Der Einfluss von Pflanzenextrakten auf die β-Amyloid induzierte Pathogenese in einem APP/PS1 Mausmodell der Alzheimer Demenz

The study explored the influence of plant extracts on neuronal degeneration caused by toxic β-amyloid in a transgenic APP/PS1 mouse model of Alzheimer‘s disease. Daily oral application of extracts of Hypericum perforatum and Sideritis spp. attenuated Aβ-induced histopathology and alleviated memory impairments in APP/PS1 mice. In detail, both extracts (i) decreased intracerebral Aβ42 and (ii) Aβ plaques, (iii) rescued neocortical neurons, and (iv) restored cognition to healthy control levels due to an enhanced Aβ42 export activity of ABCC1 and an increased phagocytic microglia activity.Die Arbeit untersucht den Einfluss von Pflanzenextrakten auf den progressiven Verlust kognitiver Fähigkeiten infolge toxischen β-Amyloids (Aβ) in einem transgenen APP/PS1 Mausmodell der Alzheimer Demenz. Die tägliche orale Gabe der Extrakte von Hypericum perforatum und Sideritis spp. führte zu (i) einer reduzierten intrazerebralen Aβ42-Belastung, (ii) einem verminderten Verlust neokortikaler Neurone und (iii) gesteigerten kognitiven Leistungen, vergleichbar mit denen nicht transgener Mäuse, aufgrund eines erhöhten Aβ-Exports durch ABCC1 und einer verstärkten Phagozytoseaktivität der Mikroglia

The Utility of Miniaturized Adsorbers in Exploring the Cellular and Molecular Effects of Blood Purification: A Pilot Study with a Focus on Immunoadsorption in Multiple Sclerosis

Immunoadsorption (IA) has proven to be clinically effective in the treatment of steroid-refractory multiple sclerosis (MS) relapses, but its mechanism of action remains unclear. We used miniaturized adsorber devices with a tryptophan-immobilized polyvinyl alcohol (PVA) gel sorbent to mimic the IA treatment of patients with MS in vitro. The plasma was screened before and after adsorption with regard to disease-specific mediators, and the effect of the IA treatment on the migration of neutrophils and the integrity of the endothelial cell barrier was tested in cell-based models. The in vitro IA treatment with miniaturized adsorbers resulted in reduced plasma levels of cytokines and chemokines. We also found a reduced migration of neutrophils towards patient plasma treated with the adsorbers. Furthermore, the IA-treated plasma had a positive effect on the endothelial cell barrier’s integrity in the cell culture model. Our findings suggest that IA results in a reduced infiltration of cells into the central nervous system by reducing leukocyte transmigration and preventing blood–brain barrier breakdown. This novel approach of performing in vitro blood purification therapies on actual patient samples with miniaturized adsorbers and testing their effects in cell-based assays that investigate specific hypotheses of the pathophysiology provides a promising platform for elucidating the mechanisms of action of those therapies in various diseases

ABC Transporters B1, C1 and G2 Differentially Regulate Neuroregeneration in Mice

Background: ATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1). Methodology and Principal Findings: Analyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter-deficient mice (ABCB1 0/0) as evidenced by lowered numbers of doublecortin + (236%) and calretinin + (237%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/ progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB1 0/0 and ABCC1 0/0 mice, whereas ABCG2 0/0 mice were mostly unaffected. Conclusion and Significance: Our data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions i

Cerebral amyloid-β proteostasis is regulated by the membrane transport protein ABCC1 in mice

In Alzheimer disease (AD), the intracerebral accumulation of amyloid-β (Aβ) peptides is a critical yet poorly understood process. Aβ clearance via the blood-brain barrier is reduced by approximately 30% in AD patients, but the underlying mechanisms remain elusive. ABC transporters have been implicated in the regulation of Aβ levels in the brain. Using a mouse model of AD in which the animals were further genetically modified to lack specific ABC transporters, here we have shown that the transporter ABCC1 has an important role in cerebral Aβ clearance and accumulation. Deficiency of ABCC1 substantially increased cerebral Aβ levels without altering the expression of most enzymes that would favor the production of Aβ from the Aβ precursor protein. In contrast, activation of ABCC1 using thiethylperazine (a drug approved by the FDA to relieve nausea and vomiting) markedly reduced Aβ load in a mouse model of AD expressing ABCC1 but not in such mice lacking ABCC1. Thus, by altering the temporal aggregation profile of Aβ, pharmacological activation of ABC transporters could impede the neurodegenerative cascade that culminates in the dementia of AD

ABC transporter-deficiency did not lead to impairments of neuronal differentiation <i>in vitro</i>.

<p>ABCG2^0/0 cells showed a significant increase in proliferation capacity (+62%, A) quantified by detection of BrdU uptake using immunofluorescence (B). The differentiation capacity was not impaired by loss of ABC expression (C) as revealed by quantification of neuronal cells positive for Tuj1 (D). Error bar: SEM; Scale bar: 50 µm.</p

Deficiency of ABCB1 impairs neuronal differentiation in the SGZ of the dentate gyrus.

<p>Shown are the relative quantities of cells positive for Sox2, DCX, calretinin and BrdU in the SGZ of the dentate gyrus in ABC transporter-deficient mice as compared to the FVB controls. A) Sox2⁺ NSPCs increased significantly in ABCC1 transporter-deficient mice (+17%), while ABCB1- or ABCG2-deficient mice were unaffected. B) Early DCX⁺ neurons were significantly decreased in the absence of ABCB1 (−36%) and ABCG2 (−23%), while later, post-mitotic calretinin⁺ cells (C) were only reduced in ABCB1 transporter-deficient mice by 37%. D) The proliferation capacity (BrdU⁺ cells) was not affected in any of the analyzed ABC transporter-deficient mice. Error bar: SEM; * p<0.05; **p<0.01.</p

Neurogenesis is induced by controlled cortical impact (CCI) trauma.

<p>The photomicrographs show the SGZ of the DG after CCI (LEFT: Control hemispheres; RIGHT: hemispheres after CCI). Shown are the marker combinations Sox2/BrdU (A), DCX/BrdU (B) and calretinin/BrdU (C). Arrowheads indicate double labeled cells. Scale bar: 20 µm.</p

ABC transporter-deficiency influences cortical architecture of layers I and VI while neuronal density is not altered.

<p>Paraffin-embedded brain sections (A) were labeled with an antibody against NeuN, digitized, and the NeuN+ area was computer-assisted determined relative to the cortical area to quantify the neuronal density of the cortex (B). The thickness of the cortical layers I, II–IV (combined), V and VI were measured (A) and analyzed (C). The loss of ABCB1 expression significantly decreased the thickness of layer I (−12%) while loss of ABCC1 only affected the thickness of layer VI (+15%) Scale bars: 500 µm (A); Error bars: SEM, *p<0.05; **p<0.01.</p