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Author: Karen Gertz (57)


Jan
2018

Delayed cell death in the penumbra region of acute ischemic stroke occurs through apoptotic mechanisms, making it amenable to therapeutic interventions. Fas/CD95 mediates apoptotic cell death in response to external stimuli. In mature neurons, Fas/CD95 signaling is modulated by Fas-apoptotic inhibitory molecule 2 (Faim2), which reduces cell death in animal models of stroke, meningitis, and Parkinson disease.

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Dec
2017

After stroke, macrophages in the ischemic brain may be derived from either resident microglia or infiltrating monocytes. Using bone marrow (BM)-chimerism and dual-reporter transgenic fate mapping, we here set out to delimit the responses of either cell type to mild brain ischemia in a mouse model of 30 min transient middle cerebral artery occlusion (MCAo). A discriminatory analysis of gene expression at 7 days post-event yielded 472 transcripts predominantly or exclusively expressed in blood-derived macrophages as well as 970 transcripts for microglia.

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Apr
2017

A growing body of evidence demonstrates that psychosocial stress is an important and often underestimated risk factor for cardiovascular disease such as myocardial infarction and stroke. In this article, we map out major biological interfaces between stress, stress-related psychiatric disorders, and stroke, placing special emphasis on the fact that stress and psychiatric disorders may be both cause and consequence of cardiovascular disease. Apart from high-risk lifestyle habits such as smoking and lack of exercise, neuroendocrine dysregulation, alterations of the hemostatic system, increased oxidative stress, and inflammatory changes have been implicated in stress-related endothelial dysfunction.

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Oct
2017

Post-traumatic stress disorder (PTSD) is a psychiatric disorder of high prevalence and major socioeconomic impact. Patients suffering from PTSD typically present intrusion and avoidance symptoms and alterations in arousal, mood and cognition that last for more than 1 month. Animal models are an indispensable tool to investigate underlying pathophysiological pathways and, in particular, the complex interplay of neuroendocrine, genetic and environmental factors that may be responsible for PTSD induction.

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May
2017

Cerebral edema caused by the disruption of the blood-brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood-brain barrier restoration after mild cerebral ischemia occlusion/reperfusion.

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Aug
2017

Microglia senescence may promote neuropsychiatric disease. This prompted us to examine the relationship between microglia activation states and telomere biology. A panel of candidate genes associated with telomere maintenance, mitochondrial biogenesis, and cell-cycle regulation were investigated in M1- and M2-polarized microglia in vitro as well as in MACS-purified CD11b+ microglia/brain macrophages from models of stroke, Alzheimer's disease, and chronic stress.

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Aug
2017

The pattern of vascular remodelling in relation to recovery after stroke remains largely unclear. We used steady-state contrast-enhanced magnetic resonance imaging to assess the development of cerebral blood volume and microvascular density in perilesional and exofocal areas from (sub)acutely to chronically after transient stroke in rats. Microvascular density was verified histologically after infusion with Evans Blue dye.

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Aug
2016

VE-cadherin is the chief constituent of endothelial adherens junctions. However, the role of VE-cadherin in the pathogenesis of cerebrovascular diseases including brain ischemia has not yet been investigated.
VE-cadherin heterozygous (VEC(+/-)) mice and wildtype controls were subjected to transient brain ischemia by 30 min filamentous middle cerebral artery occlusion (MCAo)/reperfusion.

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Dec
1969

The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenous ARC protein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD). TAT.

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Nov
2015

Genetics of alcohol use disorders: Actin gets into the act.

Proc Natl Acad Sci U S A 2015 Nov 29;112(47):E6411. Epub 2015 Oct 29.
Golo Kronenberg, Matthias Endres, Karen Gertz

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Feb
2016

To describe retinal lesion development in Susac syndrome during acute, postacute, and late phases of the disease.
Cross-sectional study of four patients with Susac syndrome and longitudinal short-interval case study of one additional patient. Retinal changes were analyzed with high-resolution spectral domain optical coherence tomography and retinal fluorescein angiography.

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Jul
2015

Myelin is essential in vertebrates for the rapid propagation of action potentials, but the molecular mechanisms driving its formation remain largely unknown. Here we show that the initial stage of process extension and axon ensheathment by oligodendrocytes requires dynamic actin filament assembly by the Arp2/3 complex. Unexpectedly, subsequent myelin wrapping coincides with the upregulation of actin disassembly proteins and rapid disassembly of the oligodendrocyte actin cytoskeleton and does not require Arp2/3.

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Apr
2016

The interplay between BDNF signaling and the serotonergic system remains incompletely understood. Using a highly sensitive enzyme-linked immunosorbent assay, we studied BDNF concentrations in hippocampus and cortex of two mouse models of altered serotonin signaling: tryptophan hydroxylase (Tph)2-deficient (Tph2 (-/-)) mice lacking brain serotonin and serotonin transporter (SERT)-deficient (SERT(-/-)) mice lacking serotonin re-uptake. Surprisingly, hippocampal BDNF was significantly elevated in Tph2 (-/-) mice, whereas no significant changes were observed in SERT(-/-) mice.

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Dec
1969

Impaired actin filament dynamics have been associated with cellular senescence. Microglia, the resident immune cells of the brain, are emerging as a central pathophysiological player in neurodegeneration. Microglia activation, which ranges on a continuum between classical and alternative, may be of critical importance to brain disease.

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Sep
2015

Recent evidence from animal and human studies suggests neuroprotective effects of the SSRI fluoxetine, e.g., in the aftermath of stroke.

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Oct
2014

Commentary.

J Neurosci Rural Pract 2014 Oct;5(4):387-8
Hagen Kunte, Karen Gertz, Golo Kronenberg

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Dec
1969

Epigenetic transcriptional regulation by histone acetylation depends on the balance between histone acetyltransferase (HAT) and deacetylase activities (HDAC). Inhibition of HDAC activity provides neuroprotection, indicating that the outcome of cerebral ischemia depends crucially on the acetylation status of histones. In the present study, we characterized the changes in histone acetylation levels in ischemia models of focal cerebral ischemia and identified cAMP-response element binding protein (CREB)-binding protein (CBP) as a crucial factor in the susceptibility of neurons to ischemic stress.

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Apr
2014

Adolescence is characterized by important molecular and anatomical changes with relevance for the maturation of brain circuitry and cognitive function. This time period is of critical importance in the emergence of several neuropsychiatric disorders accompanied by cognitive impairment, such as affective disorders and schizophrenia. The molecular mechanisms underlying these changes at neuronal level during this specific developmental stage remains however poorly understood.

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May
2013

Intravenous administration of iron oxide nanoparticles during the acute stage of experimental stroke can produce signal intensity changes in the ischemic region. This has been attributed, albeit controversially, to the infiltration of iron-laden blood-borne macrophages. The properties of nanoparticles that render them most suitable for phagocytosis is a matter of debate, as is the most relevant timepoint for administration.

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Mar
2013

In the brain, retinoic acid (RA) concentrations are under tight spatio-temporal control. Here, we show that challenge of primary mouse microglia with lipopolysaccharide (LPS) results in increased release of nitric oxide (NO) and tumor necrosis factor-α (TNF-α). Co-administration of RA attenuated microglial activation.

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Mar
2013

Evaluation of functional outcome over the course of several weeks after ischemia is a key component in improving the clinical relevance of experimental stroke studies. Using a battery of behavioral tests, we characterized functional outcome in mice over 4 weeks following 30min of proximal middle cerebral artery occlusion (MCAo). We evaluated rotarod, chimney, pole and cylinder tests to assess short term functional deficits in a transient stroke model which induces infarcts mainly in the striatum.

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Jun
2012

Ambivalent effects of interleukin-6 on the pathogenesis of ischaemic stroke have been reported. However, to date, the long-term actions of interleukin-6 after stroke have not been investigated. Here, we subjected interleukin-6 knockout (IL-6(-/-)) and wild-type control mice to mild brain ischaemia by 30-min filamentous middle cerebral artery occlusion/reperfusion.

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Aug
2012

Although poststroke depression (PSD) is a frequent chronic complication of stroke with high relevance for outcome and survival, underlying pathomechanisms remain inadequately understood. This may be because suitable animal models are largely lacking and existing models are poorly characterized.
Male 129/SV mice were subjected to 30-min middle cerebral artery occlusion (MCAo)/reperfusion and serial magnetic resonance imaging scans.

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Dec
2012

While the biological importance of the cytochrome P450 system in the liver is well established, much less is known about its role in the brain and drug interactions at the level of brain cells have hardly been investigated. Here, we show that modafinil, a well-known inducer of hepatic CYP enzymes, also increases CYP3A4 expression in human-derived neuron-like SH-SY5Y cells. Upregulation of CYP3A4 by modafinil was associated with increased retinoic acid (RA) degradation, which could be blocked by specific CYP3A4 inhibitor erythromycin.

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Nov
2011

Chronic stress is associated with increased stroke risk. However, the underlying pathophysiological mechanisms are poorly understood. We examined the effects of chronic stress on endothelial function and ischemic brain injury in a mouse model.

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Feb
2012

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neurostimulatory technique widely used in research, diagnostics, and neuro-psychiatric therapy. Despite its growing popularity, basic molecular mechanisms underlying the clinical effects of rTMS have remained largely under-researched. Here, we present a human-derived neuronal cell culture system responsive to rTMS effects.

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Jun
2011

Vascular effects of mental stress are only partially understood. Therefore, we studied effects of chronic stress and heart rate (HR) on endothelial function and cerebral ischemia.
129S6/SvEv mice were randomized to the I(f)-channel inhibitor ivabradine (10 mg/kg per day) or vehicle and underwent a chronic stress protocol for 28 days.

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Apr
2011

Strong epidemiological and experimental evidence links folate deficiency and resultant hyperhomocysteinemia with cognitive decline and neurodegeneration. Here, we tested the hypothesis that uracil misincorporation contributes to mitochondrial pathology in aged brain following folate deprivation. In a 2 × 2 design, 14-month-old mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls were subjected to a folate-deficient versus a regular diet for six weeks.

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Jan
2011

Death receptor (DR) signaling has a major impact on the outcome of numerous neurological diseases, including ischemic stroke. DRs mediate not only cell death signals, but also proinflammatory responses and cell proliferation. Identification of regulatory proteins that control the switch between apoptotic and alternative DR signaling opens new therapeutic opportunities.

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Dec
2010

Although in vitro studies suggest that non-neurogenic regions of the adult central nervous system potentially contain multipotent parenchymal progenitors, neurons are clearly not replaced in most brain regions after injury. Here, in a well-established model of mild transient brain ischemia, we explored Olig2 antagonism and Pax6 overexpression as potential avenues to redirect endogenous progenitors proliferating in situ toward a neuronal fate.
Retroviral vectors containing either Pax6 or a strong activator form of the repressor Olig2 (Olig2VP16), ie, a functionally dominant negative form of Olig2, were stereotaxically injected into the lateral striatum at 48 hours after 30 minutes middle cerebral artery occlusion (MCAo)/reperfusion.

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Jun
2010

The stem-cell marker CD93 (AA4.1/C1qRp) has been described as a potential complement C1q-receptor. Its exact molecular function, however, remains unknown.

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Mar
2010

Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain.

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Apr
2009

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists (thiazolidinediones) have anti-inflammatory effects and improve endothelium function. Here, we analyzed the effects of pioglitazone on short- and longer-term outcome after mild transient brain ischemia. 129/SV mice were subjected to 30 min filamentous middle cerebral artery occlusion (MCAo), followed by reperfusion.

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Jul
2008

Folate deficiency and resultant increased homocysteine levels have been linked experimentally and epidemiologically with neurodegenerative conditions like stroke and dementia. Moreover, folate deficiency has been implicated in the pathogenesis of psychiatric disorders, most notably depression. We hypothesized that the pathogenic mechanisms include uracil misincorporation and, therefore, analyzed the effects of folate deficiency in mice lacking uracil DNA glycosylase (Ung-/-) versus wild-type controls.

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Jul
2008

We studied the properties of GFAP-expressing cells in adult mouse striatum using acute brain slices from transgenic animals expressing EGFP under GFAP promoter. Under physiological conditions, two distinct populations of GFAP-EGFP cells could be identified: (1) brightly fluorescent cells had bushy processes, passive membrane properties, glutamate transporter activity, and high gap junction coupling rate typical for classical astrocytes; (2) weakly fluorescent cells were characterized by thin, clearly distinguishable processes, voltage-gated currents, complex responses to kainate, and low coupling rate reminiscent of an astrocyte subtype recently described in the hippocampus. Mild focal cerebral ischemia confers delayed neuronal cell death and astrogliosis in the striatum.

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Apr
2008

The purpose of this study was to evaluate vascular effects of diet supplementation with plant sterol esters (PSE).
Plant sterol esters are used as food supplements to reduce cholesterol levels. Their effects on endothelial function, stroke, or atherogenesis are not known.

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Mar
2008

p27(Kip1) (p27) blocks cell proliferation through the inhibition of cyclin-dependent kinase-2 (Cdk2). Despite its robust expression in the heart, little is known about both the function and regulation of p27 in this and other nonproliferative tissues, in which the expression of its main target, cyclin E-Cdk2, is known to be very low. Here we show that angiotensin II, a major cardiac growth factor, induces the proteasomal degradation of p27 through protein kinase CK2-alpha'-dependent phosphorylation.

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Apr
2008

Acetylation/deactylation of histones is an important mechanism to regulate gene expression and chromatin remodeling. We have previously demonstrated that the HDAC inhibitor trichostatin A (TSA) protects cortical neurons from oxygen/glucose deprivation in vitro which is mediated--at least in part--via the up regulation of gelsolin expression. Here, we demonstrate that TSA treatment dose-dependently enhances histone acetylation in brains of wildtype mice as evidenced by immunoblots of total brain lysates and immunocytochemical staining.

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Feb
2008

Statins exert rapid cholesterol-independent vasoprotective effects. Here, we tested whether postevent treatment with intravenously (i.v.

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Feb
2008

Microglia is activated by brain injury. They migrate in response to ATP and although adenosine alone has no effect on wild type microglial migration, we show that inhibition of adenosine receptors impedes ATP triggered migration. CD39 is the dominant cellular ectonucleotidase that degrades nucleotides to nucleosides, including adenosine.

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Dec
2007

Serum insulin-like growth factor I (IGF-I), which is mostly produced by the liver, has recently been shown to have the unexpected ability to modulate normal brain function as well as brain response to injury. Moreover, serum IGF-I levels are modified in many brain diseases, including stroke. However, whether these modifications are related to the disease process remains uncertain.

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Jan
2007

Statins are widely used clinical drugs that exert beneficial growth-suppressive effects in patients with cardiac hypertrophy. We investigated the role of the cell cycle inhibitor p21(CIP1/WAF1) (p21) in statin-dependent inhibition of hypertrophic growth in postmitotic cardiomyocytes. We demonstrate that lovastatin fails to inhibit cardiac hypertrophy to angiotensin II in p21(-/-) mice and that reconstitution of p21 function by TAT.

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Nov
2006

Physical activity upregulates endothelial nitric oxide synthase (eNOS), improves endothelium function, and protects from vascular disease. Here, we tested whether voluntary running would enhance neovascularization and long-term recovery following mild brain ischemia. Wild-type mice were exposed to 30 minutes of middle-cerebral artery occlusion (MCAo) and reperfusion.

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Nov
2006

This study was designed to track systemically administered mononuclear cells (MNCs) in the ischemic mouse brain using 7 T magnetic resonance imaging (MRI). Splenectomized wild-type mice were subjected to brain ischemia by 30 or 60 min filamentous occlusion of the middle cerebral artery (MCAo) and reperfusion. Spleen-derived MNCs were labeled with very small superparamagnetic iron-oxide particles (VSOP) and transfused into recipient mice 30 min, 8 h, or 24 h after MCAo via the tail vein.

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Dec
2005

The intermediate filament nestin is upregulated in response to cerebral ischemia; the significance of this, however, is incompletely understood. Here, we used transgenic mice that express green fluorescent protein (GFP) under control of the nestin promotor to characterize the fate of nestin-expressing cells up to 8 weeks after 30 mins occlusion of the middle cerebral artery (MCAo) and reperfusion. The population of nestin-GFP+ cells increased in the ischemic lesion rim and core within 4 days, did not become TUNEL-positive, and was detectable up to 8 weeks in the lesion scar.

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Feb
2005

Folate deficiency and resultant hyperhomocysteinemia impair vascular function and increase stroke risk. We tested the hypothesis that folate deficiency and high homocysteine levels promote DNA damage and increase brain injury after cerebral ischemia/reperfusion.
129/Sv mice, uracil-DNA glycosylase-deficient (Ung-/-) mice, and Ung+/+ littermate mice were exposed to a folate-deficient diet for 3 months and then subjected to 30-minute middle cerebral artery (MCA) occlusion and reperfusion.

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May
2004

The premise that the intrinsic level of expression of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase determines the relative sensitivity to the serum cholesterol raising action of dietary cholesterol was examined in 9 strains of rat. For further comparison purposes, hamsters were also examined. The basal expression of hepatic HMG-CoA reductase, extent of feedback regulation by cholesterol, and changes in serum cholesterol levels and the hepatic low-density lipoprotein (LDL) receptor in response to cholesterol challenge were determined in these animals.

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