Cause Of Neurodegeneration Research Articles

Reduced Activated T Lymphocytes (CD4+CD25+) and Plasma Levels of Cytokines in Parkinson’s Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease. The cause of neurodegeneration in PD is not completely understood, and evidence has shown that inflammatory/immune changes may be involved in PD pathophysiology. Herein, we aimed to determine the profile of the peripheral immune system in patients with PD in comparison with controls. Forty patients with PD and 25 age- and gender-matched controls were enrolled in this study. From these, 23 PD patients and 21 controls were included in the immunophenotyping analyses. Peripheral blood was drawn on the same day of the clinical assessment and submitted to plasma separation for enzyme-linked immunosorbent assay or cytometric bead array. Immunophenotyping analyses of the peripheral blood were performed by flow cytometry. We found that patients with PD presented peripheral immune changes evidenced by decreased percentage of T lymphocytes (CD3+ cells), especially activated T lymphocytes (CD4+CD25+ cells), when compared with controls. In line with these results, we also found decreased plasma levels of the cytokines IL-4, IL-6, IL-10, TNF, IFN-γ, and IL-17A in the PD group. In vitro experiments demonstrated that the production of cytokines by peripheral blood mononuclear cells harvested from healthy young donors was reduced after exposure to the anti-parkinsonian drugs levodopa and pramipexole. Our data corroborate the hypothesis that immunological mechanisms are involved in PD. It is not clear whether the differences that we have found are due to adaptive mechanisms or to changes associated with PD, including pharmacological treatment, or even directly related to the disease pathophysiology. Future studies are needed in this regard.

Alpha-synuclein and iron: two keys unlocking Parkinson's disease.

Current therapies for Parkinson's disease (PD) confer symptomatic relief and are particularly efficient in the treatment of motor symptoms in earlier disease stages. However, we are still unable to treat the causes of neurodegeneration by modification of the underlying mechanisms, which is partially due to their insufficient understanding. In this short review, we focus on two pivotal disease mechanisms: alpha-synuclein pathology and dysfunction of iron homeostasis as well as their intricate interaction. Both pathomechanisms have been extensively studied in the past and represent valid targets for disease-modifying pharmacological treatment approaches for PD. We summarize the current attempts to exploit iron chelation and modification of alpha-synuclein pathology as translational therapies in PD and discuss the chances and challenges of prospective disease-modifying approaches.

RIP3 Mediates Necroptotic Cell Death in Response to Acid Stimulation of ASIC1a

Acidosis occurs commonly under pathological conditions when body homeostasis is disrupted due to inflammation, hypoxia, cancer and other illnesses. However, the effects of acidosis on cell fates differ dramatically from one cell type to another. On one hand, acidosis is usually harmful to brain neurons, which are particularly sensitive to tissue acidosis that occurs very often among neurological disorders, including ischemic stroke. Because of this, acidotoxicity represents one of the major causes of neurodegeneration and brain injury. On the other hand, cancer cells thrive in acidity as the microenvironment of tumor is often acidic. Previously, we have shown that extracellular acid induces neuronal cell death through activation of acid-sensing ion channel isoform 1a (ASIC1a) in a manner that involves recruitment and phosphorylation of receptor interacting protein 1 (RIP1), but independent of the ion channel function of ASIC1a. Here, we demonstrate that receptor interacting protein 3 (RIP3) is also critically required for acid-induced cell death and the presence of ASIC1a and/or RIP3 determines the nature of cellular responses to acidosis. Whereas both ASIC1a and RIP3 are expressed in neurons, at least one of them tends to be absent in many cancer cell lines. In the absence of RIP3, acidosis activated NF-κB signaling to promote survival of the tumor through ASIC1a. Re-introduction of RIP3 then converted the cancer cells to undergo necrosis in response to acidosis. Conversely, inhibiting RIP3 reduced both acid-induced death of mouse cortical neurons in vitro and brain infarction in mice elicited by middle cerebral artery occlusion in vivo. Our data also implicate the formation of necrosome downstream of ASIC1a/RIP1 in response to acidosis in the presence of RIP3. Thus, ASIC1a works similarly as conventional death receptors that regulate both cell survival and demise. Differently controlling RIP3 expression and function may be of therapeutic values in treating different diseases.

Non-invasive Brain Stimulation in the Treatment of Post-stroke and Neurodegenerative Aphasia: Parallels, Differences, and Lessons Learned.

Numerous studies over the span of more than a decade have shown that non-invasive brain stimulation (NIBS) techniques, namely transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), can facilitate language recovery for patients who have suffered from aphasia due to stroke. While stroke is the most common etiology of aphasia, neurodegenerative causes of language impairment—collectively termed primary progressive aphasia (PPA)—are increasingly being recognized as important clinical phenotypes in dementia. Very limited data now suggest that (NIBS) may have some benefit in treating PPAs. However, before applying the same approaches to patients with PPA as have previously been pursued in patients with post-stroke aphasia, it will be important for investigators to consider key similarities and differences between these aphasia etiologies that is likely to inform successful approaches to stimulation. While both post-stroke aphasia and the PPAs have clear overlaps in their clinical phenomenology, the mechanisms of injury and theorized neuroplastic changes associated with the two etiologies are notably different. Importantly, theories of plasticity in post-stroke aphasia are largely predicated on the notion that regions of the brain that had previously been uninvolved in language processing may take on new compensatory roles. PPAs, however, are characterized by slow distributed degeneration of cellular units within the language system; compensatory recruitment of brain regions to subserve language is not currently understood to be an important aspect of the condition. This review will survey differences in the mechanisms of language representation between the two etiologies of aphasia and evaluate properties that may define and limit the success of different neuromodulation approaches for these two disorders.

The attenuating effects of 1,2,3,4,6 penta-O-galloyl-β-d-glucose on inflammatory cytokines release from activated BV-2 microglial cells

Alzheimer's disease (AD) is the most common cause of neurodegeneration and dementia in the elderly. Dysregulated, chronic activation of microglia, the brain's resident macrophages, induces the release of excessive amounts of pro-inflammatory cytokines which has been implicated in the early stages of AD pathology. Therefore, suppressing the expression of these inflammatory mediators may decrease or delay the progression of AD. Many natural compounds derived from plants have shown anti-inflammatory activity. The naturally occurring 1,2,3,4,6 Penta-O-Galloyl-β-d-Glucose (PGG), is a polyphenolic compound highly enriched in Rhus chinensis Millplant. It is a potent anti-inflammatory agent that act through the inhibition of many cytokines in different experimental models. In the present study, we investigated the role of PGG as an anti-inflammatory agent in LPS/IFNγ activated BV-2 microglia cells. Mouse cytokine antibody arrays were used to assess the effect of PGG on the release of pro-inflammatory cytokines, and ELISA experiments were performed to validate the results from the arrays. The results obtained from the cytokine arrays, and ELISA assays showed that PGG decreased the expression of monocyte chemotactic protein-5 (MCP-5) 8-fold, and pro-matrix metalloproteinase 9 (Pro MMP-9) 10-fold. Both of these cytokines are upregulated during the inflammatory process and have been shown to be involved in brain injury, inflammation, and neurodegeneration. Therefore, these findings suggest that the anti-inflammatory effect of PGG on activated microglia involving the attenuation of MCP-5 and Pro MMP-9 cytokines.

18F-Labeled 2-Arylquinoline Derivatives for Tau Imaging: Chemical, Radiochemical, Biological and Clinical Features.

Alzheimer's disease is the most common form of dementia among older people. Misfolding and aggregation of proteins (amyloid-β and tau) in the brain is the primary cause of neurodegeneration in the disease. Non-invasive detection of amyloid-β deposition can be realized using positron emission tomography probes, but a proportion of Aβ-positive subjects do not present with cognitive dysfunction, suggesting limitations in assessment using this method. Non-invasive detection of tau deposits in the brain can be used to diagnose, monitor, and predict Alzheimer's disease progression. Tau positron emission tomography radiolabelled probes such as T807, THK-5117, and PBB3 can image the pathology of the disease in vivo. The 18F-labeled tau imaging agents 18F-THK-5351, 18F-T807 (18F-AV-1451), and 18F-RO6958948 are presently under evaluation in clinical studies and clinical trials worldwide. This imaging methodology could be applied to enable preclinical diagnoses and disease-modifying drugs for Alzheimer's disease. In this review, we provide an overview of the pathology and potential imaging of tau in Alzheimer's disease, development of a THK series among tau tracers, and the chemical, radiochemical, biological, and clinical features of tau probes.

Amyloid Dysmetabolism Relates to Reduced Glucose Uptake in White Matter Hyperintensities

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and cause of dementia and is characterized by amyloid plaques and neurofibrillary tangles. AD has traditionally been considered to primarily affect gray matter, but multiple lines of evidence also indicate white matter (WM) pathology and associated small-vessel cerebrovascular disease. WM glucose delivery and metabolism may have implications for local tissue integrity, and [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) may be helpful to assess neuroglial and axonal function in WM. Hypothesizing that affection of oligodendroglia will be associated with loss of glucose uptake, we aimed to investigate glucose metabolism in magnetic resonance imaging (MRI) white matter hyperintensities (WMHs) and normal-appearing WM in patients with and without evidence of amyloid plaques. Subjects with mild cognitive impairment or subjective cognitive decline were included and dichotomized according to pathological (Aβ+) or normal (Aβ−) concentrations of cerebrospinal fluid amyloid-β 1–42. A total of 50 subjects were included, of whom 30 subjects were classified as Aβ(+) and 20 subjects as Aβ(−). All subjects were assessed with MRI and FDG-PET. FDG-PET images were corrected for effects of partial voluming and normalized to cerebellar WM, before determining WMH FDG-uptake. Although there were no significant differences between the groups in terms of age, WMH volume, number of individual WMHs, or WMH distribution, we found significantly lower (p = 0.021) FDG-uptake in WMHs in Aβ(+) subjects (mean = 0.662, SD = 0.113) compared to Aβ(−) subjects (mean = 0.596, SD = 0.073). There were no significant group differences in the FDG-uptake in normal-appearing WM. Similar results were obtained without correction for effects of partial voluming. Our findings add to the evidence for a link between Aβ dysmetabolism and WM pathology in AD.

Novel GLP-1R/GIPR co-agonist “twincretin” is neuroprotective in cell and rodent models of mild traumatic brain injury

Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed “twincretin,” was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.

Biological functions of selenium and its potential influence on Parkinson's disease.

Parkinson's disease is characterized by the death of dopaminergic neurons, mainly in the substantia nigra, and causes serious locomotor dysfunctions. It is likely that the oxidative damage to cellular biomolecules is among the leading causes of neurodegeneration that occurs in the disease. Selenium is an essential mineral for proper functioning of the brain, and mainly due to its antioxidant activity, it is possible to exert a special role in the prevention and in the nutritional management of Parkinson's disease. Currently, few researchers have investigated the effects of selenium on Parkinson´s disease. However, it is known that very high or very low body levels of selenium can (possibly) contribute to the pathogenesis of Parkinson's disease, because this imbalance results in increased levels of oxidative stress. Therefore, the aim of this work is to review and discuss studies that have addressed these topics and to finally associate the information obtained from them so that these data and associations serve as input to new research.

Inhibition of β-oxidation is not a valid therapeutic tool for reducing oxidative stress in conditions of neurodegeneration

According to recent reports, systemic treatment of rats with methylpalmoxirate (carnitine palmitoyltransferase-1 inhibitor) decreased peroxidation of polyunsaturated fatty acids in brain tissue. This was taken as evidence of mitochondrial β-oxidation in brain, thereby contradicting long-standing paradigms of cerebral metabolism, which claim that β-oxidation of activated fatty acids has minor importance for brain energy homeostasis. We addressed this controversy. Our experiments are the first direct experimental analysis of this question. We fueled isolated brain mitochondria or rat brain astrocytes with octanoic acid, but octanoic acid does not enhance formation of reactive oxygen species, neither in isolated brain mitochondria nor in astrocytes, even at limited hydrogen delivery to mitochondria. Thus, octanoic acid or l-octanoylcarnitine does not stimulate H2O2 release from brain mitochondria fueled with malate, in contrast to liver mitochondria (2.25-fold rise). This does obviously not support the possible occurrence of β-oxidation of the fatty acid octanoate in the brain. We conclude that a proposed inhibition of β-oxidation does not seem to be a helpful strategy for therapies aiming at lowering oxidative stress in cerebral tissue. This question is important, since oxidative stress is the cause of neurodegeneration in numerous neurodegenerative or inflammatory disease situations.

Antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in a model of central nervous system autoimmune inflammatory disease.

BackgroundNeurodegeneration is believed to be the primary cause of permanent, long-term disability in patients with multiple sclerosis. The cause of neurodegeneration in multiple sclerosis appears to be multifactorial. One mechanism that has been implicated in the pathogenesis of neurodegeneration in multiple sclerosis is the targeting of neuronal and axonal antigens by autoantibodies. Multiple sclerosis patients develop antibodies to the RNA-binding protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), which is enriched in neurons. We hypothesized that anti-hnRNP A1 antibodies would contribute to neurodegeneration in an animal model of multiple sclerosis.MethodsFollowing induction of experimental autoimmune encephalomyelitis (EAE) by direct immunization with myelin oligodendrocyte glycoprotein, mice were injected with anti-hnRNP A1 or control antibodies. Animals were examined clinically, and the central nervous system (CNS) tissues were tested for neurodegeneration with Fluoro-Jade C, a marker of degenerating neural elements.ResultsInjection of anti-hnRNP A1 antibodies in mice with EAE worsened clinical disease, altered the clinical disease phenotype, and caused neurodegeneration preferentially in the ventral spinocerebellar tract and deep white matter of the cerebellum in the CNS. Neurodegeneration in mice injected with hnRNP A1-M9 antibodies compared to control groups was consistent with “dying back” axonal degeneration.ConclusionsThese data suggest that antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in immune-mediated disease of the CNS.

ß-AMYLOID-OLIGOMER-INDUCED ALZHEIMER’S MODEL SHOWS SYNAPTIC DEGRADATION FOR USE IN TARGET VALIDATION AND DRUG DEVELOPMENT

Oligomeric forms of β-amyloid peptide (AβO) are widely accepted as the initial cause for neurodegeneration in Alzheimer’s disease (AD), related mild-cognitive impairment (MCI) and dementia, also triggering neuro-inflammatory processes and other complications. To reduce the significant attrition during drug discovery for neurodegenerative diseases, translational in vitro and in vivo models are essential. Here, we report highly reproducible in vitro and in vivo AD models, based on the neurodegenerative effects of a single injection of AβO preparations. Our AβO preparations induce dramatic neuronal cell death (monitored using multiple read-outs) in rodent primary neurons from different brain areas, as well as in human neurons derived from iPS cells. AβO-induced neuronal apoptosis is associated with neuro-inflammatory processes, increased production of pro-inflammatory cytokines, and impairment of sphingolipid cell signaling. In rodent models (mice and rats), a single brain injection of minute amounts of AβO results in dramatic and fast impairment of cognitive functions, associated with synaptic dysfunctions. A remarkable loss of synaptic marker proteins has indeed been found. Unlike transgenic models, our acute models imitate sporadic AD, are easily scalable to statistically meaningful animal numbers, and are successfully used for fast and cost effective phenotypic validation of preclinical candidates.

Alien Hand Syndrome.

Alien hand syndrome (AHS) is a rare disorder of involuntary limb movement together with a sense of loss of limb ownership. It most commonly affects the hand, but can occur in the leg. The anterior (frontal, callosal) and posterior variants are recognized, with distinguishing clinical features and anatomical lesions. Initial descriptions were attributed to stroke and neurosurgical operations, but neurodegenerative causes are now recognized as most common. Structural and functional imaging and clinical studies have implicated the supplementary motor area, pre-supplementary motor area, and their network connections in the frontal variant of AHS, and the inferior parietal lobule and connections in the posterior variant. Several theories are proposed to explain the pathophysiology. Herein, we review the literature to update advances in the understanding of the classification, pathophysiology, etiology, and treatment of AHS.

Analysis of genetics and risk factors of Alzheimer’s Disease

Alzheimer’s Disease is the leading neurodegenerative cause of dementia. The pathogenesis is not clearly understood yet, is believed to be the complex interaction between genetic and environmental factors. Consequently vascular risk factors and Apolipoprotein E genotyping are increasingly gaining importance.This study aimed at assessing the relationships between Alzheimer’s Disease and Apolipoprotein E phenotype and vascular risk factors. Patients diagnosed with “possible Alzheimer’s Disease” in the Gazi University, Department of Neurology, were included in the study and age-matched volunteer patients who attended the polyclinic were included as a control group. In this study, the risk factors including low education level, smoking, hyperlipidemia, higher serum total cholesterol levels, and hyperhomocysteinemia were found to be statistically significantly more common in the Alzheimer’s Disease group in comparison to the Control Group, while all Apolipoprotein E ε4/ε4 genotypes were found in the Alzheimer’s Disease group.The presence of the Apolipoprotein E ε4 allele is believed to increase vascular risk factors as well as to affect Alzheimer’s Disease directly. The biological indicators which are used in identifying the patients’ genes will be probably used in the treatment plan of the patients in the future.

Mass spectrometric analysis of accumulated TDP-43 in amyotrophic lateral sclerosis brains.

TDP-43 is the major disease-associated protein involved in the pathogenesis and progression of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions linked to TDP-43 pathology (FTLD-TDP). Abnormal phosphorylation, truncation and cytoplasmic mis-localization are known to be the characteristics for the aggregated forms of TDP-43, and gain of toxic abnormal TDP-43 or loss of function of physiological TDP-43 have been suggested as the cause of neurodegeneration. However, most of the post-translational modifications or truncation sites in the abnormal TDP-43 in brains of patients remain to be identified by protein chemical analysis. In this study, we carried out a highly sensitive liquid chromatography-mass spectrometry analysis of Sarkosyl-insoluble pathological TDP-43 from brains of ALS patients and identified several novel phosphorylation sites, deamidation sites, and cleavage sites. Almost all modifications were localized in the Gly-rich C-terminal half. Most of the cleavage sites identified in this study are novel and are located in N-terminal half, suggesting that these sites may be more accessible to proteolytic enzymes. The data obtained in this study provide a foundation for the molecular mechanisms of TDP-43 aggregation and ALS pathogenesis.

Immune-mediated processes in neurodegeneration: where do we stand?

Neurodegeneration is a pathological condition that predominantly affects neurons. It represents a large spectrum of disorders with heterogeneous symptoms and distinct clinical features. In addition to the devastating effects it can have on the affected individual, it constitutes a heavy burden to the society in terms of health care costs. Although the exact cause of neurodegeneration is not known, there are plenty of evidences supporting the notion that the immune system is strongly associated with various forms of neurodegenerative diseases. Given the numerous functions of immune cells, a change in their expression can either be beneficial or deleterious to the host. A better understanding of the molecular and cellular processes in neurodegeneration is therefore needed. This could facilitate the development of new therapeutic targets and provide effective means to dampen the progression of neurodegenerative disorders. The overarching aim of this paper is to provide an overview of the roles that the innate and adaptive immune systems play in the central nervous system, and to discuss their beneficial or detrimental effects during neurodegeneration. This paper also critically examines the contribution of immune and inflammatory-mediated responses in the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyloid lateral sclerosis by illustrating key findings from animal and human studies.

XPC deficiency is related to APE1 and OGG1 expression and function

Oxidative DNA damage is considered to be a major cause of neurodegeneration and internal tumors observed in syndromes that result from nucleotide excision repair (NER) deficiencies, such as Xeroderma Pigmentosum (XP) and Cockayne Syndrome (CS). Recent evidence has shown that NER aids in removing oxidized DNA damage and may interact with base excision repair (BER) enzymes. Here, we investigated APE1 and OGG1 expression, localization and activity after oxidative stress in XPC-deficient cells. The endogenous APE1 and OGG1 mRNA levels were lower in XPC-deficient fibroblasts. However, XPC-deficient cells did not show hypersensitivity to oxidative stress compared with NER-proficient cells. To confirm the impact of an XPC deficiency in regulating APE1 and OGG1 expression and activity, we established an XPC-complemented cell line. Although the XPC complementation was only partial and transient, the transfected cells exhibited greater OGG1 expression and activity compared with XPC-deficient cells. However, the APE1 expression and activity did not significantly change. Furthermore, we observed a physical interaction between the XPC and APE1 proteins. Together, the results indicate that the responses of XPC-deficient cells under oxidative stress may not only be associated with NER deficiency per se but may also include new XPC functions in regulating BER proteins.

Editorial: Golgi Pathology in Neurodegenerative Diseases

Editorial: Golgi Pathology in Neurodegenerative Diseases

Neurodegenerative Diseases Stem Cell-based Therapeutic: A Perspective

The term neurodegeneration encompasses a broad range of diseases of central and peripheral nervous system. It’s only in less than 5% of the cases a clear genetic link has been established, however, majority is sporadic and driven by a combination of genetic and environmental factors. Alzheimer’s and Parkinson’s are the most common and renowned disorders that largely affect the elderly population. However, neural degeneration and associated loss of memory in these diseases is not a normal part of ageing as it occurs only in few, not all elderly people. It is considered that neurodegeneration is a generalized systemic disorder that also inflicts other organs, although it is most pervasive in neurons. Interestingly, it is not cell-autonomous, that means multiple cell types such as astrocytes, oligodendroglia, Schwann cells etc. are also involved. Thus investigating the cause of neurodegeneration at the cellular and sub-cellular levels is most challenging. Since initially only few cells are involved, it is impossible to access those cells in human and animal models. The post-mortem tissue although relevant but offer only retrospective indicator of disease. The current modalities are only symptomatic treatment with no cure in horizon. Therefore, therapeutic interventions for neurodegenerative diseases remain the most daunting task today. The emerging new technology like stem cells based therapeutics can offer some respite and is becoming an active area of research.

Old Things New View: Ascorbic Acid Protects the Brain in Neurodegenerative Disorders.

Ascorbic acid is a key antioxidant of the Central Nervous System (CNS). Under brain activity, ascorbic acid is released from glial reservoirs to the synaptic cleft, where it is taken up by neurons. In neurons, ascorbic acid scavenges reactive oxygen species (ROS) generated during synaptic activity and neuronal metabolism where it is then oxidized to dehydroascorbic acid and released into the extracellular space, where it can be recycled by astrocytes. Other intrinsic properties of ascorbic acid, beyond acting as an antioxidant, are important in its role as a key molecule of the CNS. Ascorbic acid can switch neuronal metabolism from glucose consumption to uptake and use of lactate as a metabolic substrate to sustain synaptic activity. Multiple evidence links oxidative stress with neurodegeneration, positioning redox imbalance and ROS as a cause of neurodegeneration. In this review, we focus on ascorbic acid homeostasis, its functions, how it is used by neurons and recycled to ensure antioxidant supply during synaptic activity and how this antioxidant is dysregulated in neurodegenerative disorders.