Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders

2020 ◽  
Vol 20 (13) ◽  
pp. 1142-1153 ◽  
Author(s):  
Sreyashi Chandra ◽  
Md. Tanjim Alam ◽  
Jhilik Dey ◽  
Baby C. Pulikkaparambil Sasidharan ◽  
Upasana Ray ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Neurodegenerative Disorders ◽  
The Body ◽  
Therapeutic Approaches ◽  
Cns Disorders ◽  
Physiological Conditions ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Present Understanding ◽  
Lateral Sclerosis

Background: The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington’s disease (HD). Objective: We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD. Methods: In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them. Results: In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction. Conclusion: We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.

scholarly journals Disease Mechanisms and Therapeutic Approaches in C9orf72 ALS-FTD

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 601
Author(s):  
Keith Mayl ◽  
Christopher E. Shaw ◽  
Youn-Bok Lee
Keyword(s):  
The Body ◽  
The Novel ◽  
Therapeutic Approaches ◽  
Gain Of Function ◽  
Pathogenic Mechanisms ◽  
Hexanucleotide Repeat ◽  
Primary Driver ◽  
Hexanucleotide Repeat Expansion ◽  
Expansion Mutation ◽  
Lateral Sclerosis

A hexanucleotide repeat expansion mutation in the first intron of C9orf72 is the most common known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Since the discovery in 2011, numerous pathogenic mechanisms, including both loss and gain of function, have been proposed. The body of work overall suggests that toxic gain of function arising from bidirectionally transcribed repeat RNA is likely to be the primary driver of disease. In this review, we outline the key pathogenic mechanisms that have been proposed to date and discuss some of the novel therapeutic approaches currently in development.

scholarly journals N-Acetyl-Cysteine supplementation lowers high homocysteine plasma levels and increases Glutathione synthesis in the trans-sulfuration pathway

2019 ◽  
Vol 13 (4) ◽  
pp. 234-240
Author(s):  
Federico Cacciapuoti
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Disorders ◽  
Active Form ◽  
The Body ◽  
Glutamate Cysteine Ligase ◽  
Pathological Conditions ◽  
Transsulfuration Pathway ◽  
Antioxidant Function ◽  
Acetyl Cysteine ◽  
Rate Limiting

Glutathione (GSH), a compound derived of a combination of three amino acids – cysteine, glycine and glutamine – is the final product of homocysteine (Hcy) metabolism  in the transsulfuration pathway. The major determinants of GSH synthesis are the availability of cysteine and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). A deficiency in  transsulfuration pathway leads to excessive Hcy production (HHcy) and reduced GSH synthesis. This tripeptide, that exists in the reduced or active  form (GSH) and oxidized variant (GSH), is the main antioxidant of the  body.  Independently of its antioxidant function, the compound  has an anti-inflammatory role too, reducing the production of interleukines and the expression of TNF-alfa and iNOS synthase. A dysregulation of GSH synthesis is recognized as contributing factor to the pathogenesis of many pathological conditions. But, the insufficiency of the transsulfuration pathway is also responsible of HHcy. Besides, this condition  decreases the activity of cellular “gluthatione peroxidase”, an intracellular antioxidant enzyme that reduces hydrogen peroxide to water with the prevalence of GSSH on GSH. The consequent GSH/GSSH impaired ratio also causes some common cardiovascular and neurodegenerative disorders. In both occurrences, N-Acetyl-Cysteine (NAC) supplementation supplies the cysteine necessary for GSH synthesis and contemporarily reduces HHcy, improving  the GPx1 activity and further reducing oxidative stress.

scholarly journals n-3 PUFA and obesity: from peripheral tissues to the central nervous system

2018 ◽  
Vol 119 (11) ◽  
pp. 1312-1323 ◽  
Author(s):  
Aline Haas de Mello ◽  
Marcela Fornari Uberti ◽  
Bianca Xavier de Farias ◽  
Nathalia Alberti Ribas de Souza ◽  
Gislaine Tezza Rezin
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Cardiac Arrhythmias ◽  
The Body ◽  
Low Grade ◽  
Therapeutic Approaches ◽  
Peripheral Tissues ◽  
Inflammatory State ◽  
The Central Nervous System ◽  
Inflammatory Effect

AbstractThe current paradigms of prevention and treatment are unable to curb obesity rates, which indicates the need to explore alternative therapeutic approaches. Obesity leads to several damages to the body and is an important risk factor for a number of other chronic diseases. Furthermore, despite the first alterations in obesity being observed and reported in peripheral tissues, studies indicate that obesity can also cause brain damage. Obesity leads to a chronic low-grade inflammatory state, and the therapeutic manipulation of inflammation can be explored. In this context, the use of n-3 PUFA (especially in the form of fish oil, rich in EPA and DHA) may be an interesting strategy, as this substance is known by its anti-inflammatory effect and numerous benefits to the body, such as reduction of TAG, cardiac arrhythmias, blood pressure and platelet aggregation, and has shown potential to help treat obesity. Thereby, the aim of this narrative review was to summarise the literature related to n-3 PUFA use in obesity treatment. First, the review provides a brief description of the obesity pathophysiology, including alterations that occur in peripheral tissues and at the central nervous system. In the sequence, we describe what are n-3 PUFA, their sources and their general effects. Finally, we explore the main topic linking obesity and n-3 PUFA. Animal and human studies were included and alterations on the whole organism were described (peripheral tissues and brain).

scholarly journals Gut–Brain Axis and Neurodegeneration: State-of-the-Art of Meta-Omics Sciences for Microbiota Characterization

2020 ◽  
Vol 21 (11) ◽  
pp. 4045 ◽  
Author(s):  
Bruno Tilocca ◽  
Luisa Pieroni ◽  
Alessio Soggiu ◽  
Domenico Britti ◽  
Luigi Bonizzi ◽  
...  
Keyword(s):  
Nervous System ◽  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
State Of The Art ◽  
Integrated Approach ◽  
Microbial Genomes ◽  
Physiological Processes ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Recent advances in the field of meta-omics sciences and related bioinformatics tools have allowed a comprehensive investigation of human-associated microbiota and its contribution to achieving and maintaining the homeostatic balance. Bioactive compounds from the microbial community harboring the human gut are involved in a finely tuned network of interconnections with the host, orchestrating a wide variety of physiological processes. These includes the bi-directional crosstalk between the central nervous system, the enteric nervous system, and the gastrointestinal tract (i.e., gut–brain axis). The increasing accumulation of evidence suggest a pivotal role of the composition and activity of the gut microbiota in neurodegeneration. In the present review we aim to provide an overview of the state-of-the-art of meta-omics sciences including metagenomics for the study of microbial genomes and taxa strains, metatranscriptomics for gene expression, metaproteomics and metabolomics to identify and/or quantify microbial proteins and metabolites, respectively. The potential and limitations of each discipline were highlighted, as well as the advantages of an integrated approach (multi-omics) to predict microbial functions and molecular mechanisms related to human diseases. Particular emphasis is given to the latest results obtained with these approaches in an attempt to elucidate the link between the gut microbiota and the most common neurodegenerative diseases, such as multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS).

scholarly journals Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Hyuk Sung Kwon ◽  
Seong-Ho Koh
Keyword(s):  
Central Nervous System ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Inflammatory Responses ◽  
Therapeutic Drugs ◽  
M1 Phenotype ◽  
The Central Nervous System ◽  
The Relationship ◽  
Lateral Sclerosis ◽  
M2 Phenotype

AbstractNeuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.

scholarly journals Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases

2019 ◽  
Vol 20 (15) ◽  
pp. 3685 ◽  
Author(s):  
Roberta Cascella ◽  
Giulia Fani ◽  
Alessandra Bigi ◽  
Fabrizio Chiti ◽  
Cristina Cecchi
Keyword(s):  
Neurodegenerative Disorders ◽  
Frontotemporal Lobar Degeneration ◽  
Strong Influence ◽  
Genetic Mutations ◽  
Oxygen Species ◽  
Caspase Activation ◽  
Post Translational Modifications ◽  
Key Factor ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative disorders showing mislocalization and cytosolic accumulation of TDP-43 inclusions in the central nervous system. The decrease in the efficiency of the clearance systems in aging, as well as the presence of genetic mutations of proteins associated with cellular proteostasis in the familial forms of TDP-43 proteinopathies, suggest that a failure of these protein degradation systems is a key factor in the aetiology of TDP-43 associated disorders. Here we show that the internalization of human pre-formed TDP-43 aggregates in the murine neuroblastoma N2a cells promptly resulted in their ubiquitination and hyperphosphorylation by endogenous machineries, mimicking the post-translational modifications observed in patients. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. The inhibition of TDP-43 proteostasis in the presence of selective inhibitors against the proteasome and macroautophagy systems revealed that these two systems are both severely involved in TDP-43 accumulation and have a strong influence on each other in neurodegenerative disorders associated with TDP-43.

Neurodegenerative Disorders Progression

2019 ◽  
pp. 129-152
Author(s):  
Ramneek Kaur ◽  
Harleen Kaur ◽  
Rashi Rajput ◽  
Sachin Kumar ◽  
Rachana R. ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Neural Systems ◽  
Diverse Group ◽  
Key Factors ◽  
Neuron Death ◽  
Postsynaptic Activity ◽  
Neural Transmission ◽  
The Central Nervous System ◽  
Neural Signaling ◽  
Lateral Sclerosis

Neurodegenerative disorders (NDs) are a diverse group of disorders characterized by selective and progressive loss of neural systems that cause dysfunction of the central nervous system (CNS). The examples of NDs include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD). The aggregated proteins block or disrupt the normal proteosomal turnover, autophagy, and become abnormally modified with time, generating toxicity via pathways thereby resulting in neurodegeneration and neuron death. The chapter highlights the understanding in the areas of AD, PD, HD as illustrative of major research so as to define the key factors and events in the improvement of NDs. It defines the physiological functioning of neural transmission (presynaptic, postsynaptic activity) at neural signaling pathway, then the dynamics of neuronal dysfunctioning and its molecular mechanism. Further, it also discusses the progression from synaptic dysfunction to transmission failure followed by NDs.

scholarly journals Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1698 ◽  
Author(s):  
Sujay Paul ◽  
Luis Alberto Bravo Vázquez ◽  
Samantha Pérez Uribe ◽  
Paula Roxana Reyes-Pérez ◽  
Ashutosh Sharma
Keyword(s):  
Neurodegenerative Disorders ◽  
Muscular Atrophy ◽  
Current Status ◽  
Therapeutic Approaches ◽  
Therapeutic Drugs ◽  
High Prevalence ◽  
Attractive Option ◽  
New Generation ◽  
Near Future ◽  
Lateral Sclerosis

MicroRNAs (miRNAs) are a key gene regulator and play essential roles in several biological and pathological mechanisms in the human system. In recent years, plenty of miRNAs have been identified to be involved in the development of neurodegenerative disorders (NDDs), thus making them an attractive option for therapeutic approaches. Hence, in this review, we provide an overview of the current research of miRNA-based therapeutics for a selected set of NDDs, either for their high prevalence or lethality, such as Alzheimer’s, Parkinson’s, Huntington’s, Amyotrophic Lateral Sclerosis, Friedreich’s Ataxia, Spinal Muscular Atrophy, and Frontotemporal Dementia. We also discuss the relevant delivery techniques, pertinent outcomes, their limitations, and their potential to become a new generation of human therapeutic drugs in the near future.

scholarly journals Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy

2021 ◽  
Vol 22 (9) ◽  
pp. 4771
Author(s):  
Lalita Subedi ◽  
Bhakta Prasad Gaire ◽  
Amna Parveen ◽  
Sun-Yeou Kim
Keyword(s):  
Nitric Oxide ◽  
Neurological Disorders ◽  
Reactive Nitrogen Species ◽  
Therapeutic Strategy ◽  
No Production ◽  
Inflammatory Signaling ◽  
Cns Disorders ◽  
Prevention Therapy ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Nitric oxide (NO) is a neurotransmitter that mediates the activation and inhibition of inflammatory cascades. Even though physiological NO is required for defense against various pathogens, excessive NO can trigger inflammatory signaling and cell death through reactive nitrogen species-induced oxidative stress. Excessive NO production by activated microglial cells is specifically associated with neuroinflammatory and neurodegenerative conditions, such as Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, ischemia, hypoxia, multiple sclerosis, and other afflictions of the central nervous system (CNS). Therefore, controlling excessive NO production is a desirable therapeutic strategy for managing various neuroinflammatory disorders. Recently, phytochemicals have attracted considerable attention because of their potential to counteract excessive NO production in CNS disorders. Moreover, phytochemicals and nutraceuticals are typically safe and effective. In this review, we discuss the mechanisms of NO production and its involvement in various neurological disorders, and we revisit a number of recently identified phytochemicals which may act as NO inhibitors. This review may help identify novel potent anti-inflammatory agents that can downregulate NO, specifically during neuroinflammation and neurodegeneration.

scholarly journals Pathogenic Tau Protein Species: Promising Therapeutic Targets for Ocular Neurodegenerative Diseases

2019 ◽  
Author(s):  
Mohammad Amir Mishan ◽  
Mozhgan Rezaei Kanavi ◽  
Koorosh Shahpasand ◽  
Hamid Ahmadieh
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Therapeutic Strategy ◽  
Protein Species ◽  
Physiological Conditions ◽  
Abnormal Hyperphosphorylation ◽  
The Central Nervous System ◽  
Microtubule Structure

Tau is a microtubule-associated protein, which is highly expressed in the central nervous system as well as ocular neurons and stabilizes microtubule structure. It is a phospho-protein being moderately phosphorylated under physiological conditions but its abnormal hyperphosphorylation or some post-phosphorylation modifications would result in a pathogenic condition, microtubule dissociation, and aggregation. The aggregates can induce neuroinflammation and trigger some pathogenic cascades, leading to neurodegeneration. Taking these together, targeting pathogenic tau employing tau immunotherapy may be a promising therapeutic strategy in fighting with cerebral and ocular neurodegenerative disorders.

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