scholarly journals Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

2020 ◽  
Vol 21 (14) ◽  
pp. 5030
Author(s):  
Elena Vacchi ◽  
Alain Kaelin-Lang ◽  
Giorgia Melli
Keyword(s):  
Neurodegenerative Diseases ◽  
Alpha Synuclein ◽  
Anatomical Connectivity ◽  
Peripheral Tissues ◽  
Parkinson’S Diseases ◽  
Relevant Role ◽  
The Brain ◽  
Dying Back

In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

scholarly journals News about the Role of Fluid and Imaging Biomarkers in Neurodegenerative Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 252
Author(s):  
Jacopo Meldolesi
Keyword(s):  
Neurodegenerative Diseases ◽  
Imaging Techniques ◽  
Imaging Biomarkers ◽  
Positron Emission ◽  
Specific Proteins ◽  
Great Relevance ◽  
The Brain ◽  
Positive Point

Biomarkers are molecules that are variable in their origin, nature, and mechanism of action; they are of great relevance in biology and also in medicine because of their specific connection with a single or several diseases. Biomarkers are of two types, which in some cases are operative with each other. Fluid biomarkers, started around 2000, are generated in fluid from specific proteins/peptides and miRNAs accumulated within two extracellular fluids, either the central spinal fluid or blood plasma. The switch of these proteins/peptides and miRNAs, from free to segregated within extracellular vesicles, has induced certain advantages including higher levels within fluids and lower operative expenses. Imaging biomarkers, started around 2004, are identified in vivo upon their binding by radiolabeled molecules subsequently revealed in the brain by positron emission tomography and/or other imaging techniques. A positive point for the latter approach is the quantitation of results, but expenses are much higher. At present, both types of biomarker are being extensively employed to study Alzheimer’s and other neurodegenerative diseases, investigated from the presymptomatic to mature stages. In conclusion, biomarkers have revolutionized scientific and medical research and practice. Diagnosis, which is often inadequate when based on medical criteria only, has been recently improved by the multiplicity and specificity of biomarkers. Analogous results have been obtained for prognosis. In contrast, improvement of therapy has been limited or fully absent, especially for Alzheimer’s in which progress has been inadequate. An urgent need at hand is therefore the progress of a new drug trial design together with patient management in clinical practice.

scholarly journals Novel Ubiquitin Specific Protease-13 Inhibitors Alleviate Neurodegenerative Pathology

Metabolites ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 622
Author(s):  
Xiaoguang Liu ◽  
Kaluvu Balaraman ◽  
Ciarán C. Lynch ◽  
Michaeline Hebron ◽  
Christian Wolf ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecule ◽  
Alpha Synuclein ◽  
Protein Levels ◽  
Neurodegenerative Pathology ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
The Brain

Ubiquitin Specific Protease-13 (USP13) promotes protein de-ubiquitination and is poorly understood in neurodegeneration. USP13 is upregulated in Alzheimer’s disease (AD) and Parkinson’s disease (PD), and USP13 knockdown via shRNA reduces neurotoxic proteins and increases proteasome activity in models of neurodegeneration. We synthesized novel analogues of spautin-1 which is a non-specific USP13 inhibitor but unable to penetrate the brain. Our synthesized small molecule compounds are able to enter the brain, more potently inhibit USP13, and significantly reduce alpha-synuclein levels in vivo and in vitro. USP13 inhibition in transgenic mutant alpha-synuclein (A53T) mice increased the ubiquitination of alpha-synuclein and reduced its protein levels. The data suggest that novel USP13 inhibitors improve neurodegenerative pathology via antagonism of de-ubiquitination, thus alleviating neurotoxic protein burden in neurodegenerative diseases.

scholarly journals Novel Insights on the Role of Nitric Oxide in the Ovary: A Review of the Literature

2021 ◽  
Vol 18 (3) ◽  
pp. 980
Author(s):  
Maria Cristina Budani ◽  
Gian Mario Tiboni
Keyword(s):  
Nitric Oxide ◽  
In Vivo Studies ◽  
Published Data ◽  
Vitro Fertilization ◽  
Peripheral Neurons ◽  
Relevant Role ◽  
Oocyte Meiotic Maturation

Nitric oxide (NO) is formed during the oxidation of L-arginine to L-citrulline by the action of multiple isoenzymes of NO synthase (NOS): neuronal NOS (nNOS), endotelial NOS (eNOS), and inducible NOS (iNOS). NO plays a relevant role in the vascular endothelium, in central and peripheral neurons, and in immunity and inflammatory systems. In addition, several authors showed a consistent contribution of NO to different aspects of the reproductive physiology. The aim of the present review is to analyse the published data on the role of NO within the ovary. It has been demonstrated that the multiple isoenzymes of NOS are expressed and localized in the ovary of different species. More to the point, a consistent role was ascribed to NO in the processes of steroidogenesis, folliculogenesis, and oocyte meiotic maturation in in vitro and in vivo studies using animal models. Unfortunately, there are few nitric oxide data for humans; there are preliminary data on the implication of nitric oxide for oocyte/embryo quality and in-vitro fertilization/embryo transfer (IVF/ET) parameters. NO plays a remarkable role in the ovary, but more investigation is needed, in particular in the context of human ovarian physiology.

scholarly journals The role of CYP2D in rat brain in methamphetamine-induced striatal dopamine and serotonin release and behavioral sensitization

2021 ◽  
Author(s):  
Marlaina R. Stocco ◽  
Ahmed A. El-Sherbeni ◽  
Bin Zhao ◽  
Maria Novalen ◽  
Rachel F. Tyndale
Keyword(s):  
Neurotransmitter Release ◽  
Behavioral Sensitization ◽  
Serotonin Release ◽  
Striatal Dopamine ◽  
Irreversible Inhibitor ◽  
Drug Concentrations ◽  
Metabolite Concentrations ◽  
The Brain

Abstract Rationale Cytochrome P450 2D (CYP2D) enzymes metabolize many addictive drugs, including methamphetamine. Variable CYP2D metabolism in the brain may alter CNS drug/metabolite concentrations, consequently affecting addiction liability and neuropsychiatric outcomes; components of these can be modeled by behavioral sensitization in rats. Methods To investigate the role of CYP2D in the brain in methamphetamine-induced behavioral sensitization, rats were pretreated centrally with a CYP2D irreversible inhibitor (or vehicle) 20 h prior to each of 7 daily methamphetamine (0.5 mg/kg subcutaneous) injections. In vivo brain microdialysis was used to assess brain drug and metabolite concentrations, and neurotransmitter release. Results CYP2D inhibitor (versus vehicle) pretreatment enhanced methamphetamine-induced stereotypy response sensitization. CYP2D inhibitor pretreatment increased brain methamphetamine concentrations and decreased the brain p-hydroxylation metabolic ratio. With microdialysis conducted on days 1 and 7, CYP2D inhibitor pretreatment exacerbated stereotypy sensitization and enhanced dopamine and serotonin release in the dorsal striatum. Day 1 brain methamphetamine and amphetamine concentrations correlated with dopamine and serotonin release, which in turn correlated with the stereotypy response slope across sessions (i.e., day 1 through day 7), used as a measure of sensitization. Conclusions CYP2D-mediated methamphetamine metabolism in the brain is sufficient to alter behavioral sensitization, brain drug concentrations, and striatal dopamine and serotonin release. Moreover, day 1 methamphetamine-induced neurotransmitter release may be an important predictor of subsequent behavioral sensitization. This suggests the novel contribution of CYP2D in the brain to methamphetamine-induced behavioral sensitization and suggests that the wide variation in human brain CYP2D6 may contribute to differential methamphetamine responses and chronic effects.

scholarly journals DNAJB6b is Downregulated in Synucleinopathies

2021 ◽  
pp. 1-13
Author(s):  
Jonas Folke ◽  
Sertan Arkan ◽  
Isak Martinsson ◽  
Susana Aznar ◽  
Gunnar Gouras ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Substantia Nigra Pars Compacta ◽  
Endogenous Protein ◽  
Highly Sensitive ◽  
Brain Material ◽  
Health And Disease ◽  
Isoform B

Background: α-synuclein (α-syn) aggregation contributes to the progression of multiple neurodegenerative diseases. We recently found that the isoform b of the co-chaperone DNAJB6 is a strong suppressor of a-syn aggregation in vivo and in vitro. However, nothing is known about the role of the endogenous isoform b of DNAJB6 (DNAJB6b) in health and disease, due to lack of specific antibodies. Objective: Here we generated a novel anti-DNAJB6b antibody to analyze the localization and expression this isoform in cells, in tissue and in clinical material. Methods: To address this we used immunocytochemistry, immunohistochemistry, as well as a novel quantitative DNAJB6 specific ELISA method. Results: The endogenous protein is mainly expressed in the cytoplasm and in neurites in vitro, where it is found more in dendrites than in axons. We further verified in vivo that DNAJB6b is expressed in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), which is a neuronal subpopulation highly sensitive to α-syn aggregation, that degenerate to a large extend in patients with Parkinson’s disease (PD) and multiple system atrophy (MSA). When we analyzed the expression levels of DNAJB6b in brain material from PD and MSA patients, we found a downregulation of DNAJB6b by use of ELISA based quantification. Interestingly, this was also true when analyzing tissue from patients with progressive supranuclear palsy, a taupathic atypical parkinsonian disorder. However, the total level of DNAJB6 was upregulated in these three diseases, which may indicate an upregulation of the other major isoform of DNAJB6, DNAJB6a. Conclusion: This study shows that DNAJB6b is downregulated in several different neurodegenerative diseases, which makes it an interesting target to further investigate in relation to amyloid protein aggregation and disease progression.

The use of siRNA as a pharmacological tool to assess a role for the transcription factor NF-IL6 in the brain under in vitro and in vivo conditions during LPS-induced inflammatory stimulation

2017 ◽  
Vol 28 (6) ◽  
Author(s):  
Jelena Damm ◽  
Joachim Roth ◽  
Rüdiger Gerstberger ◽  
Christoph Rummel
Keyword(s):  
Transcription Factor ◽  
Brain Cells ◽  
Nuclear Factor ◽  
Si Rna ◽  
The Brain ◽  
Deficient Mice ◽  
Transcription Factor Nuclear Factor

AbstractBackground:Studies with NF-IL6-deficient mice indicate that this transcription factor plays a dual role during systemic inflammation with pro- and anti-inflammatory capacities. Here, we aimed to characterize the role of NF-IL6 specifically within the brain.Methods:In this study, we tested the capacity of short interfering (si) RNA to silence the inflammatory transcription factor nuclear factor-interleukin 6 (NF-IL6) in brain cells underResults:In cells of a mixed neuronal and glial primary culture from the ratConclusions:This approach was, thus, not suitable to characterize the role NF-IL6 in the brain

scholarly journals The Role of Long Noncoding RNAs in Diabetic Alzheimer’s Disease

2018 ◽  
Vol 7 (11) ◽  
pp. 461 ◽  
Author(s):  
Young-Kook Kim ◽  
Juhyun Song
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Glucose Dysregulation ◽  
Near Future ◽  
The Brain

Long noncoding RNAs (lncRNAs) are involved in diverse physiological and pathological processes by modulating gene expression. They have been found to be dysregulated in the brain and cerebrospinal fluid of patients with neurodegenerative diseases, and are considered promising therapeutic targets for treatment. Among the various neurodegenerative diseases, diabetic Alzheimer’s disease (AD) has been recently emerging as an important issue due to several unexpected reports suggesting that metabolic issues in the brain, such as insulin resistance and glucose dysregulation, could be important risk factors for AD. To facilitate understanding of the role of lncRNAs in this field, here we review recent studies on lncRNAs in AD and diabetes, and summarize them with different categories associated with the pathogenesis of the diseases including neurogenesis, synaptic dysfunction, amyloid beta accumulation, neuroinflammation, insulin resistance, and glucose dysregulation. It is essential to understand the role of lncRNAs in the pathogenesis of diabetic AD from various perspectives for therapeutic utilization of lncRNAs in the near future.

scholarly journals Neuronal spreading and plaque induction of intracellular Aβ and its disruption of Aβ homeostasis

2021 ◽  
Author(s):  
Tomas T. Roos ◽  
Megg G. Garcia ◽  
Isak Martinsson ◽  
Rana Mabrouk ◽  
Bodil Israelsson ◽  
...  
Keyword(s):  
Brain Homogenate ◽  
Fold Increase ◽  
Amyloid Beta Peptide ◽  
Intracellular Accumulation ◽  
Brain Areas ◽  
Cellular Models ◽  
Beta Peptide ◽  
The Brain

AbstractThe amyloid-beta peptide (Aβ) is thought to have prion-like properties promoting its spread throughout the brain in Alzheimer’s disease (AD). However, the cellular mechanism(s) of this spread remains unclear. Here, we show an important role of intracellular Aβ in its prion-like spread. We demonstrate that an intracellular source of Aβ can induce amyloid plaques in vivo via hippocampal injection. We show that hippocampal injection of mouse AD brain homogenate not only induces plaques, but also damages interneurons and affects intracellular Aβ levels in synaptically connected brain areas, paralleling cellular changes seen in AD. Furthermore, in a primary neuron AD model, exposure of picomolar amounts of brain-derived Aβ leads to an apparent redistribution of Aβ from soma to processes and dystrophic neurites. We also observe that such neuritic dystrophies associate with plaque formation in AD-transgenic mice. Finally, using cellular models, we propose a mechanism for how intracellular accumulation of Aβ disturbs homeostatic control of Aβ levels and can contribute to the up to 10,000-fold increase of Aβ in the AD brain. Our data indicate an essential role for intracellular prion-like Aβ and its synaptic spread in the pathogenesis of AD.

scholarly journals A novel antioxidant ergothioneine PET radioligand for in vivo imaging applications

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
William J. Behof ◽  
Clayton A. Whitmore ◽  
Justin R. Haynes ◽  
Adam J. Rosenberg ◽  
Mohammed N. Tantawy ◽  
...  
Keyword(s):  
Amino Acid ◽  
Mouse Model ◽  
Peripheral Tissues ◽  
Molar Activity ◽  
Model Of Alzheimer’S Disease ◽  
Specific Retention ◽  
5Xfad Mice ◽  
The Brain

AbstractErgothioneine (ERGO) is a rare amino acid mostly found in fungi, including mushrooms, with recognized antioxidant activity to protect tissues from damage by reactive oxygen species (ROS) components. Prior to this publication, the biodistribution of ERGO has been performed solely in vitro using extracted tissues. The aim of this study was to develop a feasible chemistry for the synthesis of an ERGO PET radioligand, [11C]ERGO, to facilitate in vivo study. The radioligand probe was synthesized with identical structure to ERGO by employing an orthogonal protection/deprotection approach. [11C]methylation of the precursor was performed via [11C]CH3OTf to provide [11C]ERGO radioligand. The [11C]ERGO was isolated by RP-HPLC with a molar activity of 690 TBq/mmol. To demonstrate the biodistribution of the radioligand, we administered approximately 37 MBq/0.1 mL in 5XFAD mice, a mouse model of Alzheimer’s disease via the tail vein. The distribution of ERGO in the brain was monitored using 90-min dynamic PET scans. The delivery and specific retention of [11C]ERGO in an LPS-mediated neuroinflammation mouse model was also demonstrated. For the pharmacokinetic study, the concentration of the compound in the serum started to decrease 10 min after injection while starting to distribute in other peripheral tissues. In particular, a significant amount of the compound was found in the eyes and small intestine. The radioligand was also distributed in several regions of the brain of 5XFAD mice, and the signal remained strong 30 min post-injection. This is the first time the biodistribution of this antioxidant and rare amino acid has been demonstrated in a preclinical mouse model in a highly sensitive and non-invasive manner.

scholarly journals Molecular Analysis of the gyrA and gyrB Quinolone Resistance-Determining Regions of Fluoroquinolone-Resistant Clostridium difficile Mutants Selected In Vitro

2009 ◽  
Vol 53 (6) ◽  
pp. 2463-2468 ◽  
Author(s):  
Patrizia Spigaglia ◽  
Fabrizio Barbanti ◽  
Thomas Louie ◽  
Frédéric Barbut ◽  
Paola Mastrantonio
Keyword(s):  
Clostridium Difficile ◽  
Clinical Isolates ◽  
Fluoroquinolone Resistance ◽  
Toxin B ◽  
Relevant Role ◽  
Vitro Development ◽  
Selection Of

ABSTRACT Recent studies have suggested that exposure to fluoroquinolones represents a risk factor for the development of Clostridium difficile infections and that the acquisition of resistance to the newer fluoroquinolones is the major reason facilitating wide dissemination. In particular, moxifloxacin (MX) and levofloxacin (LE) have been recently associated with outbreaks caused by the C. difficile toxinotype III/PCR ribotype 027/pulsed-field gel electrophoresis type NAP1 strain. In this study, we evaluated the potential of MX and LE in the in vitro development of fluoroquinolone resistance mediated by GyrA and GyrB alterations. Resistant mutants were obtained from five C. difficile parent strains, susceptible to MX, LE, and gatifloxacin (GA) and belonging to different toxinotypes, by selection in the presence of increasing concentrations of MX and LE. Stable mutants showing substitutions in GyrA and/or GyrB were obtained from the parent strains after selection by both antibiotics. Mutants had MICs ranging from 8 to 128 μg/ml for MX, from 8 to 256 μg/ml for LE, and from 1.5 to ≥32 μg/ml for GA. The frequency of mutation ranged from 3.8 × 10−6 to 6.6 × 10−5 for MX and from 1.0 × 10−6 to 2.4 × 10−5 for LE. In total, six different substitutions in GyrA and five in GyrB were observed in this study. The majority of these substitutions has already been described for clinical isolates or has occurred at positions known to be involved in fluoroquinolone resistance. In particular, the substitution Thr82 to Ile in GyrA, the most common found in resistant C. difficile clinical isolates, was observed after selection with LE, whereas the substitution Asp426 to Val in GyrB, recently described in toxin A-negative/toxin B-positive epidemic strains, was observed after selection with MX. Interestingly, a reduced susceptibility to fluoroquinolones was observed in colonies isolated after the first and second steps of selection by both MX and LE, with no substitution in GyrA or GyrB. The results suggest a relevant role of fluoroquinolones in the emergence and selection of fluoroquinolone-resistant C. difficile strains also in vivo.

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