Analysis of the Impact of CD200 on Neurodegenerative Diseases

As the average age and life expectancy increases, the incidence of both acute and chronic central nervous system (CNS) pathologies will increase. Understanding mechanisms underlying neuroinflammation as the common feature of any neurodegenerative pathology, we can exploit the pharmacology of cell specific ion channels to improve the outcome of many CNS diseases. As the main cellular player of neuroinflammation, microglia play a central role in this process. Although microglia are considered non-excitable cells, they express a variety of ion channels under both physiological and pathological conditions that seem to be involved in a plethora of cellular processes. Here, we discuss the impact of modulating microglia voltage-gated, potential transient receptor, chloride and proton channels on microglial proliferation, migration, and phagocytosis in neurodegenerative diseases.

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Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies

Translational Neurodegeneration ◽

10.1186/s40035-021-00240-7 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Dunhui Li ◽

Craig Stewart McIntosh ◽

Frank Louis Mastaglia ◽

Steve Donald Wilton ◽

May Thandar Aung-Htut

Keyword(s):

Alternative Splicing ◽

Neurodegenerative Diseases ◽

Messenger Rna ◽

Muscular Atrophy ◽

Single Gene ◽

Synaptic Function ◽

Coding Regions ◽

Splicing Defects ◽

The Impact ◽

Splicing Patterns

AbstractPrecursor messenger RNA (pre-mRNA) splicing is a fundamental step in eukaryotic gene expression that systematically removes non-coding regions (introns) and ligates coding regions (exons) into a continuous message (mature mRNA). This process is highly regulated and can be highly flexible through a process known as alternative splicing, which allows for several transcripts to arise from a single gene, thereby greatly increasing genetic plasticity and the diversity of proteome. Alternative splicing is particularly prevalent in neuronal cells, where the splicing patterns are continuously changing to maintain cellular homeostasis and promote neurogenesis, migration and synaptic function. The continuous changes in splicing patterns and a high demand on many cis- and trans-splicing factors contribute to the susceptibility of neuronal tissues to splicing defects. The resultant neurodegenerative diseases are a large group of disorders defined by a gradual loss of neurons and a progressive impairment in neuronal function. Several of the most common neurodegenerative diseases involve some form of splicing defect(s), such as Alzheimer’s disease, Parkinson’s disease and spinal muscular atrophy. Our growing understanding of RNA splicing has led to the explosion of research in the field of splice-switching antisense oligonucleotide therapeutics. Here we review our current understanding of the effects alternative splicing has on neuronal differentiation, neuronal migration, synaptic maturation and regulation, as well as the impact on neurodegenerative diseases. We will also review the current landscape of splice-switching antisense oligonucleotides as a therapeutic strategy for a number of common neurodegenerative disorders.

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Aerobic or strength training and flexibility activities and mild cognitive impairment: CETI cohort

European Journal of Public Health ◽

10.1093/eurpub/ckaa165.884 ◽

2020 ◽

Vol 30 (Supplement_5) ◽

Author(s):

C Dupré ◽

B Bongue ◽

L Fruteau de Laclos ◽

J Blais ◽

M-J Sirois

Keyword(s):

Physical Activity ◽

Cognitive Impairment ◽

Neurodegenerative Diseases ◽

Cognitive Impairments ◽

Cognitive Status ◽

Physical Activities ◽

Community Dwelling ◽

Different Types ◽

Initiative Program ◽

The Impact

Abstract Background Previous studies have been notably criticized for not studying the different types of physical activity. The objective of this work was to examine the association between types of physical activity and cognitive decline in older people. Methods This is a sub-group analysis from the CETI cohort, a multicenter prospective study conducted by the Canadian Emergency Team Initiative Program (CETIE), between 2011 and 2016. Participants were community-dwelling seniors aged ≥ 65 years, consult emergency services for minor injuries with follow-up at 3 and 6 months. Physical activity was assessed by the RAPA (Rapid assessment of Physical activity), which describes the level of aerobic activities and the overall level of muscle strength and flexibility activities. The cognitive status was assessed with the Montreal Cognitive Assessment (MoCA) and the Telephone Interview for Cognitive Status (TICS), using their current cut-offs (MoCA <26/30 and TICS < = 35/50) for mild cognitive impairments (MCI). Logistic regression, COX models and splines were used to examine the association between the type of physical activities and the onset of cognitive impairment. Results At inclusion, 281 individuals were free of MCI, or 43.8% of the total sample, with an average age of 73 years. During follow-ups, MCI appeared in 31.7% of participants initially free of it. The risk of MCI was lower with higher muscular strength & flexibility physical activities (HR = 0.84 [0.70-0.99]), while the relationship with aerobic physical activities was not significant. Conclusions These results showed a potential link between strength & flexibility activities and cognitive impairments, but not with aerobic physical activities. Further analyses are needed to examine whether these relationships persist as a function of the adjustment variables, or statistical methods. This study contributes to the debate on the evaluation of physical activity in the elderly, and its link with neurodegenerative diseases. Key messages This study analyzed the link between types of physical activity and mild cognitive disorders. The aim is to put in place preventive policies of aging, specially in neurodegenerative diseases. The work allowed us to see the effect of the different types of physical activity and the impact of the statistical method on the results.

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Kinetic Modeling of the Mitochondrial Energy Metabolism of Neuronal Cells: The Impact of Reducedα-Ketoglutarate Dehydrogenase Activities on ATP Production and Generation of Reactive Oxygen Species

International Journal of Cell Biology ◽

10.1155/2012/757594 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 15

Author(s):

Nikolaus Berndt ◽

Sascha Bulik ◽

Hermann-Georg Holzhütter

Keyword(s):

Reactive Oxygen Species ◽

Neurodegenerative Diseases ◽

Neuronal Cells ◽

Reactive Oxygen ◽

Oxygen Species ◽

Mitochondrial Energy Metabolism ◽

Atp Production ◽

Dependent Inactivation ◽

The Impact ◽

Ketoglutarate Dehydrogenase

Reduced activity of brain α-ketoglutarate dehydrogenase complex (KGDHC) occurs in a number of neurodegenerative diseases like Parkinson's disease and Alzheimer's disease. In order to quantify the relation between diminished KGDHC activity and the mitochondrial ATP generation, redox state, transmembrane potential, and generation of reactive oxygen species (ROS) by the respiratory chain (RC), we developed a detailed kinetic model. Model simulations revealed a threshold-like decline of the ATP production rate at about 60% inhibition of KGDHC accompanied by a significant increase of the mitochondrial membrane potential. By contrast, progressive inhibition of the enzyme aconitase had only little impact on these mitochondrial parameters. As KGDHC is susceptible to ROS-dependent inactivation, we also investigated the reduction state of those sites of the RC proposed to be involved in ROS production. The reduction state of all sites except one decreased with increasing degree of KGDHC inhibition suggesting an ROS-reducing effect of KGDHC inhibition. Our model underpins the important role of reduced KGDHC activity in the energetic breakdown of neuronal cells during development of neurodegenerative diseases.

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Microglia: Agents of the CNS Pro-Inflammatory Response

Cells ◽

10.3390/cells9071717 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1717 ◽

Cited By ~ 11

Author(s):

José A. Rodríguez-Gómez ◽

Edel Kavanagh ◽

Pinelopi Engskog-Vlachos ◽

Mikael K.R. Engskog ◽

Antonio J. Herrera ◽

...

Keyword(s):

Immune Response ◽

Inflammatory Response ◽

Neurodegenerative Diseases ◽

Current Knowledge ◽

Reactive Microglia ◽

Holistic View ◽

Human Microglia ◽

Positron Emission ◽

New Research ◽

The Impact

The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

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Regulatory Roles of Bone in Neurodegenerative Diseases

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2020.610581 ◽

2020 ◽

Vol 12 ◽

Author(s):

Zhengran Yu ◽

Zemin Ling ◽

Lin Lu ◽

Jin Zhao ◽

Xiang Chen ◽

...

Keyword(s):

Stem Cells ◽

Neurodegenerative Diseases ◽

The Elderly ◽

Lymphoid Organ ◽

The Body ◽

Hematopoietic Stem ◽

Brain Functions ◽

And Function ◽

The Impact ◽

The Brain

Osteoporosis and neurodegenerative diseases are two kinds of common disorders of the elderly, which often co-occur. Previous studies have shown the skeletal and central nervous systems are closely related to pathophysiology. As the main structural scaffold of the body, the bone is also a reservoir for stem cells, a primary lymphoid organ, and an important endocrine organ. It can interact with the brain through various bone-derived cells, mostly the mesenchymal and hematopoietic stem cells (HSCs). The bone marrow is also a place for generating immune cells, which could greatly influence brain functions. Finally, the proteins secreted by bones (osteokines) also play important roles in the growth and function of the brain. This article reviews the latest research studying the impact of bone-derived cells, bone-controlled immune system, and bone-secreted proteins on the brain, and evaluates how these factors are implicated in the progress of neurodegenerative diseases and their potential use in the diagnosis and treatment of these diseases.

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The Role of Gene Editing in Neurodegenerative Diseases

Cell Transplantation ◽

10.1177/0963689717753378 ◽

2018 ◽

Vol 27 (3) ◽

pp. 364-378 ◽

Cited By ~ 5

Author(s):

Hueng-Chuen Fan ◽

Ching-Shiang Chi ◽

Yih-Jing Lee ◽

Jeng-Dau Tsai ◽

Shinn-Zong Lin ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Gene Editing ◽

Clinical Manifestations ◽

Zinc Finger Nucleases ◽

Diagnostic Tools ◽

Pathological Feature ◽

Transcription Activator ◽

Substantial Impact ◽

Parkinson’S Diseases ◽

The Impact

Neurodegenerative diseases (NDs), at least including Alzheimer’s, Huntington’s, and Parkinson’s diseases, have become the most dreaded maladies because there are no precise diagnostic tools or definite treatments for these debilitating diseases. The increased prevalence and a substantial impact on the social–economic and medical care of NDs propel governments to develop policies to counteract the impact. Although the etiologies of NDs are still unknown, growing evidence suggests that genetic, cellular, and circuit alternations may cause the generation of abnormal misfolded proteins, which uncontrolledly accumulate to damage and eventually overwhelm the protein-disposal mechanisms of these neurons, leading to a common pathological feature of NDs. If the functions and the connectivity can be restored, alterations and accumulated damages may improve. The gene-editing tools including zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats–associated nucleases (CRISPR/CAS) have emerged as a novel tool not only for generating specific ND animal models for interrogating the mechanisms and screening potential drugs against NDs but also for the editing sequence-specific genes to help patients with NDs to regain function and connectivity. This review introduces the clinical manifestations of three distinct NDs and the applications of the gene-editing technology on these debilitating diseases.

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The Role of Dietary Antioxidants in the Pathogenesis of Neurodegenerative Diseases and Their Impact on Cerebral Oxidoreductive Balance

Nutrients ◽

10.3390/nu12020435 ◽

2020 ◽

Vol 12 (2) ◽

pp. 435 ◽

Cited By ~ 4

Author(s):

Anna Winiarska-Mieczan ◽

Ewa Baranowska-Wójcik ◽

Małgorzata Kwiecień ◽

Eugeniusz R. Grela ◽

Dominik Szwajgier ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Negative Impact ◽

Functional Disorders ◽

Brain Functions ◽

Diet Supplements ◽

The Impact ◽

The Brain ◽

All Diseases

Neurodegenerative diseases are progressive diseases of the nervous system that lead to neuron loss or functional disorders. Neurodegenerative diseases require long-term, sometimes life-long pharmacological treatment, which increases the risk of adverse effects and a negative impact of pharmaceuticals on the patients’ general condition. One of the main problems related to the treatment of this type of condition is the limited ability to deliver drugs to the brain due to their poor solubility, low bioavailability, and the effects of the blood-brain barrier. Given the above, one of the main objectives of contemporary scientific research focuses on the prevention of neurodegenerative diseases. As disorders related to the competence of the antioxidative system are a marker in all diseases of this type, the primary prophylactics should entail the use of exogenous antioxidants, particularly ones that can be used over extended periods, regardless of the patient’s age, and that are easily available, e.g., as part of a diet or as diet supplements. The paper analyzes the significance of the oxidoreductive balance in the pathogenesis of neurodegenerative diseases. Based on information published globally in the last 10 years, an analysis is also provided with regard to the impact of exogenous antioxidants on brain functions with respect to the prevention of this type of diseases.

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IMMUND: an Early Stage Diagnostic and Therapeutic Frame for Neurodegenerative Diseases and Multiple Sclerosis based on Immunological Markers

10.1101/2021.05.09.442890 ◽

2021 ◽

Author(s):

Sagnik Sen ◽

Ashmita Dey ◽

Dwipanjan Sanyal ◽

Ujjwal Maulik ◽

Krishnananda Chattopadhyay

Keyword(s):

Multiple Sclerosis ◽

Neurodegenerative Diseases ◽

Early Stage ◽

Cellular Systems ◽

P Value ◽

Research Areas ◽

Immunological Markers ◽

Therapeutic Frame ◽

Comprehensive Framework ◽

The Impact

For neurodegenerative diseases, the impact of immunological markers is one of the modern research areas. It has been observed that neuroinflammation increases the cellular precipitation of some of the key proteins associated with neurodegenerative diseases. Therefore, the possibility of functional loss can be enhanced due to neuroinflammation which leads to the initiation of any related diseases. In this regard, autoantibodies, which are known for their autophagy nature, can be considered as key elements for early diagnostic as well as early therapeutics. In this article, we have proposed a comprehensive framework to unveil the diagnostic as well as the therapeutic possibility of the autoantibodies which are largely associated with Mild-Moderate Alzheimer's Disease, Early-Stage Parkinson's Disease, and Multiple Sclerosis. Here, we have introduced a new concept of average p-value where multiple p-values of an autoantibody in a singular disease have been considered as a multi-occurrence of that sample in cellular systems. Also, multiple proteins from a single protein family under a differentially expressed range have been prioritized. As a result, the top ten autoantibodies have been selected for further study and also considered as diagnostic markers. Interestingly, most of the selected autoantibodies are either cytokines or immunoglobulins. Subsequently, we have performed an evolutionary sequence-structure space study to identify the druggable structural facet for the selected autoantibodies. To make the therapeutic perspective more robust, we have introduced the concept of protein moonlighting. Hence, it provides more robustness in therapeutic identification. Finally, two autoantibodies i.e., Q9NYV4 and P01602 are identified as a novel marker.

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Induction of autophagy mitigates TDP-43 pathology and translational repression of neurofilament mRNAs in mouse models of ALS/FTD

10.21203/rs.3.rs-29102/v1 ◽

2020 ◽

Author(s):

Sunny Kumar ◽

Daniel Phaneuf ◽

Pierre Cordeau ◽

Hejer Boutej ◽

Jasna Kriz ◽

...

Keyword(s):

Transgenic Mice ◽

Oral Administration ◽

Neurodegenerative Diseases ◽

Mouse Models ◽

Synaptic Function ◽

Neurofilament Proteins ◽

Type Iv ◽

One Year ◽

The Impact ◽

The Brain

Abstract Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile remains unknown. Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used a Ribotag approach combined with microarray and proteomic analyses to investigate the neuronal translational profiles in mouse model of ALS/FTD. Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induces autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function. Conclusions: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

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