APLP1). Mechanistic analysis revealed that both endophilin and APLP1 reduce the rate of APP endocytosis and strongly increase APP cleavage by alpha-secretase. This review summarizes the results of the expression cloning screen in the context of recent developments in our understanding of the cellular regulation of APP alpha-secretase cleavage. Moreover, it highlights the particular importance of endocytic APP trafficking as a prime modulator of APP shedding. Copyright (c) 2006 S. Karger AG, Basel

Site of Prenylation Reaction in Synthesis of Phylloquinone (Vitamin K1) by Spinach Chloroplasts

In spinach chloroplasts, 1,4-dihydroxy-2-naphthoate is prenylated by phytyldiphosphate and subsequently methylated by S-adenosylmethionine to form phylloquinol. The site of the prenylation reaction is the chloroplast envelope membrane

Nonsteroidal Anti-Inflammatory Drugs and Ectodomain Shedding of the Amyloid Precursor Protein

Background: Epidemiological studies have suggested that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). Several mechanisms have been proposed to explain these findings including increased shedding of the soluble ectodomain of the amyloid precursor protein (sAPP), which functions as a neurotrophic and neuroprotective factor in vitro and in vivo. Objective: To clarify whether NSAIDs consistently stimulate sAPP secretion. Methods: 293-EBNA cells with stable overexpression of an APP-alkaline phosphatase fusion protein (APP-AP), SH-SY5Y and PC12 cells or primary telencephalic chicken neurons were treated with ibuprofen or indomethacin. APP shedding was then determined by measuring AP activity in conditioned media, Western blot analysis with antibodies against total sAPP or specific for sAPP-alpha, or in a pulse-chase paradigm. Results: AP activity in conditioned media was not increased after NSAID treatment of 293-EBNA cells whereas it was elevated by phorbol ester. Surprisingly, ibuprofen or indomethacin treatment of SH-SY5Y and PC12 cells expressing endogenous APP did not cause changes in sAPP or sAPP-alpha secretion or downregulation of cellular APP. These findings were further corroborated in primary chicken neuronal cultures. Conclusions: Using various experimental settings, we were unable to confirm sAPP or sAPP-alpha stimulation with the NSAIDs ibuprofen and indomethacin in transfected and nontransfected cells of neuronal and nonneuronal origin. Importantly, these findings seem to rule out chronic sAPP stimulation as an alternative mechanism of NSAID action in AD. Copyright (C) 2008 S. Karger AG, Base

Neutron Transfer reactions induced by 8Li on 9Be

Angular distributions for the elastic scattering of 8Li on 9Be and the neutron transfer reactions 9Be(8Li,7Li)10Be and 9Be(8Li,9Li)8Be have been measured with a 27 MeV 8Li radioactive nuclear beam. Spectroscopic factors for 8Li|n=9Li and 7Li|n=8Li bound systems were obtained from the comparison between the experimental differential cross section and finite-range DWBA calculations with the code FRESCO. The spectroscopic factors obtained are compared to shell model calculations and to other experimental values from (d,p) reactions. Using the present values for the spectroscopic factor, cross sections for the direct neutron-capture reactions 7Li(n,g)8Li and 8Li(n,g)9Li were calculated in the framework of a potential model.Comment: 24 pages, 8 Figures, submitted as regular article to PR

Localization and synthesis of prenylquinones in isolated outer and inner envelope membranes from spinach chloroplasts

The prenylquinone content and biosynthetic capabilities of membrane fractions enriched in outer and inner envelope membranes from spinach chloroplasts were analyzed. Both envelope membranes contain prenylquinones, and in almost similar amounts (on a protein basis). However, the outer envelope membrane contains more -tocopherol than the inner one although this prenylquinone is the major one in both fractions. On the contrary, plastoquinone-9 is present in higher amounts in the inner envelope membrane than in the outer one. In addition, it has been demonstrated that all the enzymes involved in the last steps of -tocopherol and plastoquinone-9 biosynthesis i.e., homogentisate decarboxylase polyprenyltransferase, S-adenosyl-methionine: methyl-6-phytylquinol methyltransferase, S-adenosyl-methionine: -tocopherol methyltransferase, homogentisate decarboxylase solanesyltransferase, S-adenosyl-methionine:methyl-6-solanesylquinol methyltransferase, and possibly 2,3-dimethylphytylquinol cyclase, are localized on the inner envelope membrane. These results demonstrate that the inner membrane of the chloroplast envelope plays a key role in chloroplast biogenesis, and especially for the synthesis of the two major plastid prenylquinones

Jostling for Advantage or Not: Choosing Between Patent Portfolio Races and Ex Ante Licensing

Complex high technology industries are increasingly affected by patent thickets in which firms’ patents mutually block the use of important technologies. Firms facing patent thickets patent intensively to acquire bargaining chips and use licensing to ensure freedom to operate. Such licensing allows rivals to either avoid or resolve hold-up from blocking patents. R&D incentives depend on whether licensing takes place ex ante or ex post. We model the choice between ex ante licensing and entry into patent portfolio races leading to ex post licensing. It is shown that higher degrees of blocking lead firms to license ex post, while stronger product market competition leads firms to license ex ante. Empirical results support these theoretical predictions

Using longitudinal survival probabilities to test field vigour estimates in sugar maple (Acer saccharum Marsh.)

Tree mortality is a major force driving forest dynamics. To foresters, however, tree mortality is often considered a loss in productivity. To reduce tree mortality, silvicultural systems, such as selection cuts, aim at removing trees that are more likely to die. In order to identify trees with higher risks of mortality, field classifications are employed that assess vigour based on external characteristics of trees. We used a novel longitudinal approach for estimating survival probabilities based on ring-width measurements, initially developed by Bigler and Bugmann [Bigler, C., Bugmann, H., 2004. Predicting the time of tree death using dendrochronological data. Ecol. Appl. 14 (3), 902-914], to parameterize a survival probability model for sugar maple (Acer saccharum Marsh.) and to test whether field-assessed tree vigour classes are corroborated by survival probabilities determined from radial growth history. Data from 56 dead and 321 live sugar maples were collected in stands in western Quebec (Canada) that had undergone a selection cut ≈10 years prior to sampling. Our results showed that tree vigour established from external defects and pathological symptoms, using the classification of Boulet [Boulet, B., 2005. D

Effect of irrigation water regimes on yield of Tetragonia tetragonioides

The main purpose of this experiment was to study the effect of several irrigation water regimes on Tetragonia tetragonioides (Pall) O. Kuntze in semi-arid regions. During the experiment period, it was measured that several irrigation regimes were affected in terms of growth, biomass production, total yield, mineral composition, and photosynthetic pigments. The experiment was conducted in the greenhouse at the University of Algarve (Portugal). The study lasted from February to April in 2010. Three irrigation treatments were based on replenishing the 0.25-m-deep pots to field capacity when the soil water level was dropped to 70% (T1, wet treatment), 50% (T2, medium treatment), and 30% (T3, dry treatment) of the available water capacity. The obtained results showed that the leaf mineral compositions of chloride and sodium, the main responsible ions for soil salinization and alkalization in arid and semi-arid regions, enhanced with the decrease in soil water content. However, the minimum amounts of chlorophyll, carotenoids, and soluble carbohydrates in the leaf content were obtained in the medium and driest treatments. On the other hand, growth differences among the several irrigation regimes were very low, and the crop yield increased in the dry treatment compared to the medium treatment; thus, the high capacity of salt-removing species suggested an advantage of its cultivation under dry conditions.info:eu-repo/semantics/publishedVersio

BACE2 distribution in major brain cell types and identification of novel substrates

β-Site APP-cleaving enzyme 1 (BACE1) inhibition is considered one of the most promising therapeutic strategies for Alzheimer's disease, but current BACE1 inhibitors also block BACE2. As the localization and function of BACE2 in the brain remain unknown, it is difficult to predict whether relevant side effects can be caused by off-target inhibition of BACE2 and whether it is important to generate BACE1-specific inhibitors. Here, we show that BACE2 is expressed in discrete subsets of neurons and glia throughout the adult mouse brain. We uncover four new substrates processed by BACE2 in cultured glia: vascular cell adhesion molecule 1, delta and notch-like epidermal growth factor-related receptor, fibroblast growth factor receptor 1, and plexin domain containing 2. Although these substrates were not prominently cleaved by BACE2 in healthy adult mice, proinflammatory TNF induced a drastic increase in BACE2-mediated shedding of vascular cell adhesion molecule 1 in CSF. Thus, although under steady-state conditions the effect of BACE2 cross-inhibition by BACE1-directed inhibitors is rather subtle, it is important to consider that side effects might become apparent under physiopathological conditions that induce TNF expression