Cytokine profiles and the role of cellular prion protein in patients with vascular dementia and vascular encephalopathy

Schmitz, Matthias; Hermann, Péter; Oikonomou, Pantelis; Stoeck, Katharina; Ebert, Elisabeth; Poliakova, Tatjana; Schmidt, C. Max; Llorens, Franc; Zafar, Saima; Zerr, Inga

doi:10.1016/j.neurobiolaging.2015.05.013

Cited by 41 publications

(29 citation statements)

References 50 publications

(9 reference statements)

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“…Under pathological conditions, infiltration of IFNγ-producing T cells in the brain is enhanced due to brain damage or aging-associated increased permeability of the blood brain barrier. Consequently, enhanced IFNγ concentrations have been found in the aged brain [18], following traumatic brain injury [19] and at early stages of neurodegenerative diseases, including Alzheimer’s disease [20], Parkinson’s disease [21] and vascular dementia [22]. …”

Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

et al. 2016

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Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME. Together, our data indicate that priming of microglial ROS production involves reduction of intracellular glutathione levels, upregulation of NADPH oxidase subunit NOX2 and increases in nitric oxide production, and suggest that these simultaneously occurring processes result in enhanced production of neurotoxic peroxynitrite. Furthermore, IFNγ-induced priming of microglial ROS production was reduced upon blockade of Kir2.1 inward rectifier K+ channels with ML133. Inhibitory effects of ML133 on microglial priming were mediated via regulation of intracellular glutathione levels and nitric oxide production. These data suggest that microglial Kir2.1 channels may represent novel therapeutic targets to inhibit excessive ROS production by primed microglia in brain pathology.

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Section: Introductionmentioning

confidence: 99%

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

et al. 2016

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“…Therefore, a total of 46 papers were eventually included in this study ( Figure 1) and the main findings are summarized in Table 1. More in details, 8 studies deal with serum biomarkers [9][10][11][12][13][14][15][16], 10 with cerebrospinal fluid (CSF) [17][18][19][20][21][22][23][24][25][26], 4 with neuroimaging [27][28][29][30], 6 with histopathology [31][32][33][34][35][36], and 14 with transcranial magnetic stimulation (TMS) [37][38][39][40][41][42][43][44][45][46][47][48][49][50]; 4 studies included more than one technique: one studied both serum and CSF markers [51], two both serum and neuroimaging [52,53], and one both CSF and neuroimaging…”

Section: Resultsmentioning

confidence: 99%

“…Notably, a positive correlation between Aβ40, T-tau, P-tau, and CSF-cellular prion protein levels was observed in VaD patients [51]. Additionally, the increase of selected protein panel, such as Aβ1-42, T-tau, P-tau, myelin basic protein, tissue inhibitors of metalloproteinases-1 (TIMP-1), NF-L, matrix metalloproteinases (MMP)-9, and MMP-2, was found to be helpful in differentiating SIVD patients with cognitive decline from AD, with a sensitivity of 89%, a specificity of 90% [20].…”

Section: Cerebrospinal Fluidmentioning

confidence: 90%

“…Increased levels of three proinflammatory cytokines (interleukin (IL)-1b, tumor necrosis factor-alpha (TNF-α), and interferon-gamma (IFN-γ)), two anti-inflammatory cytokines (IL-4 and IL-5), and one chemokine (granulocyte-colony stimulating factor (G-CSF)) were found in serum of VaD patients compared with AD and controls. Furthermore, cytokine levels of macrophage inflammatory protein-1beta (MIP-1β) and IL-8 correlated with neuropsychological test scores [51].…”

Section: Serummentioning

confidence: 99%

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Update on the Neurobiology of Vascular Cognitive Impairment: From Lab to Clinic

Vinciguerra

Lanza

Puglisi

et al. 2020

IJMS

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In the last years, there has been a significant growth in the literature exploring the pathophysiology of vascular cognitive impairment (VCI). As an "umbrella term" encompassing any degree of vascular-related cognitive decline, VCI is deemed to be the most common cognitive disorder in the elderly, with a significant impact on social and healthcare expenses. Interestingly, some of the molecular, biochemical, and electrophysiological abnormalities detected in VCI seem to correlate with disease process and progression, eventually promoting an adaptive plasticity in some patients and a maladaptive, dysfunctional response in others. However, the exact relationships between vascular lesion, cognition, and neuroplasticity are not completely understood. Recent findings point out also the possibility to identify a panel of markers able to predict cognitive deterioration in the so-called "brain at risk" for vascular or mixed dementia. This will be of pivotal importance when designing trials of disease-modifying drugs or non-pharmacological approaches, including non-invasive neuromodulatory techniques. Taken together, these advances could make VCI a potentially preventable cause of both vascular and degenerative dementia in late life. This review provides a timely update on the recent serological, cerebrospinal fluid, histopathological, imaging, and neurophysiological studies on this "cutting-edge" topic, including the limitations, future perspectives and translational implications in the diagnosis and management of VCI patients.

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“…While the pathophysiological relevance of this observation is yet to be determined, an association between neurodegenerative disorders and inflammatory cytokine responses has been suggested recently (Schmitz et al, 2015). These cytokines are known for their pleiotropic function and are implicated in activation of microglia, proliferation, migration, and homing of different immune and non-immune cells.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy

Zaccai

Savitzki

Zivony-Elboum

et al. 2016

Brain

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*These authors contributed equally to this work.Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A 2 -activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E 2 and cytosolic phospholipase A 2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E 2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E 2 and cytosolic phospholipase A 2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E 2 . The non-functional phospholipase A 2 -activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance.

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Cytokine profiles and the role of cellular prion protein in patients with vascular dementia and vascular encephalopathy

Cited by 41 publications

References 50 publications

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

Update on the Neurobiology of Vascular Cognitive Impairment: From Lab to Clinic

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy

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Cytokine profiles and the role of cellular prion protein in patients with vascular dementia and vascular encephalopathy

Cited by 41 publications

References 50 publications

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production

Update on the Neurobiology of Vascular Cognitive Impairment: From Lab to Clinic

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Contact Info

Product

Resources

About

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy