scholarly journals Regional variability, genotypic effects, and pharmacodynamic impact on prion protein concentration in the central nervous system

2021 ◽  
Author(s):  
Meredith A Mortberg ◽  
Hien T Zhao ◽  
Andrew G Reidenbach ◽  
Juliana E Gentile ◽  
Eric Kuhn ◽  
...  
Keyword(s):  
Prion Protein ◽  
Regional Variation ◽  
Protein Concentration ◽  
Brain Parenchyma ◽  
Relative Reduction ◽  
Target Engagement ◽  
Regional Variability ◽  
Cynomolgus Macaques ◽  
The Central Nervous System ◽  
Negative Controls

Reliable and scalable quantification of prion protein (PrP) is vital to the development of PrP- lowering drugs for prion disease. Here we develop a plate-based immunoassay reactive for PrP across six species of interest and applicable to brain and cerebrospinal fluid (CSF). Brain PrP shows similar patterns of regional variation in mice, cynomolgus macaques and humans. CSF PrP concentration does not appear to differ according to age, sex, or common PRNP variants, but it is reduced in the presence of rare pathogenic PRNP variants, with carriers of P102L displaying 55% and of D178N just 31% the CSF PrP concentration of mutation-negative controls. In rodents, pharmacologic reduction of brain Prnp RNA is reflected in brain parenchyma PrP, and in turn in CSF PrP. Our findings support the use of CSF PrP as a pharmacodynamic biomarker for PrP-lowering drugs, and suggest that relative reduction from individual baseline CSF PrP concentration may be an appropriate marker for target engagement.

scholarly journals Intracerebral haemorrhage in Down syndrome: protected or predisposed?

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 876 ◽  
Author(s):  
Lewis Buss ◽  
Elizabeth Fisher ◽  
John Hardy ◽  
Dean Nizetic ◽  
Jurgen Groet ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Intracerebral Haemorrhage ◽  
Early Onset ◽  
Epidemiological Data ◽  
Haemorrhagic Stroke ◽  
Brain Parenchyma ◽  
Chromosome 21 ◽  
Clinical Consequence ◽  
Increased Risk ◽  
The Central Nervous System

Down syndrome (DS), which arises from trisomy of chromosome 21, is associated with deposition of large amounts of amyloid within the central nervous system. Amyloid accumulates in two compartments: as plaques within the brain parenchyma and in vessel walls of the cerebral microvasculature. The parenchymal plaque amyloid is thought to result in an early onsetAlzheimer’s disease (AD) dementia, a phenomenon so common amongst people with DS that it could be considered a defining feature of the condition. The amyloid precursor protein (APP) gene lies on chromosome 21 and its presence in three copies in DS is thought to largely drive the early onset AD. In contrast, intracerebral haemorrhage (ICH), the main clinical consequence of vascular amyloidosis, is a more poorly defined feature of DS. We review recent epidemiological data on stroke (including haemorrhagic stroke) in order to make comparisons with a rare form of familial AD due to duplication (i.e. having three copies) of the APP region on chromosome 21, here called ‘dup-APP’, which is associated with more frequent and severe ICH. We conclude that although people with DS are at increased risk of ICH, this is less common than in dup-APP, suggesting the presence of mechanisms that act protectively. We review these mechanisms and consider comparative research into DS and dup-APP that may yield further pathophysiological insight.

scholarly journals Vascular Dysfunction Induced by Mercury Exposure

2019 ◽  
Vol 20 (10) ◽  
pp. 2435 ◽  
Author(s):  
Tetsuya Takahashi ◽  
Takayoshi Shimohata
Keyword(s):  
Oxidative Stress ◽  
Vascular Dysfunction ◽  
Brain Parenchyma ◽  
Transport Systems ◽  
Mehg Exposure ◽  
In Vivo Models ◽  
The Central Nervous System ◽  
The Brain

Methylmercury (MeHg) causes severe damage to the central nervous system, and there is increasing evidence of the association between MeHg exposure and vascular dysfunction, hemorrhage, and edema in the brain, but not in other organs of patients with acute MeHg intoxication. These observations suggest that MeHg possibly causes blood–brain barrier (BBB) damage. MeHg penetrates the BBB into the brain parenchyma via active transport systems, mainly the l-type amino acid transporter 1, on endothelial cell membranes. Recently, exposure to mercury has significantly increased. Numerous reports suggest that long-term low-level MeHg exposure can impair endothelial function and increase the risks of cardiovascular disease. The most widely reported mechanism of MeHg toxicity is oxidative stress and related pathways, such as neuroinflammation. BBB dysfunction has been suggested by both in vitro and in vivo models of MeHg intoxication. Therapy targeted at both maintaining the BBB and suppressing oxidative stress may represent a promising therapeutic strategy for MeHg intoxication. This paper reviews studies on the relationship between MeHg exposure and vascular dysfunction, with a special emphasis on the BBB.

Myelin Basic Protein inhibits the calcium response to phytohaemagglutinin in human lymphocytes

1990 ◽  
Vol 10 (1) ◽  
pp. 55-59
Author(s):  
Tiziana Bellini ◽  
Diana Degani ◽  
Maurizio Matteuzzi ◽  
Franco Dallocchio
Keyword(s):  
Myelin Basic Protein ◽  
Protein Concentration ◽  
Basic Protein ◽  
Human Lymphocytes ◽  
Cytosolic Calcium ◽  
Free Calcium ◽  
Cellular Activation ◽  
The Central Nervous System ◽  
Pre Treatment ◽  
Preincubation Time

Myelin Basic Protein, one of the major membrane protein component of the central nervous system, was used to probe the molecular mechanism of cellular activation by phytohaemagglutinin. Pre-treatment of human lymphocytes with myelin basic protein results in a lower rising of cytosolic concentration of free calcium after stimulation with phytohaemagglutinin. This effect is dependent on myelin basic protein concentration and on the preincubation time of the protein with the cells. It is not due to a interaction between myelin basic protein and phytohaemagglutinin, but appears to be a consequence of the binding of the protein to the cell surface. The reduction of the rise of cytosolic calcium induced by phytohaemagglutinin is specific for the myelin basic protein because other proteins like albumin and protamine have no effect.

Fatal Parasitic Meningoencephalomyelitis Caused By Halicephalobus deletrix: A Case Report and Review of the Literature

2010 ◽  
Vol 134 (4) ◽  
pp. 625-629
Author(s):  
Sarah L. Ondrejka ◽  
Gary W. Procop ◽  
Keith K. Lai ◽  
Richard A. Prayson
Keyword(s):  
Fatal Case ◽  
Brain Biopsy ◽  
Altered Mental Status ◽  
Brain Parenchyma ◽  
Review Of The Literature ◽  
Inflammatory Infiltration ◽  
Granulomatous Vasculitis ◽  
Helminthic Infection ◽  
The Central Nervous System ◽  
The Brain

Abstract Infection with the saprophagous nematode Halicephalobus species is uncommon but has been reported in horses worldwide. Only 3 human cases have been previously described, all of which have been fatal. We report a fourth fatal case, which occurred in a 39-year-old woman who presented with meningeal signs, altered mental status, and a prodromal pruritic rash. Diagnostic evaluation included an open brain biopsy, which was diagnosed as granulomatous vasculitis. The patient subsequently died after a course of steroids and cyclophosphamide. At autopsy, a robust perivascular mixed inflammatory infiltration of the brain parenchyma, meninges, and ventricular system was present with larval forms and mature nematodes morphologically consistent with Halicephalobus deletrix. Although extremely rare, this organism needs to be considered in the differential diagnosis of human helminthic infection of the central nervous system.

The neuroepidemiology of human prion disease

2020 ◽  
pp. 367-378
Author(s):  
Patrick JM Urwin ◽  
Anna M Molesworth
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Protein Misfolding ◽  
Prion Diseases ◽  
Prion Protein Gene ◽  
Human Prion Disease ◽  
Disease States ◽  
Jakob Disease ◽  
The Central Nervous System ◽  
Sporadic Disease

Human prion diseases comprise a number of rare and fatal neurodegenerative conditions that result from the accumulation in the central nervous system of an abnormal form of a naturally occurring protein, called the prion protein. The diseases occur in genetic, sporadic, and acquired forms: genetic disease is associated with mutations in the prion protein gene (PRNP); sporadic disease is thought to result from a spontaneous protein misfolding event; acquired disease results from transmission of infection from an animal or another human. The potential transmissibility of the prion in any of these forms, either in disease states or during the incubation period, has implications for public health. Here we focus on Creutzfeldt-Jakob Disease (CJD), including variant Creutzfeldt-Jakob Disease (vCJD), although we will also discuss other forms of human prion disease.

scholarly journals Immune cells and CNS physiology: Microglia and beyond

2018 ◽  
Vol 216 (1) ◽  
pp. 60-70 ◽  
Author(s):  
Geoffrey T. Norris ◽  
Jonathan Kipnis
Keyword(s):  
Central Nervous System ◽  
Immune Cells ◽  
Brain Function ◽  
Brain Parenchyma ◽  
The Body ◽  
Immune Repertoire ◽  
Perivascular Macrophages ◽  
The Central Nervous System ◽  
Cns Immunity ◽  
The Brain

Recent advances have directed our knowledge of the immune system from a narrative of “self” versus “nonself” to one in which immune function is critical for homeostasis of organs throughout the body. This is also the case with respect to the central nervous system (CNS). CNS immunity exists in a segregated state, with a marked partition occurring between the brain parenchyma and meningeal spaces. While the brain parenchyma is patrolled by perivascular macrophages and microglia, the meningeal spaces are supplied with a diverse immune repertoire. In this review, we posit that such partition allows for neuro–immune crosstalk to be properly tuned. Convention may imply that meningeal immunity is an ominous threat to brain function; however, recent studies have shown that its presence may instead be a steady hand directing the CNS to optimal performance.

scholarly journals Presence of amastigotes in the central nervous system of hamsters infected with Leishmania sp.

2011 ◽  
Vol 20 (2) ◽  
pp. 97-102 ◽  
Author(s):  
Elisangela de Oliveira ◽  
Elisa Teruya Oshiro ◽  
Rebeca Vieira Pinto ◽  
Bruna Corrêa de Castro ◽  
Karla Borges Daniel ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Signs ◽  
Direct Examination ◽  
Mato Grosso ◽  
The Central Nervous System ◽  
Animal House ◽  
Immunohistochemical Studies ◽  
Negative Controls ◽  
The Brain

Visceral leishmaniasis (VL) is a severe chronic disease caused by Leishmania (Leishmania) infantum chagasi. Better knowledge on the effects caused by this disease can help develop adequate clinical management and treatment. Parasitological and immunohistochemical studies were performed golden hamsters Mesocricetus auratus infected with bone marrow from individuals with VL in the State of Mato Grosso do Sul, central-west Brazil. The effects of parasitism in the spleen, liver, kidneys, lungs, heart and brain of the animals were examined. Eighteen hamsters were inoculated intraperitoneally, and six healthy animals were used as negative controls. The animals were kept in the animal house and checked for clinical signs. Specimens of each organ were examined for the presence of amastigotes. Immunohistochemical technique was performed in all brain specimens and organs negative on the direct examination of parasites. Direct examination of amastigotes was positive in the spleen and liver of all infected animals; 33.3% showed the parasite in the kidneys and lungs, and 16.7% in the heart. Parasitic forms were seen in 83.3% (15/18) of the brain examined. Immunohistochemistry confirmed the results of the direct examination, except in two specimens of lung tissue and in the brain specimens. Other studies are needed to further clarify the effect of the parasite in the central nervous system.

scholarly journals Neuroinvasion in Prion Diseases: The Roles of Ascending Neural Infection and Blood Dissemination

2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Sílvia Sisó ◽  
Lorenzo González ◽  
Martin Jeffrey
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Prion Protein ◽  
Prion Diseases ◽  
Autonomic Nerves ◽  
Peripheral Organs ◽  
Prion Strains ◽  
New Variant ◽  
Jakob Disease ◽  
The Central Nervous System

Prion disorders are infectious, neurodegenerative diseases that affect humans and animals. Susceptibility to some prion diseases such as kuru or the new variant of Creutzfeldt-Jakob disease in humans and scrapie in sheep and goats is influenced by polymorphisms of the coding region of the prion protein gene, while other prion disorders such as fatal familial insomnia, familial Creutzfeldt-Jakob disease, or Gerstmann-Straussler-Scheinker disease in humans have an underlying inherited genetic basis. Several prion strains have been demonstrated experimentally in rodents and sheep. The progression and pathogenesis of disease is influenced by both genetic differences in the prion protein and prion strain. Some prion diseases only affect the central nervous system whereas others involve the peripheral organs prior to neuroinvasion. Many experiments undertaken in different species and using different prion strains have postulated common pathways of neuroinvasion. It is suggested that prions access the autonomic nerves innervating peripheral organs and tissues to finally reach the central nervous system. We review here published data supporting this view and additional data suggesting that neuroinvasion may concurrently or independently involve the blood vascular system.

scholarly journals Immune System in the Brain: A Modulatory Role on Dendritic Spine Morphophysiology?

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Oscar Kurt Bitzer-Quintero ◽  
Ignacio González-Burgos
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Immune System ◽  
Dendritic Spines ◽  
Cell Lineage ◽  
Myeloid Cell ◽  
Brain Parenchyma ◽  
Immune Mediators ◽  
The Central Nervous System ◽  
The Brain

The central nervous system is closely linked to the immune system at several levels. The brain parenchyma is separated from the periphery by the blood brain barrier, which under normal conditions prevents the entry of mediators such as activated leukocytes, antibodies, complement factors, and cytokines. The myeloid cell lineage plays a crucial role in the development of immune responses at the central level, and it comprises two main subtypes: (1) resident microglia, distributed throughout the brain parenchyma; (2) perivascular macrophages located in the brain capillaries of the basal lamina and the choroid plexus. In addition, astrocytes, oligodendrocytes, endothelial cells, and, to a lesser extent, neurons are implicated in the immune response in the central nervous system. By modulating synaptogenesis, microglia are most specifically involved in restoring neuronal connectivity following injury. These cells release immune mediators, such as cytokines, that modulate synaptic transmission and that alter the morphology of dendritic spines during the inflammatory process following injury. Thus, the expression and release of immune mediators in the brain parenchyma are closely linked to plastic morphophysiological changes in neuronal dendritic spines. Based on these observations, it has been proposed that these immune mediators are also implicated in learning and memory processes.

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