TRICHLOROETHYLENE EXPOSURE AND TRAUMATIC BRAIN INJURY INTERACT AND PRODUCE DUAL INJURY BASED PATHOLOGY AND PIOGLITAZONE CAN ATTENUATE DEFICITS FOLLOWING TRAUMATIC BRAIN INJURY

The development of Parkinson\u27s disease (PD) in humans has been linked to genetic and environmental factors for many years. However, finding common single insults which can produce pathology in humans has proved difficult. Exposure to trichloroethylene (TCE) or traumatic brain injury (TBI) has been shown to be linked to PD and it has also been proposed that multiple insults may be needed for disease development. The present studies show that exposure to TCE prior to a TBI can result in pathology similar to early PD and that the interaction of both insults is required for impairment in behavioral function, and cell loss. Following exposure to TCE for 2 weeks there is a 75% impairment in mitochondrial function but it has yet to be shown if the addition of a TBI can make this worse. If the exposure to TCE is reduced to 1 week and combined with TBI a 50% reduction in mitochondrial function is observed following the dual injury which requires both insults. These studies provide further support for the hypothesis that PD may result from a multifactorial mechanism. It had been established that regional differences exist in mitochondrial function across brain regions. The present studies indicate that previous findings are not likely to be the result of differences in individual mitochondria isolated from the cortex, striatum, and hippocampus. Further analysis of the effect of mitochondrial inhibitors on enzyme activity and oxygen consumption reveal that the different regions of the brain are similarly affected by the inhibitors. These results suggest that findings from previous studies indicating regionally specific deficits following systemic toxin exposure, such as with TCE, are not the result of regional differences in the individual mitochondria. Given that TBI results in significant dysfunction, finding effective therapeutics for TBI will provide substantial benefits to individuals suffering an insult. Treatment with Pioglitazone following TBI reduced mitochondrial dysfunction, cognitive impairment, cortical tissue loss, and inflammation. These findings provide initial evidence that treatment with Pioglitazone may be an effective intervention for TBI

Minimal long-term neurobehavioral impairments after endovascular perforation subarachnoid hemorrhage in mice

AbstractCognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.</jats:p

Literaturrecherche und -analyse zur Genetik der altersabhängigen Makuladegeneration (AMD)

Die aktuell umfassenste GWAS zur Genetik der altersabhängigen Makuladegeneration (AMD), einer komplexen progressiv-degenerativen Erkrankung der zentralen Netzhaut, fand über 7.000 assoziierte Varianten in 52 unabhängigen Signalen, die in 34 Genorte des Genoms verteilt sind. Die Interpretation von GWAS-Ergebnissen weist jedoch Limitationen auf. Von einer genetischen Assoziation alleine kann nicht auf Kausalität geschlossen werden. Daher sind weiterführende Analysen wichtig, um die GWAS-Befunde genauer zu analysieren und die kausalen Varianten und deren Konsequenzen zu identifizieren. Solche Folgestudien, die sich auf eine umfassende GWAS stützen, sind Objekt der Forschung dieser Arbeit. Es soll ausgehend von der gegenwärtig umfassensten und aktuellsten GWAS zur AMD (Fritsche et al. 2016) ein Überblick über den Stand der laufenden Forschung zur Pathogenese der AMD erstellt werden. Weiter sollen mit Hilfe der zweitjüngsten GWAS zur AMD von 2013 (Fritsche et al. 2013) zeitliche Trends in der Forschung ermittelt werden. Zuletzt werden Bereiche herausgearbeitet, denen in der ophthalmologischen Forschung bisher wenig Aufmerksamkeit zuteil wurde, so dass weitere Forschung wünschenswert wäre. Im Fokus dieser Arbeit steht eine systematische Literaturrecherche mittels des Web of Science (WoS), einer Online-Zitationsdatenbank von Clarivate Analytics. Diese enthält Zugänge zu über 18.000 verschiedenen Zeitschriften und über eine Milliarde Querverweise bezüglich Zitationen. Die Daten werden durch die im WoS integrierte Suche nach zitierenden Referenzen gefiltert und anschließend händisch analysiert und kategorisiert. Unter den Studientypen der Folgestudien finden sich vor allem genetische Assoziationsstudien und Übersichtsarbeiten, gefolgt von experimentellen Studien. Die Studienkohorten der genetischen Assoziationsstudien waren größtenteils von europäischer Ethnizität oder transethnisch, wobei in keiner Arbeit beispielsweise eine rein afrikanische Studienpopulation untersucht wurde. In Sachen Krankheitsstatus wurde meist die AMD ohne weitere Differenzierung betrachtet. Analysen von Subgruppen der AMD konzentrierten sich fast ausnahmslos auf die Spätform oder deren Unterform, die NV-AMD. Im zeitlichen Verlauf von 2013 auf 2016 konnte unter den Genotypisierungsdaten eine Veränderung von der Genotypisierung einzelner SNPs in einem Gen hin zu Genotypisierungs-Microarrays, die SNPs aus dem kompletten Genom untersuchten, festgestellt werden. Als Mosdellsysteme für funktionelle Untersuchungen waren Tierversuche führend, gefolgt von Zellversuchen, menschlichem Spendergewebe und Bioproben. Dabei wurden vor allem Locusuntersuchungen verfolgt, jedoch auch Therapieoptionen, Stoffwechsel, Stressreaktion, Genexpression und Biomarker. Unter den in dieser Arbeit genauer betrachteten Loci der Arbeiten, die Fritsche et al. (2016) zitierten, wurden fünf schon vor 2016 bekannte Loci in den Folgejahren nicht weiter untersucht. In der kombinierten Analyse der GWAS aus dem Jahr 2013 und 2016 fällt auf, dass alle bekannten Loci bereits untersucht wurden, unter den 16 Loci, die 2016 erstmals neu berichtet wurden, jedoch lediglich zwei. Zusammenfassend ist zu sagen, dass die Forschung zur Genetik der AMD in viele verschiedene Richtungen erfolgt, wobei eine vergleichende Analyse dieser Richtungen sinnvoll wäre. Dies gestaltet sich jedoch kompliziert. Neu gefundene Assoziationen finden dabei in die weiterführende Forschung nur sehr wenig Eingang, obwohl eine funktionelle Validierung und Abklärung vielversprechend wären

Mitochondria, Amyloid β, and Alzheimer's Disease

Hypometabolism is a hallmark of Alzheimer's disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Aβ) accumulation precedes extracellular Aβ deposition. In addition to increasing oxidative stress, Aβ has been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial enzymes as a result of oxidative damage or Aβ interaction perpetuates oxidative stress and leads to a hypometabolic state. Additionally, Aβ has also been shown to interact with cyclophilin D, a component of the mitochondrial permeability transition pore, which may promote cell death. Therefore, ample evidence exists indicating that the mitochondrion plays a vital role in the pathophysiology observed in AD

modCHIMERA: A novel murine closed-head model of moderate traumatic brain injury

AbstractTraumatic brain injury is a major source of global disability and mortality. Preclinical TBI models are a crucial component of therapeutic investigation. We report a tunable, monitored model of murine non-surgical, diffuse closed-head injury—modCHIMERA—characterized by impact as well as linear and rotational acceleration. modCHIMERA is based on the Closed-Head Impact Model of Engineered Rotational Acceleration (CHIMERA) platform. We tested this model at 2 energy levels: 1.7 and 2.1 Joules—substantially higher than previously reported for this system. Kinematic analysis demonstrated linear acceleration exceeding injury thresholds in humans, although outcome metrics tracked impact energy more closely than kinematic parameters. Acute severity metrics were consistent with a complicated-mild or moderate TBI, a clinical population characterized by high morbidity but potentially reversible pathology. Axonal injury was multifocal and bilateral, neuronal death was detected in the hippocampus, and microglial neuroinflammation was prominent. Acute functional analysis revealed prolonged post-injury unconsciousness, and decreased spontaneous behavior and stimulated neurological scores. Neurobehavioral deficits were demonstrated in spatial learning/memory and socialization at 1-month. The overall injury profile of modCHIMERA corresponds with the range responsible for a substantial portion of TBI-related disability in humans. modCHIMERA should provide a reliable platform for efficient analysis of TBI pathophysiology and testing of treatment modalities.</jats:p

SEQUIN: An imaging and analysis platform for quantification and characterization of synaptic structures in mouse

Synapses are crucial to brain function and frequent disease targets, but current analysis methods cannot report on individual synaptic component

Mitochondria, Amyloid β, and Alzheimer\u27s Disease

Hypometabolism is a hallmark of Alzheimer\u27s disease (AD) and implicates a mitochondrial role in the neuropathology associated with AD. Mitochondrial amyloid-beta (Aβ) accumulation precedes extracellular Aβ deposition. In addition to increasing oxidative stress, Aβ has been shown to directly inhibit mitochondrial enzymes. Inhibition of mitochondrial enzymes as a result of oxidative damage or Aβ interaction perpetuates oxidative stress and leads to a hypometabolic state. Additionally, Aβ has also been shown to interact with cyclophilin D, a component of the mitochondrial permeability transition pore, which may promote cell death. Therefore, ample evidence exists indicating that the mitochondrion plays a vital role in the pathophysiology observed in AD