Early-Onset and Robust Amyloid Pathology in a New Homozygous Mouse Model of Alzheimer's Disease

BACKGROUND: Transgenic mice expressing mutated amyloid precursor protein (APP) and presenilin (PS)-1 or -2 have been successfully used to model cerebral beta-amyloidosis, one of the characteristic hallmarks of Alzheimer's disease (AD) pathology. However, the use of many transgenic lines is limited by premature death, low breeding efficiencies and late onset and high inter-animal variability of the pathology, creating a need for improved animal models. Here we describe the detailed characterization of a new homozygous double-transgenic mouse line that addresses most of these issues. METHODOLOGY/PRINCIPAL FINDINGS: The transgenic mouse line (ARTE10) was generated by co-integration of two transgenes carrying the K670N/M671L mutated amyloid precursor protein (APP(swe)) and the M146V mutated presenilin 1 (PS1) both under control of a neuron-specific promoter. Mice, hemi- as well as homozygous for both transgenes, are viable and fertile with good breeding capabilities and a low rate of premature death. They develop robust AD-like cerebral beta-amyloid plaque pathology with glial inflammation, signs of neuritic dystrophy and cerebral amyloid angiopathy. Using our novel image analysis algorithm for semi-automatic quantification of plaque burden, we demonstrate an early onset and progressive plaque deposition starting at 3 months of age in homozygous mice with low inter-animal variability and 100%-penetrance of the phenotype. The plaques are readily detected in vivo by PiB, the standard human PET tracer for AD. In addition, ARTE10 mice display early loss of synaptic markers and age-related cognitive deficits. By applying a gamma-secretase inhibitor we show a dose dependent reduction of soluble amyloid beta levels in the brain. CONCLUSIONS: ARTE10 mice develop a cerebral beta-amyloidosis closely resembling the beta-amyloid-related aspects of human AD neuropathology. Unifying several advantages of previous transgenic models, this line particularly qualifies for the use in target validation and for evaluating potential diagnostic or therapeutic agents targeting the amyloid pathology of AD

Alternative Functions of Core Cell Cycle Regulators in Neuronal Migration, Neuronal Maturation, and Synaptic Plasticity

Recent studies have demonstrated that boundaries separating a cycling cell from a postmitotic neuron are not as concrete as expected. Novel and unique physiological functions in neurons have been ascribed for proteins fundamentally required for cell cycle progression and control. These “core” cell cycle regulators serve diverse postmitotic functions that span various developmental stages of a neuron, including neuronal migration, axonal elongation, axon pruning, dendrite morphogenesis, and synaptic maturation and plasticity. In this review, we detail the nonproliferative postmitotic roles that these cell cycle proteins have recently been reported to play, the significance of their expression in neurons, mechanistic insight when available, and future prospects.National Institutes of Health (U.S.) (PO1 grant AG27916)National Institutes of Health (U.S.) (RO1 grant NS51876

Attractive enrichment material to reduce tail and ear damages in pigs

Schwanzbeißen ist eine Verhaltensanomalie, die häufig bei konventionell gehaltenen Hausschweinen auftritt. Dabei kann es das Wohlergehen betroffener Schweine beeinträchtigen und ökonomische Verluste für den landwirtschaftlichen Betrieb bedeuten. Die Ursachen von Schwanzbeißen sind multifaktoriell, weshalb die bis heute gängigste Methode zur Reduktion von Schwanzschäden bei Schweinen das präventive Kupieren des Schwanzes darstellt. Neben dem invasiven Eingriff wirkt jedoch auch der Einsatz von Beschäftigungsmaterial reduzierend auf Schwanzschäden, indem das arttypische Explorationsverhalten gesteigert wird. Dabei stellt die schnelle Habituation von Schweinen eine Herausforderung bei der Auswahl geeigneter Beschäftigungsmaterialien dar. Im Rahmen des Projekts Label-Fit wurden unterschiedliche organische Beschäftigungsmaterialien für Aufzucht- und Mastschweine untersucht, die in konventionellen Haltungssystemen mit Spaltenböden eingesetzt werden können. Das Ziel der vorliegenden Arbeit war die Identifikation von attraktivem Beschäftigungsmaterial anhand der Explorationsdauer der Tiere. Gleichzeitig wurde der Einfluss der eingesetzten Beschäftigungsmaterialien auf Schwanz- und Ohrschäden bei Schweinen mit unkupiertem Schwanz untersucht. Vor der Durchführung von drei Langzeituntersuchungen wurden zwei Wahlversuche zur Eingrenzung der für Schweine attraktiven organischen Beschäftigungsmaterialien durchgeführt. Dabei wurden den Schweinen in einem Trog mit sechs Fächern unterschiedlich strukturierte Materialien oder verschiedene fressbare Zusätze in Stroh parallel angeboten. Anhand der individuell erfassten Beschäftigungsdauer zeigten Schweine Präferenzen für pelletierte Materialien und gehäckseltes Stroh mit einem fressbaren Zusatz. Diese Ergebnisse wurden zur Auswahl von Beschäftigungsmaterialien für die anschließenden Langzeituntersuchungen herangezogen. Für die drei Langzeituntersuchungen wurden die mit Beschäftigungsmaterialien befüllten Beschäftigungstürme mit einem UHF-RFID-System ausgestattet, um die Beschäftigungsdauer der Schweine aufzuzeichnen. Beim Wechsel der alternierend angebotenen Beschäftigungsmaterialien wurden die Schwänze und Ohren der Schweine gemäß dem Deutschen Schweine Boniturschlüssel bewertet. In der ersten Langzeituntersuchung erhielten die Schweine vier Beschäftigungsmaterialien mit unterschiedlichen Strukturen (Luzernepellets, Strohpellets, gehäckseltes Heu, gehäckseltes Stroh) im zweiwöchigen Wechsel. Dabei präferierten Aufzuchtschweine pelletierte Materialien und Mastschweine gehäckseltes Heu sowie Luzernepellets. Darüber hinaus stieg die Beschäftigungsdauer von der Aufzucht zur Mast an. Beim Einsatz der Materialien, die die höchste Beschäftigungsdauer in der Aufzucht erzielten (Luzernepellets oder Strohpellets), wurden die wenigsten Teilverluste am Schwanz erfasst. Jedoch traten beim Einsatz von Strohpellets in der Aufzucht die meisten Hautdurchbrechungen an den Schwänzen auf. Die zweite Langzeituntersuchung befasste sich mit der Frage, ob die Beschäftigungsdauer von Schweinen beim Einsatz von gehäckseltem Stroh gesteigert werden kann, wenn Maiskörner als fressbarer Zusatz untergemischt werden. Im Vergleich zu Schweinen, die gehäckseltes Stroh ohne Mais erhielten, zeigten Schweine, denen gehäckseltes Stroh mit Mais angeboten wurde, in der Aufzucht und Mast eine höhere Beschäftigungsdauer am Beschäftigungsturm. Die Beschäftigungsdauer konnte zudem von der Aufzucht zur Mast gesteigert werden, obwohl kein Materialwechsel innerhalb der Gruppen stattfand. Erstaunlicherweise traten bei den Schweinen, die gehäckseltes Stroh ohne Mais erhielten, im Vergleich zu den Schweinen, die gehäckseltes Stroh mit Mais erhielten, geringere Teilverluste am Schwanz auf. In der dritten Langzeituntersuchung wurden den Schweinen unterschiedlich aromatisierte Strohpellets im wöchentlichen Wechsel angeboten. Die höchste Beschäftigungsdauer wurde in der Aufzucht für Strohpellets mit Bratzwiebel- oder Mandel-Aroma erfasst. In der Mast beschäftigten sich die Schweine am längsten mit Strohpellets ohne Aroma oder mit Erdbeer-Aroma. Dabei konnte die Beschäftigungsdauer von der Aufzucht bis zur Mast konstant gehalten werden. Die meisten Hautdurchbrechungen am Schwanz traten in der Aufzucht bei der Verwendung von Vanille- oder Bratzwiebel-Aroma auf, wobei Vanille im Unterschied zu Bratzwiebel zu den Aromen mit den geringsten Beschäftigungsdauern zählte. Anhand der vorliegenden Untersuchungen konnten klare Präferenzen von Schweinen für bestimmte organische Beschäftigungsmaterialien gezeigt werden, die arttypisches Explorationsverhalten steigerten. Jedoch konnten Beschäftigungsmaterialien, für die eine hohe Beschäftigungsdauer erfasst wurde, Schwanzschäden (Längenverluste und Hautdurchbrechungen) nicht reduzieren. Dies verdeutlicht, dass neben dem Zugang zu Beschäftigungsmaterial weitere Faktoren auf die Prävalenz für Schwanzschäden einwirken, welche zusammenhängend betrachtet werden müssen.Tail biting is a behavioural disorder that often occurs in commercially housed domestic pigs. It may affect welfare of involved pigs and cause economic losses for the farm. The causes of tail biting are multifactorial, which is why preventive tail docking is the most comon method to reduce tail damages in pigs until today. However, besides invasive interventions, the use of enrichment materials can reduce tail biting by increasing species-specific exploration behaviour. Thereby, the rapid habituation of pigs poses a challenge in the selection of enrichment materials. Within the research project Label-Fit Schweinehaltung fit für das Tierschutzlabel, different plant-based enrichment materials for rearing and fattening pigs were investigated, which can be used in conventional housing systems with slatted floors. The aim of the present study was to identify attractive enrichment material based on the exploration duration. Furthermore, the influence of the enrichment materials on tail and ear damages was investigated in pigs with undocked tails. Prior to three long-term investigations, two choice tests were carried out for better delimination of plant-based enrichment materials considered attractive for pigs. Therefore, pigs were offered enrichment materials of different structure or, in the second test, straw with different edible additives. In both tests materials were offered in parallel in six boxes. By means of the individually recorded exploration durations, pigs showed clear preferences for pelleted materials and preferred chopped straw with edible additives, such as maize kernels. These results were used to select enrichment materials for further long-term investigations. In the three long-term investigations, material dispensers were equipped with an UHF-RFID system to record exploration durations of the pigs at the material dispenser filled with enrichment materials. Enrichment materials were offered in an alternating order and at each change of material the tails and ears of the pigs were recorded according to the Deutscher Schweine Bonitur Schlüssel (DSBS) regarding partial losses and skin injuries. In the first long-term investigation, rearing and fattening pigs received four enrichment materials with different structures (lucerne pellets, straw pellets, chopped hay and chopped straw) in a two-weekly change. Rearing pigs preferred pelletized materials, while fattening pigs showed preferences for chopped hay and lucerne pellets. Furthermore, exploration duration increased from rearing to fattening. When offering the enrichment materials that achieved the highest exploration durations in rearing (lucerne pellets or straw pellets), the fewest partial losses of the tails were recorded. However, when offering straw pellets in rearing, most injuries at the tails occurred. The second long-term investigation dealed with the question, if exploration duration of rearing and fattening pigs for chopped straw can be increased by adding maize kernels. Compared with pigs that received chopped straw without maize, pigs that received chopped straw with maize kernels showed higher exploration durations at the material dispenser during rearing and fattening. Furthermore, exploration duration could be increased from rearing to fattening, although there was no change of the material within the groups. Additionally, saisonal differences in the diurnal pattern of exploration of pigs were found. Interestingly, pigs that received chopped straw without maize kernels showed fewer length losses of the tails compared to pigs that received chopped straw with maize kernels. In the third long-term investigation, rearing and fattening pigs received different flavoured straw pellets in a weekly change. Different preferences for flavours were found between rearing and fattening pigs. During rearing, highest exploration durations were recorded for straw pellets with fried onion flavour or almond flavour. During fattening, pigs explored straw pellets without flavour or with strawberry flavour longest. Exploration duration could be maintained at a constant level from rearing to fattening. Most skin injuries at the tails occurred when using vanilla flavour or fried onion flavour during rearing, whereby vanilla, unlike fried onion, was one of the flavours with the lowest exploration durations. On the basis of the present investigations clear preferences of pigs for specific plant-based enrichment materials could be shown, which increased species-specific exploration behaviour. However, enrichment materials for which high exploration durations were recorded could not reduce tail damages, such as partial losses or skin injuries. This illustrates that, apart from the access to enrichment material, further factors influence the prevalence of tail damages, which have to be considered in relation to each other

Effect of plant-based enrichment materials on exploration in rearing and fattening pigs (Sus scrofa domesticus)

Kauselmann K, Krause T, Glitz B, Gallmann E, Schrade H, Schrader L. Effect of plant-based enrichment materials on exploration in rearing and fattening pigs (Sus scrofa domesticus). Applied Animal Behaviour Science. 2021;236: 105261.When pigs cannot perform innate species-specific behaviours (e.g. rooting or chewing), behavioural disorders, like tail biting, can occur. However, it seems that various enrichment materials enhance the pigs to perform exploration behaviour and therefore can help to reduce and prevent tail biting. The aim of this study was to identify such highly explored plant-based enrichment material for undocked pigs during rearing and fattening. Furthermore, we evaluated the impact of the offered enrichment materials on tail length and injuries. Therefore, we continuously recorded the individuals’ exploration durations in 20 groups by using an ultra-high-frequency radio-frequency identification system, installed at material dispensers. Lucerne pellets (LP), straw pellets (SP), chopped hay (CH) and chopped straw (CS) were offered in a systematically alternating order for two-week sections, respectively. At weaning and at days of material change (i.e. eight times in total), animals were weighed and scored for tail length losses and tail injuries. For analysis, the changes in tail length compared to the previous section were calculated as Δ-tail-length losses. Our study revealed that the different offered plant-based enrichment materials affected the duration of exploration behaviour (e.g. rooting, nosing or chewing) during rearing (4 groups, LME, p < 0.0001) and fattening (16 groups, LME, p < 0.0001). In piglets, exploration duration was higher for pelletized materials (LP, SP) than for chopped materials. Fattening pigs explored materials of hay (CH) more often compared to straw-based materials (CS, SP). Daily weight gains of rearing pigs were affected by the type of enrichment material offered in the respective section (LME, p < 0.0001). The highest daily weight gains were achieved when CH was offered. Exploration duration during rearing and fattening was affected by section (LME, both p < 0.0001 for rearing and fattening). Exploration duration during rearing was highest in section 4 and continuously increased from the first section to the last section during fattening. During rearing, the plant-based enrichment materials affected tail injuries (GLMM, p < 0.0001) and Δ-tail-length losses tended to be affected (GLMM, p = 0.057). Fewest tail injuries and Δ-tail-length losses occurred when SP was offered. During fattening, section affected tail injuries (GLMM, p = 0.01). Most injuries occurred during sections 1 and 2. Our results show that pigs of different ages seem to prefer different plant-based enrichment materials. High exploration durations do not necessarily maintain intact tails if material is changed biweekly. However, exploration durations can be maintained at high levels from rearing through fattening period by regularly alternating the provided plant-based enrichment materials

Tasty straw pellets – Exploration of flavoured rooting material by pigs

Kauselmann K, Schrader L, Glitz B, Gallmann E, Schrade H, Krause T. Tasty straw pellets – Exploration of flavoured rooting material by pigs. Animal. 2021;15(6): 100239.Tail biting is a common problem in pigs kept in conventional fully slatted pens. Suitable enrichment materials can help to prevent the occurrence of this behavioural disorder by encouraging pigs to increase exploration behaviour. We investigated whether additional flavours can increase exploration behaviour in undocked pigs. Therefore, we offered straw pellets flavoured with either fried onion (FO), strawberry (SB), ginger, almond (AL), vanilla or without flavour (control) during rearing (eight groups in total) and fattening (16 groups in total). Flavoured pellets were offered in an altering order during intervals of 1 week in material dispensers. Exploration duration at the material dispensers was continuously recorded via an ultra-high-frequency radio-frequency identification system. Pigs were weighed weekly and their tail lengths and tail injuries were scored in four categories. For analysis, changes in tail length scores compared to the previous week were calculated as Δ-tail length. The different flavours affected pigs’ exploration durations in both rearing (factor flavour, P < 0.0001) and fattening (factor flavour, P < 0.0001). Highest exploration durations during rearing were recorded when straw pellets were flavoured with FO and AL compared to all others. During fattening, exploration duration was highest towards controls without significant difference to SB. Exploration durations additionally were affected by temporal effects, i.e. week and day during rearing (both factors: P < 0.0001) and fattening (both factors: P < 0.0001). During rearing, highest exploration durations were recorded in the first week and on the first day within week after changing the flavour of the straw pellets. During fattening, exploration durations varied between weeks and within weeks. The highest durations were recorded at the end of weeks, i.e. on the fifth and seventh days after material change. During rearing, tail injuries were affected by week (P < 0.0001). From the fourth week of rearing, the prevalence of tail injuries significantly increased. During the fattening period, tail injuries were affected by flavour (P < 0.05). Fattening pigs had fewest tail injuries after straw pellets flavoured with AL were offered. Altogether, based on the exploration durations, rearing pigs showed different preferences for the flavoured straw pellets but highly explored flavours differed between rearing and fattening pigs. Despite a weekly change of the flavour of straw pellets, exploration durations decreased during rearing but increased again in the transition between rearing and fattening. Thus, straw pellets with alternating flavours are a suitable possibility to provide environmental enrichment to pigs but will not prevent tail biting

Short-term choice of fattening pigs for additional plant-based materials

Kauselmann K, Krause T, Glitz B, Gallmann E, Schrade H, Schrader L. Short-term choice of fattening pigs for additional plant-based materials. Applied Animal Behaviour Science. 2020: 104975