System In Neurodegenerative Disorders Research Articles

The degeneration of locus coeruleus occurring during Alzheimer's disease clinical progression: a neuroimaging follow-up investigation.

The noradrenergic nucleus Locus Coeruleus (LC) is precociously involved in Alzheimer's Disease (AD) pathology, and its degeneration progresses during the course of the disease. Using Magnetic Resonance Imaging (MRI), researchers showed also in vivo in patients the disruption of LC, which can be observed both in Mild Cognitively Impaired individuals and AD demented patients. In this study, we report the results of a follow-up neuroradiological assessment, in which we evaluated the LC degeneration overtime in a group of cognitively impaired patients, submitted to MRI both at baseline and at the end of a 2.5-year follow-up. We found that a progressive LC disruption can be observed also in vivo, involving the entire nucleus and associated with clinical diagnosis. Our findings parallel neuropathological ones, which showed a continuous increase of neuronal death and volumetric atrophy within the LC with the progression of Braak's stages for neurofibrillary pathology. This supports the reliability of MRI as a tool for exploring the integrity of the central noradrenergic system in neurodegenerative disorders.

β-Caryophyllene decreases neuroinflammation and exerts neuroprotection of dopaminergic neurons in a model of hemiparkinsonism through inhibition of the NLRP3 inflammasome

IntroductionParkinson's disease represents a neurodegenerative condition characterized by the progressive loss of dopaminergic neurons within the Substantia Nigra pars compacta (SNpc), resulting in diminished dopamine levels in the striatum (STR) and chronic neuroinflammation. Recent investigations have proposed the neuroprotective potential of the endocannabinoid system in neurodegenerative disorders. β-caryophyllene (BCP) is recognized for its antioxidant and anti-inflammatory properties, attributed to its activation of the type 2 cannabinoid receptor. This study aimed to assess the neuroprotective impact of BCP on dopaminergic neurons, with a particular focus on inhibiting the NLRP3 inflammasome. MethodsA model of hemiparkinsonism, induced by 6-hydroxydopamine (6-OHDA), served as the experimental framework. Motor function was evaluated using the cylinder test, and inflammasome inhibition was determined by assessing the expression of NLRP3, caspase-1, and the pro-inflammatory cytokine IL-1β in both the SNpc and STR through ELISA analysis. Furthermore, the evaluation of oxidative stress was facilitated by quantifying malondialdehyde (MDA) levels in the same regions. ResultsBCP treatment demonstrated significant improvements in motor dysfunction, as assessed by the cylinder test (p=0.0011) and exhibited a neuroprotective effect on dopaminergic neurons within the SNpc (p=0.0017), as well as nerve fibers in the STR (p=0.0399). In terms of its ability to inhibit the inflammasome, BCP led to decreased expression levels of NLRP3 (p=0.0401 in STR and p = 0.0139 in SNpc), caspase-1 (p=0.0004 in STR), and MDA (p=0.0085 in STR and p=0.0414 in SNpc). ConclusionThese results point to BCP's potential in mitigating the motor deficit, inhibiting NLRP3 inflammasome activation, and attenuating lipid peroxidation induced by 6-OHDA.

Changes in Functional Activity of Rabbit’s Retina During Flicker Photostimulation with Scale-free Dynamics

Neuroplasticity-based stimulation therapy assists in restoring the visual system in neurodegenerative disorders. Scale-free fluctuations peculiar to healthy physiological rhythms disappear as the disease progresses. Fractal visual stimuli positively influence CNS plasticity and increase the efficiency of visual rehabilitation. To determine the effect of a lengthy course of fractal photostimulation (FS) on the electroretinogram (ERG) in healthy rabbits, a device for FS was created. For twelve healthy rabbits, 20-minute FS sessions were conducted once a day from 9 to 11 a.m., five times a week. Before and after 1, 4, and 12 weeks of FS, full-field ERGs, flicker ERGs, and the pattern-ERGs were registered. The observed positive impact of FS consisted of shortening peak latency of the maximal scotopic ERG b-wave and a significant increase in the amplitude of the cone ERG a- and b-waves and low-frequency flicker ERGs (p<0.05). For the first time, we describe the effect of FS on the ERG. The long-term FS does not impair retinal activity and can be safely used in the clinic. The dynamics of the positive influence of FS on retinal activity argue that the duration of the FS course of 1 to 4 weeks is optimal for subsequent studies.

Impacts of Immune System in an Experimental Social Behavior Model: Review Article

There is growing evidence supports the regulatory role of the immune system in neuronal function and mental health. Many studies have demonstrated the impact of the immune system in neurodegenerative disorders. There are beneficial therapeutic effects of targeting the immune system in the management of these disorders. However, there are gaps in the available knowledge and many steps are needed to move forward. Sensory contact model (SCM) is an experimental social behavior model which allows the formation of different psychopathological conditions which are originated between male mice by the repeated agonistic interactions; resemble those in human. SCM has been developed to investigate aggression and submission behaviors. It gives the chance to study the pharmacological actions of novel psychoactive drugs. The current study aims to review the possible relations between the immune system and social behavior; using the SCM as an experimental model of aggression and depression. To encourage the production of novel psychoactive drugs target the immune system and inflammatory pathways.

High-Throughput Small Molecule Screen Identifies Modulators of Mitochondrial Function in Neurons.

SummaryWe developed a high-throughput assay for modulators of mitochondrial function in neurons measuring inner mitochondrial membrane potential (ΔΨm) and ATP production. The assay was used to screen a library of small molecules, which led to the identification of structural/functional classes of mitochondrial modulators such as local anesthetics, isoflavones, COXII inhibitors, adrenergic receptor blockers, and neurotransmitter system effectors. Our results show that some of the isolated compounds promote mitochondrial health, enhance oxygen consumption rate, and protect neurons against toxic insults found in the cellular environment of Alzheimer disease. These studies offer a set of compounds that may provide efficacy in protecting the mitochondrial system in neurodegenerative disorders.

Neuroprotection mediated by cystatin C-loaded extracellular vesicles

Cystatin C (CysC) is implicated in neuroprotection and repair in the nervous system in response to diverse neurotoxic conditions. In addition to being secreted from cells in a soluble form, CysC is released by cells in association with extracellular vesicles (EVs), including exosomes. We demonstrate that EVs containing CysC protect cultured cells from starvation-induced death. Moreover, while EVs secreted by CysC-deficient cells were not protective, EVs secreted by CysC-deficient cells treated with exogenous human CysC significantly enhanced the survival of the cells. CysC also plays a role in modulating the secretion of EVs, enhancing secretion of EVs by primary cortical neurons and primary cortical smooth muscle cells. Confirming these in vitro findings, higher EV levels were observed in the brain extracellular space of transgenic mice expressing human CysC as compared to littermate controls. Regulation of cell-secreted EV levels and content in the brain is likely to be essential to maintaining normal brain function. We propose that enhanced EV release could rescue the deleterious effects of dysfunction of the endosomal-lysosomal system in neurodegenerative disorders. Moreover, a higher level of CysC-loaded EVs released from cells in the central nervous system has important protective functions, representing a potential therapeutic tool for disorders of the central nervous system.

Autoimmunity in Parkinson's Disease: The Role of α-Synuclein-Specific T Cells.

Evidence from a variety of studies implicates a role for the adaptive immune system in Parkinson's disease (PD). Similar to multiple sclerosis (MS) patients who display a high number of T cells in the brain attacking oligodendrocytes, PD patients show higher numbers of T cells in the ventral midbrain than healthy, age-matched controls. Mouse models of the disease also show the presence of T cells in the brain. The role of these infiltrating T cells in the propagation of disease is controversial; however, recent studies indicate that they may be autoreactive in nature, recognizing disease-altered self-proteins as foreign antigens. T cells of PD patients can generate an autoimmune response to α-synuclein, a protein that is aggregated in PD. α-Synuclein and other proteins are post-translationally modified in an environment in which protein processing is altered, possibly leading to the generation of neo-epitopes, or self-peptides that have not been identified by the host immune system as non-foreign. Infiltrating T cells may also be responding to such modified proteins. Genome-wide association studies (GWAS) have shown associations of PD with haplotypes of major histocompatibility complex (MHC) class II genes, and a polymorphism in a non-coding region that may increase MHC class II in PD patients. We speculate that the inflammation observed in PD may play both pathogenic and protective roles. Future studies on the adaptive immune system in neurodegenerative disorders may elucidate steps in disease pathogenesis and assist with the development of both biomarkers and treatments.

WITHDRAWN: Histological and Behavioral Alterations Following hADSCs Intravenous Administration in Alzheimer’s Rat Model

BackgroundAlzheimer’s disease (AD) is a progressive cognitive disorder that is generally age-related. Although there has been great research focusing on this disease, there is still a lack of reliable therapeutic methods. Amyloid-β (Aβ) peptide has a critical function in neuropathology of AD. Stem cell therapy provides treatment by improving the neuronal system in neurodegenerative disorders. Human adipose-derived stem cells (hADSCs) are the most appropriate sources of stem cells due to their safety, high proliferative potential, and easy isolation.ObjectivesThe present study was designed to evaluate the histological and behavioral alterations after intravenous administration of hADSCs in the AD rat model.MethodsIn this study, 32 male rats were used in four groups, as follows: control, sham, AD rat model, and hADSCs-treated group. We used Morris Water Maze (MWM) for evaluating behavioral changes and Nissl staining for determining the histological studies.ResultsIn this study, the AD model was confirmed by behavioral and histological analysis. Behavioral results showed that the spatial memory improved after hADSCs injection in the AD rat model while the time spent in the target quadrant was significantly higher in the hADSCs-treated group than in the AD rat model group. On the other hand, the number of dead cells significantly decreased in the hADSCs-treated group as analyzed by Nissl staining.ConclusionsOur findings revealed that hADSCs could transfer into the brain and improve memory and neuronal damage in the AD rat model.

Reciprocal Interactions of Mitochondria and the Neuroimmunoendocrine System in Neurodegenerative Disorders: An Important Role for Melatonin Regulation.

Structural and functional alterations of mitochondria are intimately linked to a wide array of medical conditions. Many factors are involved in the regulation of mitochondrial function, including cytokines, chaperones, chemokines, neurosteroids, and ubiquitins. The role of diffusely located cells of the neuroendocrine system, including biogenic amines and peptide hormones, in the management of mitochondrial function, as well as the role of altered mitochondrial function in the regulation of these cells and system, is an area of intense investigation. The current article looks at the interactions among the cells of the neuronal-glia, immune and endocrine systems, namely the diffuse neuroimmunoendocrine system (DNIES), and how DNIES interacts with mitochondrial function. Whilst changes in DNIES can impact on mitochondrial function, local, and systemic alterations in mitochondrial function can alter the component systems of DNIES and their interactions. This has etiological, course, and treatment implications for a wide range of medical conditions, including neurodegenerative disorders. Available data on the role of melatonin in these interactions, at cellular and system levels, are reviewed, with directions for future research indicated.

Endocannabinoid system in neurodegenerative disorders.

Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.

Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization.

Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of α-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, α-NETA exhibited an IC50 of ~30 μM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer’s disease.

Unrestricted somatic stem cells as vehicle for nerve growth factor gene transfer

Objective: Nerve growth factor (NGF), a member of the neurotrophic factor family, plays a critical role in the maintenance and regeneration of different types of neurons. To overcome drastic challenges in the peripheral delivery of NGF, transplantation of NGF secreting stem cells to the target site of an injury may be an effective procedure. Unrestricted somatic stem cells (USSCs), a subtype of umbilical cord blood (UCB) stem cells, have shown promise for gene therapy purposes, and proper results have been observed from transplantation experiments in neurodegenerative disorders. Based on the considerable potential of USSCs for gene delivery applications, the goal of the current study was to establish a betaNGF gene containing USSCs, which is able to secrete functional recombinant betaNGF protein.Methods: Unrestricted somatic stem cells were isolated from UCB and were cultured in a DMEM medium. The betaNGF gene was cloned in the EFalpha-promoting lentiviral vector, and virus production was performed as a third generation lentivirus packaging system. Enzyme-linked immunosorbent assay, real-time PCR, co-culture, MTT, and immunocytochemistry assays were performed to evaluate the genetically engineered USSCs.Results: Overexpression of betaNGF gene in human USSCs created a USSC line that is able to secrete high amounts of functional betaNGF protein. betaNGF-secreting USSCs showed a high rate of viability along with acceptable immunological and morphological properties for transplantation into the nervous system.Discussion: Long-term expression of functional betaNGF, high viability of betaNGF producing USSCs, and expression of primary neuronal markers suggest that USSCs may be useful to deliver betaNGF into targeted sites of the nervous system in neurodegenerative disorders.

Olfactory dysfunctions in neurodegenerative disorders

Olfactory dysfunction is a common symptom in the patients with neurodegenerative disorders, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). Recently, studies of olfactory dysfunction have focused on its potential as a medication-independent biomarker for disease progression and as an early indicator for the diagnosis of neurodegenerative disorders. In the past decades, great achievements have been obtained in elucidating the neuroanatomy and the function of olfactory system, yet the pathogenesis of olfactory dysfunction in neurodegenerative disorders remains elusive. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb, primary olfactory cortices, and their secondary targets changes. This article summarizes the up-to-date knowledge on pathophysiological changes of the olfactory system in neurodegenerative disorders and attempts to find the association between olfactory dysfunction and neurodegenerative disorders.

P.P.3 04 Autophagic vacuolar myopathies: Immunochemical and molecular characterization

Elucidation of mechanisms involved in toxic protein accumulation and vacuole formation in inclusion body myopathies. Accumulation of altered proteins is a common pathogenic mechanism in several neurodegenerative disorders. Skeletal muscle from sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathy (h-IBM) patients, similarly to the nervous system in neurodegenerative disorders, typically contains intracellular aggregated protein depositions such as beta amyloid, tau and prion proteins. We examined muscle biopsies from 34 patients with hIBM, sIBM, oculopharyngeal muscle dystrophy, Danon disease, distal dystrophy with rimmed vacuoles, acid maltase deficiency, and genetically unclassified autophagic vacuolar myopathies with distal or proximal weakness. We studied by immunohistochemistry or immunoblot the expression of components of the proteolytic pathways (lysosomal/endosomal, Ca2+-dependent and ubiquitin-proteasomal), and the expression of toxic proteins and of proteins involved in membrane vesicle fusion and membrane repair. We also analysed the GNE gene in 10 patients. We identified abnormal accumulation of toxic proteins and of ubiquitin proteasomal proteins in most examined muscles. Lysosomal/endosomal components were variably expressed in the different pathologies. Vacuoles were positive for sarcolemmal proteins in most cases and accumulated dysferlin in sIBM and in some genetically unclassified autophagic vacuolar myopathies. GNE mutations were detected in two patients. Histopathological and immunochemical features of the autophagic vacuoles may help to distinguish the different clinical entities and give some hints on the origin of vacuoles.

Peptidase activities of the 20/26S proteasome and a novel protease in human brain.

Many neurodegenerative diseases are characterized by ubiquitin-positive protein aggregates or inclusion bodies. Ubiquitin-conjugated proteins are degraded by the 20/26S proteasome, and reduced proteasome peptidase activities in brain homogenates have been reported in pathologic lesions of Parkinson's and Alzheimer's diseases. However, it is unknown whether crude extracts of human brain contain other proteases having peptidase activities. We found a novel protease of molecular weight of approximately 105 kDa in normal human brain, which exhibited trypsin-like (T-L) and chymotrypsin-like (ChT-L) activities (corresponding to 52% and 21% of the total activities in crude extracts) but not peptidyl glutamyl peptide hydrolase activity. Both T-L and ChT-L activities of this protease were partially inhibited by proteasome inhibitors (MG132, lactacystin) and, in contrast to those of the proteasome, also by sodium dodecyl sulfate. A simple method to obtain a brain fraction specific to the 20/26S proteasome was developed. Our human brain data suggest that T-L and ChT-L activity levels of the proteasome reported previously may include those of the 105 kDa protease, an enzyme of as yet unknown biological significance, and that it is necessary to separate the proteasome from this protease to evaluate the actual status of the ubiquitin-proteasome system in neurodegenerative disorders.

The role of the immune system in neurodegenerative disorders.

Movement DisordersVolume 12, Issue 6 p. 855-858 Viewpoint The role of the immune system in neurodegenerative disorders Dr. Edith G. McGeer, Corresponding Author Dr. Edith G. McGeer Kinsmen Laboratory of Neurological Research and the Neurodegeneative Disorders Centre, University of British ColumbiaKinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Westbrook Mall, vancouver, BC, V6T 1Z3, CanadaSearch for more papers by this authorPatrick L. McGeer, Patrick L. McGeer Kinsmen Laboratory of Neurological Research and the Neurodegeneative Disorders Centre, University of British ColumbiaSearch for more papers by this author Dr. Edith G. McGeer, Corresponding Author Dr. Edith G. McGeer Kinsmen Laboratory of Neurological Research and the Neurodegeneative Disorders Centre, University of British ColumbiaKinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Westbrook Mall, vancouver, BC, V6T 1Z3, CanadaSearch for more papers by this authorPatrick L. McGeer, Patrick L. McGeer Kinsmen Laboratory of Neurological Research and the Neurodegeneative Disorders Centre, University of British ColumbiaSearch for more papers by this author First published: 04 November 2004 https://doi.org/10.1002/mds.870120604Citations: 64AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume12, Issue6November 1997Pages 855-858 RelatedInformation