scholarly journals In vitro Modeling of Prion Strain Tropism

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 236
Author(s):  
Etienne Levavasseur ◽  
Nicolas Privat ◽  
Stéphane Haïk
Keyword(s):  
Protein Misfolding ◽  
Genetic Material ◽  
Brain Regions ◽  
Experimental Models ◽  
Neuronal Cultures ◽  
Infectious Agents ◽  
Prion Strain ◽  
Specific Targeting ◽  
The Brain

Prions are atypical infectious agents lacking genetic material. Yet, various strains have been isolated from animals and humans using experimental models. They are distinguished by the resulting pattern of disease, including the localization of PrPsc deposits and the spongiform changes they induce in the brain of affected individuals. In this paper, we discuss the emerging use of cellular and acellular models to decipher the mechanisms involved in the strain-specific targeting of distinct brain regions. Recent studies suggest that neuronal cultures, protein misfolding cyclic amplification, and combination of both approaches may be useful to explore this under-investigated but central domain of the prion field.

scholarly journals ANTI-PSYCHOTIC ACTIVITY OF PYRUS COMMUNIS JUICE

2017 ◽  
Vol 9 (4) ◽  
pp. 113
Author(s):  
Arzoo Singh Pannu ◽  
Milind Parle
Keyword(s):  
Experimental Models ◽  
Pyrus Communis ◽  
Anti Psychotic ◽  
Head Bobbing ◽  
Stereotypic Behaviour ◽  
Biochemical Estimation ◽  
Pear Juice ◽  
The Brain ◽  
Grooming Behaviour

Objective: The present study aim to investigate the anti-psychotic potential of pyrus communis in the rodents.Methods: The fresh juice of pyrus communis (Pear) was administered orally to rodents for 21 d and the anti-psychotic activity was assessed by in vitro methods viz ketamine induced stereotypic behaviour, pole climbing avoidance in rats and swim induced grooming behaviour experimental models. The biochemical estimation was done on 21 d.Results: The different concentrations of fresh pyrus communis juice was assayed. When pyrus communis juice (PCJ) was administered chronically for 21 d remarkably decreased ketamine induced falling, head-bobbing, weaving and turning counts. Administration of Pear juice significantly delayed the latency time taken by the animals to climb the pole in Cook’s pole climb apparatus. In swim induced grooming behaviour model, Pear juice significantly reduced swim induced grooming behaviour. Moreover, Pear juice significantly decreased the brain dopamine levels and inhibited acetyl cholinesterase activity. In the present study, Pear juice significantly enhanced reduced glutathione levels in the brains of mice, thereby reflecting enhanced scavenging of free radicals and in turn preventing occurrence of psychotic attack.Conclusion: The present study revealed that pyrus communis juice possessed significant anti-psychotic activity.

scholarly journals Neurotoxic astrocytic glypican-4 drives APOE4-dependent tau pathology

2021 ◽  
Author(s):  
Sivaprakasam Ramamoorthy ◽  
Kirill Gorbachev ◽  
Ana Pereira
Keyword(s):  
Late Onset ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Brain Regions ◽  
Tau Proteins ◽  
Tau Pathology ◽  
Density Lipoprotein Receptor ◽  
Apoe Receptor ◽  
The Brain

Apolipoprotein E4 (APOE4) is the crucial genetic risk factor of late-onset Alzheimer disease (AD). Aggregation of tau proteins into insoluble filaments and their spreading across the brain regions are major drivers of neurodegeneration in tauopathies, including in AD. However, the exact mechanisms through which APOE4 induces tau pathology remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), a novel binding partner of APOE4, drives tau pathology. GPC-4 preferentially interacts with APOE4 in comparison to other APOE isoforms and post-mortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. The astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9 mediated activation of GPC-4 in a tauopathy animal model robustly induced tau pathology. Further, APOE4-induced tau pathology was greatly diminished in the absence of GPC-4. We found that GPC-4 promoted the stabilization of the APOE receptor low-density lipoprotein receptor-related protein 1 (LRP1) on the cellular surface, which effectively facilitates endocytosis of tau protein. Together, our data comprehensively demonstrate that one of the key APOE4-induced tau pathologies is directly mediated by GPC-4.

scholarly journals Differential effects of propofol and ketamine on critical brain dynamics

2020 ◽  
Vol 16 (12) ◽  
pp. e1008418
Author(s):  
Thomas F. Varley ◽  
Olaf Sporns ◽  
Aina Puce ◽  
John Beggs
Keyword(s):  
Cellular Level ◽  
Brain Dynamics ◽  
Neuronal Cultures ◽  
Altered States ◽  
Differential Effects ◽  
States Of Consciousness ◽  
Anaesthetized Rats ◽  
And Control ◽  
The Brain

Whether the brain operates at a critical “tipping” point is a long standing scientific question, with evidence from both cellular and systems-scale studies suggesting that the brain does sit in, or near, a critical regime. Neuroimaging studies of humans in altered states of consciousness have prompted the suggestion that maintenance of critical dynamics is necessary for the emergence of consciousness and complex cognition, and that reduced or disorganized consciousness may be associated with deviations from criticality. Unfortunately, many of the cellular-level studies reporting signs of criticality were performed in non-conscious systems (in vitro neuronal cultures) or unconscious animals (e.g. anaesthetized rats). Here we attempted to address this knowledge gap by exploring critical brain dynamics in invasive ECoG recordings from multiple sessions with a single macaque as the animal transitioned from consciousness to unconsciousness under different anaesthetics (ketamine and propofol). We use a previously-validated test of criticality: avalanche dynamics to assess the differences in brain dynamics between normal consciousness and both drug-states. Propofol and ketamine were selected due to their differential effects on consciousness (ketamine, but not propofol, is known to induce an unusual state known as “dissociative anaesthesia”). Our analyses indicate that propofol dramatically restricted the size and duration of avalanches, while ketamine allowed for more awake-like dynamics to persist. In addition, propofol, but not ketamine, triggered a large reduction in the complexity of brain dynamics. All states, however, showed some signs of persistent criticality when testing for exponent relations and universal shape-collapse. Further, maintenance of critical brain dynamics may be important for regulation and control of conscious awareness.

Noninvasive Detection of Misfolded Proteins in the Brain Using [11C]BF-227 PET

2013 ◽  
pp. 438-445
Author(s):  
Nobuyuki Okamura ◽  
Shozo Furumoto ◽  
Manabu Tashiro ◽  
Katsutoshi Furukawa ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Protein A ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Brain Regions ◽  
Postmortem Brain ◽  
In Vivo Detection ◽  
Misfolding Diseases ◽  
The Brain

Alzheimer’s disease (AD) and many other neurodegenerative disorders belong to the family of protein misfolding diseases. These diseases are characterized by the deposition of insoluble protein aggregates containing an enriched ß-sheet structure. To evaluate PET amyloid-imaging tracer [11C]BF-227 as an agent for in vivo detection of various kinds of misfolded protein, a [11C]BF-227 PET study was performed in patients with various protein misfolding diseases, including AD, frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS). BF-227 binds to ß-amyloid fibrils with high affinity. Most of the AD patients showed prominent retention of [11C]BF-227 in the neocortex. In addition, neocortical retention of BF-227 was observed in the subjects with mild cognitive impairment who converted to AD during follow-up. DLB patients had elevated [11C]BF-227 uptake in the neocortex. However, FTD and sCJD patients showed no cortical retention of [11C]BF-227. Patients with multiple system atrophy had elevated BF-227 binding in the putamen. Finally, GSS patients had elevated BF-227 uptake in the cerebellum and other brain regions. This chapter confirms that BF-227 can selectively bind to a-synuclein and prion protein deposits using postmortem brain samples. Based on these findings, [11C]BF-227 is not necessarily specific for ß-amyloid in AD patients. However, this tracer could be used to detect various types of protein aggregates in the brain.

Thoughts for the Future

2020 ◽  
pp. 497-508
Author(s):  
Richard McCarty
Keyword(s):  
Mental Disorders ◽  
Specific Area ◽  
Neuronal Cultures ◽  
Common Theme ◽  
Use Of Data ◽  
The Future ◽  
Induced Pluripotent ◽  
The Brain

Several exciting lines of research have emerged from the study of animal models of mental disorders. This chapter presents seven opportunities for enhancing the diagnosis and treatment of mental disorders. They include improvements to the system for diagnosis of mental disorders, use of induced pluripotent stem cells from patients to generate neuronal cultures for in vitro determination of effective drug therapies for those individuals, use of data-mining techniques for understanding patient variability, a commitment to a greater focus on the prevention of mental disorders, innovative uses of smartphones to track patients and individuals at high risk of developing a mental disorder, and developing next-generation therapies and delivery systems that target a specific area of the brain rather than the entire brain. A common theme in these seven thoughts for the future is a commitment to bringing precision medicine tools to the treatment of patients with mental disorders.

scholarly journals The emergence of classical BSE from atypical/Nor98 scrapie

2019 ◽  
Vol 116 (52) ◽  
pp. 26853-26862 ◽  
Author(s):  
Alvina Huor ◽  
Juan Carlos Espinosa ◽  
Enric Vidal ◽  
Hervé Cassard ◽  
Jean-Yves Douet ◽  
...  
Keyword(s):  
Prion Disease ◽  
Protein Misfolding ◽  
Small Ruminants ◽  
Public Health Perspective ◽  
Prion Strain ◽  
Low Levels ◽  
Insight Into ◽  
New Occurrences

Atypical/Nor98 scrapie (AS) is a prion disease of small ruminants. Currently there are no efficient measures to control this form of prion disease, and, importantly, the zoonotic potential and the risk that AS might represent for other farmed animal species remains largely unknown. In this study, we investigated the capacity of AS to propagate in bovine PrP transgenic mice. Unexpectedly, the transmission of AS isolates originating from 5 different European countries to bovine PrP mice resulted in the propagation of the classical BSE (c-BSE) agent. Detection of prion seeding activity in vitro by protein misfolding cyclic amplification (PMCA) demonstrated that low levels of the c-BSE agent were present in the original AS isolates. C-BSE prion seeding activity was also detected in brain tissue of ovine PrP mice inoculated with limiting dilutions (endpoint titration) of ovine AS isolates. These results are consistent with the emergence and replication of c-BSE prions during the in vivo propagation of AS isolates in the natural host. These data also indicate that c-BSE prions, a known zonotic agent in humans, can emerge as a dominant prion strain during passage of AS between different species. These findings provide an unprecedented insight into the evolution of mammalian prion strain properties triggered by intra- and interspecies passage. From a public health perspective, the presence of c-BSE in AS isolates suggest that cattle exposure to small ruminant tissues and products could lead to new occurrences of c-BSE.

HORMONES MODULATE THE CONCENTRATION OF CYTOPLASMIC PROGESTIN RECEPTORS IN THE BRAIN OF MALE RING DOVES (STREPTOPELIA RISORIA)

1980 ◽  
Vol 86 (2) ◽  
pp. 251-261 ◽  
Author(s):  
J. BALTHAZART ◽  
J. D. BLAUSTEIN ◽  
M. F. CHENG ◽  
H. H. FEDER
Keyword(s):  
Testosterone Propionate ◽  
Brain Regions ◽  
Posterior Hypothalamus ◽  
Vitro Assay ◽  
Progestin Receptors ◽  
Streptopelia Risoria ◽  
Oestradiol Benzoate ◽  
Ring Doves ◽  
The Brain

A cytoplasmic progestin receptor has been characterized in the brain of castrated ring doves using an in-vitro assay that measures the binding of a synthetic progestin, [3H]17α,21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione(promegestone; R5020). The affinity of the receptor was similar in both the hyperstriatum and the hypothalamus (Kd≃4 × 10−10 mol/l). Its concentration was higher in the anterior hypothalamus–preoptic area (63 ± 4 fmol/mg (s.e.m.) protein) than in other brain regions (posterior hypothalamus, 33 ± 5; hyperstriatum, 28 ± 3; midbrain, 17 ± 4 fmol/mg protein; n = 7). Progesterone and R5020 competed well for binding but oestradiol and 5β-dihydrotestosterone did not. Corticosterone and, to a lesser extent, testosterone and 5α-dihydrotestosterone competed for binding but much higher concentrations were required than for progestins. Injections of testosterone (200 pg testosterone propionate daily for 7 days) significantly increased the concentration of progestin receptors in the anterior and posterior hypothalamus without having any significant effect on other brain areas. Shorter treatment, lasting for 2 days, with testosterone propionate (200 μg daily), 5α-dihydrotestosterone (200 μg daily) or oestradiol benzoate (50 μg daily) did not always cause this increase but seven injections of oestradiol benzoate (50 pg daily for 7 days) were even more effective than seven injections of testosterone propionate (200 μg daily for 7 days). These data suggested that the sensitivity to progesterone of the brain of the bird changes as a consequence of increases in the level of testosterone in the circulation.

Chemical targeting of voltage sensitive dyes to specific cells and molecules in the brain

2020 ◽  
Author(s):  
Tomas Fiala ◽  
Jihang Wang ◽  
Matthew Dunn ◽  
Peter Šebej ◽  
Se Joon Choi ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Brain Tissue ◽  
Fluorescent Dyes ◽  
Brain Slices ◽  
Brain Regions ◽  
Expression Levels ◽  
Specific Targeting ◽  
The Impact ◽  
Voltage Sensitive Dyes ◽  
The Brain

Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. These sensors, rendered highly lipophilic to anchor the conjugated pi-wire molecular framework in the membrane, offer several favorable functional parameters including fast response kinetics and high sensitivity to membrane potential changes. The impact of VSDs has, however, been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a non-genetic molecular platform for cell- and molecule-specific targeting of synthetic voltage sensitive dyes in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of voltage sensitive dyes by dynamic encapsulation, and high-affinity ligands to target the construct to specific neuronal cells utilizing only native components of the neurotransmission machinery at physiological expression levels. Dichloropane, a monoamine transporter ligand, enables targeting of dense dopaminergic axons in the mouse striatum and sparse noradrenergic axons in the mouse cortex in acute brain slices. PFQX in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-type glutamate receptors in the same brain regions. Probe variants bearing either a classical electrochromic ANEP dye or state-of-the-art VoltageFluor-type dye respond to membrane potential changes in a similar manner to the parent dyes, as shown by whole-cell patch recording. We demonstrate the feasibility of optical voltage recording with our probes in brain tissue with one-photon and two-photon fluorescence microscopy and define the signal limits of optical voltage imaging with synthetic sensors under a low photon budget determined by the native expression levels of the target proteins. We envision that modularity of our platform will enable its application to a variety of molecular targets and sensors, as well as lipophilic drugs and signaling modulators. This work demonstrates the feasibility of a chemical targeting approach and expands the possibilities of cell-specific imaging and pharmacology.

Noninvasive Detection of Misfolded Proteins in the Brain Using [11C]BF-227 PET

2011 ◽  
pp. 212-219
Author(s):  
Nobuyuki Okamura ◽  
Shozo Furumoto ◽  
Manabu Tashiro ◽  
Katsutoshi Furukawa ◽  
Hiroyuki Arai ◽  
...  
Keyword(s):  
Protein Misfolding ◽  
Protein A ◽  
Lewy Bodies ◽  
Protein Aggregates ◽  
Brain Regions ◽  
Postmortem Brain ◽  
In Vivo Detection ◽  
Misfolding Diseases ◽  
The Brain

Alzheimer’s disease (AD) and many other neurodegenerative disorders belong to the family of protein misfolding diseases. These diseases are characterized by the deposition of insoluble protein aggregates containing an enriched ß-sheet structure. To evaluate PET amyloid-imaging tracer [11C]BF-227 as an agent for in vivo detection of various kinds of misfolded protein, a [11C]BF-227 PET study was performed in patients with various protein misfolding diseases, including AD, frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Sträussler-Scheinker disease (GSS). BF-227 binds to ß-amyloid fibrils with high affinity. Most of the AD patients showed prominent retention of [11C]BF-227 in the neocortex. In addition, neocortical retention of BF-227 was observed in the subjects with mild cognitive impairment who converted to AD during follow-up. DLB patients had elevated [11C]BF-227 uptake in the neocortex. However, FTD and sCJD patients showed no cortical retention of [11C]BF-227. Patients with multiple system atrophy had elevated BF-227 binding in the putamen. Finally, GSS patients had elevated BF-227 uptake in the cerebellum and other brain regions. This chapter confirms that BF-227 can selectively bind to a-synuclein and prion protein deposits using postmortem brain samples. Based on these findings, [11C]BF-227 is not necessarily specific for ß-amyloid in AD patients. However, this tracer could be used to detect various types of protein aggregates in the brain.

scholarly journals Morphological and Calcium Signaling Alterations of Neuroglial Cells in Cerebellar Cortical Dysplasia Induced by Carmustine

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1581
Author(s):  
Cynthia Alejandra Rodríguez-Arzate ◽  
Marianne Lizeth Martínez-Mendoza ◽  
Israel Rocha-Mendoza ◽  
Yryx Luna-Palacios ◽  
Jacob Licea-Rodríguez ◽  
...  
Keyword(s):  
Neuronal Migration ◽  
Brain Cortex ◽  
Motor Coordination ◽  
Cortical Dysplasia ◽  
Experimental Models ◽  
Glutamatergic Transmission ◽  
Intracellular Calcium Dynamics ◽  
Cortical Dysplasias ◽  
The Brain

Cortical dysplasias are alterations in the organization of the layers of the brain cortex due to problems in neuronal migration during development. The neuronal component has been widely studied in experimental models of cortical dysplasias. In contrast, little is known about how glia are affected. In the cerebellum, Bergmann glia (BG) are essential for neuronal migration during development, and in adult they mediate the control of fine movements through glutamatergic transmission. The aim of this study was to characterize the morphology and intracellular calcium dynamics of BG and astrocytes from mouse cerebellum and their modifications in a model of cortical dysplasia induced by carmustine (BCNU). Carmustine-treated mice were affected in their motor coordination and balance. Cerebellar dysplasias and heterotopias were more frequently found in lobule X. Morphology of BG cells and astrocytes was affected, as were their spontaneous [Ca2+]i transients in slice preparation and in vitro.

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