scholarly journals The Role of Tau in Neurodegenerative Diseases and Its Potential as a Therapeutic Target

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-20 ◽  
Author(s):  
Michael S. Wolfe
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Pathological Feature ◽  
Tau Pathology ◽  
Gene Encoding ◽  
Protein Tau ◽  
Molecular Events ◽  
Potential Therapeutics ◽  
Key Questions

The abnormal deposition of proteins in and around neurons is a common pathological feature of many neurodegenerative diseases. Among these pathological proteins, the microtubule-associated protein tau forms intraneuronal filaments in a spectrum of neurological disorders. The discovery that dominant mutations in theMAPTgene encoding tau are associated with familial frontotemporal dementia strongly supports abnormal tau protein as directly involved in disease pathogenesis. This and other evidence suggest that tau is a worthwhile target for the prevention or treatment of tau-associated neurodegenerative diseases, collectively called tauopathies. However, it is critical to understand the normal biological roles of tau, the specific molecular events that induce tau to become neurotoxic, the biochemical nature of pathogenic tau, the means by which pathogenic tau exerts neurotoxicity, and how tau pathology propagates. Based on known differences between normal and abnormal tau, a number of approaches have been taken toward the discovery of potential therapeutics. Key questions still remain open, such as the nature of the connection between the amyloid-βprotein of Alzheimer’s disease and tau pathology. Answers to these questions should help better understand the nature of tauopathies and may also reveal new therapeutic targets and strategies.

scholarly journals She Doesn’t Even Go Here: The Role of Inflammatory Astrocytes in CNS Disorders

2021 ◽  
Vol 15 ◽  
Author(s):  
Jacqueline Kelsey Reid ◽  
Hedwich Fardau Kuipers
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Therapeutic Targeting ◽  
Future Directions ◽  
Cns Disorders ◽  
Disease Modifying Therapies ◽  
Astrocyte Heterogeneity ◽  
Disease Modifying ◽  
Innovative Techniques

Astrocyte heterogeneity is a rapidly evolving field driven by innovative techniques. Inflammatory astrocytes, one of the first described subtypes of reactive astrocytes, are present in a variety of neurodegenerative diseases and may play a role in their pathogenesis. Moreover, genetic and therapeutic targeting of these astrocytes ameliorates disease in several models, providing support for advancing the development of astrocyte-specific disease modifying therapies. This review aims to explore the methods and challenges of identifying inflammatory astrocytes, the role these astrocytes play in neurological disorders, and future directions in the field of astrocyte heterogeneity.

Does Altered Probability of Real Time Diffusional Collisions of Membrane Molecules Trigger or Delay Alzheimers Disease

2020 ◽  
Vol 5 (5) ◽  
pp. 1-4
Author(s):  
Deepak Nair ◽  
Shekhar Kedia ◽  
Mini Jose
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurodegenerative Diseases ◽  
Real Time ◽  
Time Scale ◽  
Product Formation ◽  
Molecular Events ◽  
Millisecond Time Scale ◽  
Stochastic Events ◽  
Random Diffusion

Understanding stochastic events that control the molecular events leading to the onset of neurodegenerative diseases such as Alzheimer's Disease (AD) is not well understood. Though the bulk of the attention is attributed to the increased burden of detrimental proteoforms generated by the processing of Amyloid Precursor Protein, there lacks a clear consensus on how the molecular events that control the localization and trafficking contribute to the onset. Here, we discuss emerging evidence that indicate the role of nanoscale compositionality of the membrane and random diffusion at the millisecond time scale that contribute to the onset of AD. We believe that intuitive knowledge of nanobiology controlling the local rates of product formation holds the clue for next-generation therapeutics that might delay or halt the onset of AD.

scholarly journals TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy

2017 ◽  
Vol 114 (43) ◽  
pp. 11524-11529 ◽  
Author(s):  
Cheryl E. G. Leyns ◽  
Jason D. Ulrich ◽  
Mary B. Finn ◽  
Floy R. Stewart ◽  
Lauren J. Koscal ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Potential Role ◽  
Piriform Cortex ◽  
Tau Pathology ◽  
Gene Encoding ◽  
Gene Expression Analyses ◽  
Unexpected Findings ◽  
Microglial Response ◽  
The Brain

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer’s disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed Trem2+/+ (T2+/+) and Trem2−/− (T2−/−) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2−/−PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2+/+PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2−/−PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex compared with T2+/+PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2−/−PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.

scholarly journals Metallothionein in Brain Disorders

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Daniel Juárez-Rebollar ◽  
Camilo Rios ◽  
Concepción Nava-Ruíz ◽  
Marisela Méndez-Armenta
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Regulation Of Gene Expression ◽  
Main Function ◽  
Brain Disorders ◽  
Essential Metals ◽  
The Central Nervous System

Metallothioneins are a family of proteins which are able to bind metals intracellularly, so their main function is to regulate the cellular metabolism of essential metals. There are 4 major isoforms of MTs (I–IV), three of which have been localized in the central nervous system. MT-I and MT-II have been localized in the spinal cord and brain, mainly in astrocytes, whereas MT-III has been found mainly in neurons. MT-I and MT-II have been considered polyvalent proteins whose main function is to maintain cellular homeostasis of essential metals such as zinc and copper, but other functions have also been considered: detoxification of heavy metals, regulation of gene expression, processes of inflammation, and protection against free radicals generated by oxidative stress. On the other hand, the MT-III has been related in events of pathogenesis of neurodegenerative diseases such as Parkinson and Alzheimer. Likewise, the participation of MTs in other neurological disorders has also been reported. This review shows recent evidence about the role of MT in the central nervous system and its possible role in neurodegenerative diseases as well as in brain disorders.

scholarly journals Repertoires of Autophagy in the Pathogenesis of Ocular Diseases

2015 ◽  
Vol 35 (5) ◽  
pp. 1663-1676 ◽  
Author(s):  
Yu-jie Li ◽  
Qin Jiang ◽  
Guo-fan Cao ◽  
Jin Yao ◽  
Biao Yan
Keyword(s):  
Infectious Diseases ◽  
Neurodegenerative Diseases ◽  
Therapeutic Target ◽  
Human Diseases ◽  
Pathological Feature ◽  
Ocular Diseases ◽  
Pharmacological Manipulation ◽  
Cytoplasmic Proteins ◽  
Related Proteins

Autophagy is an important intracellular degradative process that delivers cytoplasmic proteins to lysosome for degradation. Dysfunction of autophagy is implicated in several human diseases, such as neurodegenerative diseases, infectious diseases, and cancers. Autophagy-related proteins are constitutively expressed in the eye. Increasing studies have revealed that abnormal autophagy is an important pathological feature of several ocular diseases. Pharmacological manipulation of autophagy may provide an alternative therapeutic target for some ocular diseases. In this manuscript, we reviewed the relevant progress about the role of autophagy in the pathogenesis of ocular diseases.

scholarly journals Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-18 ◽  
Author(s):  
Khushwant S. Bhullar ◽  
H. P. Vasantha Rupasinghe
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Drug Targets ◽  
Nutritional Intervention ◽  
Testable Hypothesis ◽  
Brain Physiology ◽  
Age Related ◽  
Therapeutic Outcomes ◽  
Polyphenol Intake

Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer’s disease (AD), stroke, multiple sclerosis (MS), Parkinson’s disease (PD), and Huntington’s disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders.

scholarly journals Preventing Neurodegeneration by Controlling Oxidative Stress: The Role of OXR1

2020 ◽  
Vol 14 ◽  
Author(s):  
Michael R. Volkert ◽  
David J. Crowley
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Stress Resistance ◽  
Molecular Level ◽  
Neuronal Damage ◽  
Gene Products ◽  
Oxidative Stress Resistance ◽  
Molecular Events ◽  
Regulatory Functions

Parkinson’s disease, diabetic retinopathy, hyperoxia induced retinopathy, and neuronal damage resulting from ischemia are among the notable neurodegenerative diseases in which oxidative stress occurs shortly before the onset of neurodegeneration. A shared feature of these diseases is the depletion of OXR1 (oxidation resistance 1) gene products shortly before the onset of neurodegeneration. In animal models of these diseases, restoration of OXR1 has been shown to reduce or eliminate the deleterious effects of oxidative stress induced cell death, delay the onset of symptoms, and reduce overall severity. Moreover, increasing OXR1 expression in cells further increases oxidative stress resistance and delays onset of disease while showing no detectable side effects. Thus, restoring or increasing OXR1 function shows promise as a therapeutic for multiple neurodegenerative diseases. This review examines the role of OXR1 in oxidative stress resistance and its impact on neurodegenerative diseases. We describe the potential of OXR1 as a therapeutic in light of our current understanding of its function at the cellular and molecular level and propose a possible cascade of molecular events linked to OXR1’s regulatory functions.

A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration

2020 ◽  
Vol 31 (4) ◽  
pp. 351-362 ◽  
Author(s):  
Alessio Guglielmi
Keyword(s):  
Neurodegenerative Diseases ◽  
Sigmund Freud ◽  
Neurological Disorders ◽  
Hereditary Spastic Paraplegia ◽  
Dna Analysis ◽  
Therapeutic Strategies ◽  
Lower Limbs ◽  
Spastic Paraplegia ◽  
Adolf Von Strümpell

AbstractAt the end of 19th century, Adolf von Strümpell and Sigmund Freud independently described the symptoms of a new pathology now known as hereditary spastic paraplegia (HSP). HSP is part of the group of genetic neurodegenerative diseases usually associated with slow progressive pyramidal syndrome, spasticity, weakness of the lower limbs, and distal-end degeneration of motor neuron long axons. Patients are typically characterized by gait symptoms (with or without other neurological disorders), which can appear both in young and adult ages depending on the different HSP forms. The disease prevalence is at 1.3–9.6 in 100 000 individuals in different areas of the world, making HSP part of the group of rare neurodegenerative diseases. Thus far, there are no specific clinical and paraclinical tests, and DNA analysis is still the only strategy to obtain a certain diagnosis. For these reasons, it is mandatory to extend the knowledge on genetic causes, pathology mechanism, and disease progression to give clinicians more tools to obtain early diagnosis, better therapeutic strategies, and examination tests. This review gives an overview of HSP pathologies and general insights to a specific HSP subtype called spastic paraplegia 31 (SPG31), which rises after mutation of REEP1 gene. In fact, recent findings discovered an interesting endoplasmic reticulum antistress function of REEP1 and a role of this protein in preventing τ accumulation in animal models. For this reason, this work tries to elucidate the main aspects of REEP1, which are described in the literature, to better understand its role in SPG31 HSP and other pathologies.

scholarly journals Protein Glutathionylation in the Pathogenesis of Neurodegenerative Diseases

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Sun Joo Cha ◽  
Hayoung Kim ◽  
Hyun-Jun Choi ◽  
Sanghyun Lee ◽  
Kiyoung Kim
Keyword(s):  
Neurodegenerative Diseases ◽  
Posttranslational Modification ◽  
Neurological Disorders ◽  
Metabolic Pathways ◽  
Thiol Group ◽  
Therapeutic Interventions ◽  
Biological Functions ◽  
Target Proteins ◽  
Specific Proteins

Protein glutathionylation is a redox-mediated posttranslational modification that regulates the function of target proteins by conjugating glutathione with a cysteine thiol group on the target proteins. Protein glutathionylation has several biological functions such as regulation of metabolic pathways, calcium homeostasis, signal transduction, remodeling of cytoskeleton, inflammation, and protein folding. However, the exact role and mechanism of glutathionylation during irreversible oxidative stress has not been completely defined. Irreversible oxidative damage is implicated in a number of neurological disorders. Here, we discuss and highlight the most recent findings and several evidences for the association of glutathionylation with neurodegenerative diseases and the role of glutathionylation of specific proteins in the pathogenesis of neurodegenerative diseases. Understanding the important role of glutathionylation in the pathogenesis of neurodegenerative diseases may provide insights into novel therapeutic interventions.

scholarly journals Mitophagy and the Brain

2020 ◽  
Vol 21 (24) ◽  
pp. 9661
Author(s):  
Natalie S. Swerdlow ◽  
Heather M. Wilkins
Keyword(s):  
Clinical Trials ◽  
Neurodegenerative Diseases ◽  
Neuronal Loss ◽  
Cell Stress ◽  
Compensatory Mechanisms ◽  
Lysosome Degradation ◽  
The Brain ◽  
Potential Therapeutics

Stress mechanisms have long been associated with neuronal loss and neurodegenerative diseases. The origin of cell stress and neuronal loss likely stems from multiple pathways. These include (but are not limited to) bioenergetic failure, neuroinflammation, and loss of proteostasis. Cells have adapted compensatory mechanisms to overcome stress and circumvent death. One mechanism is mitophagy. Mitophagy is a form of macroautophagy, were mitochondria and their contents are ubiquitinated, engulfed, and removed through lysosome degradation. Recent studies have implicated mitophagy dysregulation in several neurodegenerative diseases and clinical trials are underway which target mitophagy pathways. Here we review mitophagy pathways, the role of mitophagy in neurodegeneration, potential therapeutics, and the need for further study.

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