Die Ackerkratzdistel kann vor allem in Bioackerbaubetrieben mit guten Boden ein Problem werden. Eine Patentlosung zu ihrer Regulierung existiert bisher fur den Biobetrieb nicht. Unter Beachtung gewisser pflanzenbaulicher Regeln und in Kombination mit einer gezielten Bodenbearbeitung lasst sie sich aber trotzdem erfolgreich regulieren. Das Merkblatt listet die Ursachen von Distelproblemen auf und liefert, basierend auf Praxiserfahrungen in mehreren Landern, Empfehlungen zur Regulierung von der Vorbeugung einer Verunkrautung bis zu Massnahmen bei grossflachigem Befall.

In recent years, the creeping thistle has become a problematic weed, especially for organic arable farms with good soils. Wherever it grows, it is competing with crops for water and nutrients. Once established, the thistle can only be reduced to a tolerable density with a lot of patience. So far, there is no patent remedy for its control on organic farms. By abiding certain rules of plant cultivation in combination with direct methods, the thistle can be effectively controlled.

With 90% of neuroscience clinical trials failing to see efficacy, there is a clear need for the development of disease biomarkers that can improve the ability to predict human Alzheimer's disease (AD) trial outcomes from animal studies. Several lines of evidence, including genetic susceptibility and disease studies, suggest the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) as a potential biomarker with congruency between humans and animal models. For example, early in AD, patients present with decreased glucose metabolism in the entorhinal cortex and several regions of the brain associated with disease pathology and cognitive decline. While several of the commonly used AD mouse models fail to show all the hallmarks of the disease or the limbic to cortical trajectory, there has not been a systematic evaluation of imaging-derived biomarkers across animal models of AD, contrary to what has been achieved in recent years in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (Miller, 2009). If animal AD models were found to mimic endpoints that correlate with the disease onset, progression, and relapse, then the identification of such markers in animal models could afford the field a translational tool to help bridge the preclinical-clinical gap. Using a combination of FDG-PET and functional magnetic resonance imaging (fMRI), we examined the Tg2576 mouse for global and regional measures of brain glucose metabolism at 7 and 19 months of age. In experiment 1 we observed that at younger ages, when some plaque burden and cognitive deficits have been reported, Tg2576 mice showed hypermetabolism as assessed with FDG-PET. This hypermetabolism decreased with age to levels similar to wild type (WT) counterparts such that the 19-month-old transgenic (Tg) mice did not differ from age matched WTs. In experiment 2, using cerebral blood volume (CBV) fMRI, we demonstrated that the hypermetabolism observed in Tg mice at 7 months could not be explained by changes in hemodynamic parameters as no differences were observed when compared with WTs. Taken together, these data identify brain hypermetabolism in Tg2576 mice which cannot be accounted for by changes in vascular compliance. Instead, the hypermetabolism may reflect a neuronal compensatory mechanism. Our data are discussed in the context of disease biomarker identification and target validation, suggesting little or no utility for translational based studies using Tg2576 mice.

Although amyloid-beta (Ab) fibril-containing amyloid plaques are one of the hallmarks of Alzheimer's disease (AD), oligomers of the Aβ peptide have been thought to play a crucial role in early neuropathologic changes in AD. We have prepared a synthetic Aβ-20-42 oligomer (named globulomer) with a different conformation to monomeric and fibrillar Aβ peptide, enabling the generation of highly Aβ oligomer-specific monoclonal antibodies. The globulomer-specific antibody A-887755 was able to prevent Aβ oligomer binding and dynamin cleavage in primary hippocampal neurons and to reverse globulomer-induced reduced synaptic transmission (Hillen et al., 2010) In amyloid precursor protein (APP) transgenic mice, vaccination with Aβ globulomer and treatment with A-887755 improved novel object recognition. This cognitive improvement is likely attributable to reversing a deficit in hippocampal synaptic spine density in APP transgenic mice as observed after treatment with A-887755 (Hillen et al., 2010). Secondary symptoms of AD, such as hyperactivity, agitation, disturbed emotional reactivity and aggression, are largely neglected compared with cognitive symptoms, yet they represent other psychiatrically relevant features of the AD patients. A general elevation of basal locomotor activity in the home cage is also found in APP transgenic mice. In the present study, five-month old Tg2576 mice and their wildtype littermates received a total of 5 injections of A-887755 or a control antibody (500 μg/mice, every 5th day). After the last injection, animals were placed in a home cage activity monitoring setup for 4 days, where the locomotor activity was recorded in bins of 5 min. In the present study, we demonstrated that immunotherapy with A-887755 was able to restore this elevated increased home cage activity in Tg2576 mice to the levels of the wildtype littermates. These results demonstrate that selective reduction of Aβ oligomers by immunotherapy is able not only to normalize cognitive behavior and synaptic deficits, but also to reverse hyperactivity in APP transgenic mice.

One major hallmark of Alzheimer's disease (AD) is the massive loss of synapses that occurs at an early clinical stage of the disease. In this study, we characterize alterations in spine density and the expression of synapse-associated immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the hippocampal CA1 regions of two different amyloid precursor protein (APP) transgenic mouse lines before plaque development and their connection to performance in hippocampus-dependent memory tests. The density of mushroom-type spines was reduced by 34% in the basal dendrites proximal to the soma of CA1 pyramidal neurons in 5.5-month-old Tg2576 mice, carrying the Swedish mutation, compared with wild-type littermates. A similar reduction of 42% was confirmed in the same region of 8-month-old APP/Lo mice, carrying the London mutation. In this strain, the reduction extended to the distal dendritic spines (28%), although no differences were found in apical dendrites in either transgenic mouse line. Both transgenic mice lines presented a significant increase in Arc protein expression in CA1 compared with controls, suggesting rather an overactivity and increased spine turnover that was supported by a significant decrease in number of somatostatin-immunopositive inhibitory interneurons in the stratum oriens of CA1. Behaviorally, the transgenic mice showed decrease freezing in the fear contextual conditioning test and impairment in spatial memory assessed by Morris water maze test. These data indicate that cognitive impairment in APP transgenic mice is correlated with impairment of synaptic connectivity in hippocampal CA1, probably attributable to loss of inhibitory interneurons and subsequent hyperactivity.

In recent years immunotherapy-based approaches for treating Alzheimer's disease have become the subject of intensive research. However, an important mechanistic-related safety concern is exacerbation of the risk of microhemorrhage that may be associated with fast removal of amyloid-β (Aβ) deposits found in blood vessels or brain parenchyma. Rapid in vivo detection of microhemorrhages in living amyloid precursor protein transgenic mice has not been described, and histological analysis can take several months before this risk is assessed. Aged transgenic mice were divided into two groups that would undergo longitudinal passive immunotherapy for 12 or 18 weeks. 6G1, a nonselective anti-Aβ monoclonal antibody, and 8F5, a more selective antioligomeric Aβ monoclonal antibody, were examined in both longitudinal studies. High-resolution T2*-weighted magnetic resonance microscopy (100 × 100 × 400 μm) was used for microhemorrhage detection in vivo. Cerebral microhemorrhages by magnetic resonance imaging were compared with histological hemosiderin staining in each animal; results showed that T2*-weighted magnetic resonance microscopy can reliably detect microhemorrhages of ≥60 μm in diameter at baseline and after 12 to 18 weeks of treatment in the same animals in vivo. This correlated significantly with histological readings. This new imaging safety biomarker can be readily applied to preclinical antibody screening in a longitudinal manner. 6G1 and 8F5, however, both increased microhemorrhage incidence in aged amyloid precursor protein transgenic mice compared with their baseline and vehicle treatment. A highly selective antibody for soluble Aβ is needed to address the question of whether antibodies that do not bind to deposited Aβ have microhemorrhage liability.

11ß-hydroxysteroid dehydrogenase-1 (11ß HSD-1) converts inactive glucocorticoid to its active form: corticosterone in rodents and cortisol in humans, thus reducing local tissue concentrations corticosterone/cortisol in liver, fat and brain. In Alzheimer's disease (AD), elevated glucocorticoid concentrations have been associated with increased pathology. Direct evidence, however, that reduction of glucocorticoid concentrations would be disease modifying is lacking. In the present studies, we investigated the effects of chronic treatment with the 11ß HSD-1 inhibitor, A-918446, in wild type and Tg2576 mice that overproduce human APPsw. Animals were chronically treated with A-918446 on a high fat diet (606 μg/g). A-918446 reduced plasma corticosterone concentrations after a stressful event, reaching significance in wild type mice. ACTH concentrations were elevated by treatment independent of transgene, probably due to glucocorticoid receptor-dependent feedback. In the cortex of wild type and transgenic mice, A-918446 significantly increased mRNA expression of glucocorticoid and mineralocorticoid receptors, suggesting that chronic 11ß HSD-1 inhibition can reduce overall glucocorticoid activity. In addition, A-918446 significantly reduced total soluble Aß, and tended to lower Aß globulomer concentrations in the hippocampus of Tg2576 mice. It also reduced the area covered by Aß deposits in hippocampal and cortical regions, reaching overall significance in cortex. Together, our data support the hypothesis that chronic 11ß HSD-1 inhibition may have disease-modifying properties in AD.

Oligomers of the beta-amyloid (A beta) peptide have been indicated in early neuropathologic changes in Alzheimer's disease. Here, we present a synthetic A beta(20-42) oligomer (named globulomer) with a different conformation to monomeric and fibrillar A beta peptide, enabling the generation of highly A beta oligomer-specific monoclonal antibodies. The globulomer-derived antibodies specifically detect oligomeric but not monomeric or fibrillar A beta in various A beta preparations. The globulomer-specific antibody A-887755 was able to prevent A beta oligomer binding and dynamin cleavage in primary hippocampal neurons and to reverse globulomer-induced reduced synaptic transmission. In amyloid precursor protein (APP) transgenic mice, vaccination with A beta globulomer and treatment with A-887755 improved novel object recognition. The cognitive improvement is likely attributable to reversing a deficit in hippocampal synaptic spine density in APP transgenic mice as observed after treatment with A-887755. Our findings demonstrate that selective reduction of A beta oligomers by immunotherapy is sufficient to normalize cognitive behavior and synaptic deficits in APP transgenic mice.

Although Amyloid-beta (Aβ) fibril-containing amyloid plaques are one of the hallmarks of Alzheimer's disease (AD) a recent paradigm shift put Aβ-oligomers as crucial neuropathogenic culprits of AD. Several human Aβ-expressing transgenic mouse lines have been widely used as preclinical models for AD. While Aβ-induced cognitive deficits develop before amyloid plaques in these mice, the time course of oligomeric Aβ is not fully established. We therefore investigated the age dependent Aβ-oligomer formation in APP overexpressing Tg2576 mouse brain to enable the design of experiments to specifically target Aβ-oligomers. Total soluble Aβ peptide (Aβ-oligomers plus Aβ monomer) was extracted from the hippocampus of 4.5-14 month old Tg2576 mice. The concentration of total soluble Aβ-peptide was determined by means of immunoprecipitation with the Aβ-conformer unselective antibody 6E10 and subsequent quantitative Western blot. Likewise, Aβ-oligomer concentration was determined by the highly Aβ-oligomer selective monoclonal antibody A-887755 which was generated against an Aβ20-42 oligomer preparation (named Aβ20-42 Globulomer, Barghorn et al. 2005). Already at 4.5 month age a significant amount of Aβ-oligomers could be detected, however, compared to the total soluble Aβ-peptide the Aβ-oligomer concentration was low. While the total soluble Aβ-peptide concentration remained constant from an age of 4.5-10 months, the Aβ-oligomer content of Tg2576 hippocampus increased 40-fold from 0.07% to 2.7%. With the onset of amyloid plaque deposition at ∼10-12 month age the variability in both total soluble Aβ-peptide and Aβ-oligomer increased strongly. Quantitative immunoprecipitation using the Aβ-oligomer selective antibody A-887755 proved to be well suited to specifically quantify Aβ-oligomers in the presence of other Aβ-forms in brain tissue. Aβ-oligomers were detected as early as 4.5 months of age in the hippocampus of Tg2576 mice fitting well to previously described early cognitive deficits. Interestingly, whereas the level of total soluble Aβ-peptide was rather constant between 4.5-10 months of age, a very strong increase of Aβ-oligomers was observed during that period, particularly between 6-8 months indicating a yet unrevealed unconstant mechanism leading to Aβ-peptide misfolding and Aβ-oligomer formation or accumulation. Our study furthermore defines the correct time periods for experiments to study Aβ-oligomer related disease mechanisms in Tg2576 mice.