[Approaches from genetical analyses on human diseases: neurodegenerative diseases].
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Alzheimer Disease↗
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[Proteins and mutations: a new vision (molecular) of neurodegenerative diseases].
Neurodegenerative diseases have long been considered to be poorly defined, misunderstood, and inadequately treated. In recent years, research on Alzheimer's disease has led to numerous advances that have improved our understanding of this form of dementia and also of the entire category of neurodegenerative diseases. It now appears that numerous neurodegenerative diseases of the central nervous system correspond to the aggregation of specific proteins: beta-amyloid in Alzheimer disease, tau protein in Alzheimer disease, fronto-temporal dementia, progressive supranuclear palsy and corticobasal degeneration, alpha-synuclein in Parkinson disease and Lewy body dementia, PrP protein in prion diseases, SOD in amyotrophic lateral sclerosis, polyglutamine expansions in Huntington's disease and other diseases, etc. It is remarkable that in all these cases mutations have been identified for genes coding for these proteins and able to cause the disease and, moreover, that the introduction of the corresponding gene into transgenic mice (or other transgenic animals) has made it possible to create animal models of these conditions. This suggests that the proteins in question play a determinative role in the pathogenesis of these diseases and are not simply consequences of it. Neurodegenerative diseases are proteinopathies. But they are also networkopathies because the neuronal proteins are organized in functional networks. We must also note that all these diseases are associated with the process of aging, for they do not appear in the young. This fact suggests that the anomaly (genetic or otherwise) concerning a given protein does not suffice by itself to induce the disease process. Many observations suggest that the additional event involved, common to all neurodegenerative conditions, may be the intervention of free radicals. We thus propose here the theory that the diversity of neurodegenerative diseases is explained by the combination of two pathogenic events: one specific and associated with the aggregation of a particular protein in the nervous system, the other, non-specific and associated with aging and with the production and harmful actions of free radicals. This unified interpretation leads directly to treatment hypotheses: the development of drugs capable either of inhibiting the production or aggregation of proteins specifically implicated in diverse diseases (or promoting their elimination) or of inhibiting the production or action of free radicals in the nervous system. The former should target one of these various diseases, and the latter should act on a wide range of diseases. The two approaches may conceivably be combined.
Aging↗
An update on pharmacological approaches to neurodegenerative diseases.
Neurodegenerative diseases are now generally considered as a group of disorders that seriously and progressively impair the functions of the nervous system through selective neuronal vulnerability of specific brain regions. Alzheimer's disease is the most common neurodegenerative disease, followed in incidence by Parkinson's disease; much less common are frontotemporal dementia, Huntington's disease, amyothrophic lateral sclerosis (Lou Gehrig's disease), progressive supranuclear palsy, spinocerebellar ataxia, Pick's disease and, lastly, prion disease. In this review, the authors intend to survey new drugs in different clinical phases but not in the preclinical or discovery stages nor already in the market, with new molecules aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. Drugs in different pharmacological phases are under study or are ready to be introduced into therapy for Alzheimer's disease, which display anti-beta-amyloid activity or nerve growth factor-like activity or anti-inflammatory properties. Other drugs possess mixed mechanisms of action, such as acetylcholinesterase inhibition and impairment of beta-amyloid formation through inhibition of beta-amyloid precursor protein synthesis and/or modulation of secretase activity. Other therapeutic approaches are based on immunotherapy, control of metal ions interactions with beta-amyloid and ensuing oxidative reactions as well as metabolic or hormonal regulation. The symptomatic therapy of motor behaviour in Parkinson's disease, based on l-DOPA, is registering adenosine A(2A) receptor antagonists, monoamine oxidase B inhibitors and ion channel modulators, as well as dopamine uptake inhibitors and glutamate AMPA receptor antagonists. There are also many other drugs involved, including astrocyte-modulating agents, 5-HT(1A) agonists and alpha(2)-adrenergic receptor antagonists, which are targeted at preventing or ameliorating Parkinson's disease-related or l-DOPA-induced dyskinesias. Huntington's disease therapy envisages a Phase III drug, LAX-101, which displays antiapoptotic properties by promoting membrane stabilisation and mitochondrial integrity. Other drugs with antioxidant and antiapoptotic steroid-like and neuroprotective activity are under investigation for the therapy of the less common neurodegenerative diseases.
Animals↗
CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.
Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.
Humans↗
How the microbiome shapes epigenetic trained memory in neuroinflammation: Implications for neurodegenerative diseases.
Neurodegenerative diseases are increasingly recognized as disorders involving immune dysregulation. However, the mechanisms underlying this dysfunction remain poorly characterized. Trained immunity has recently emerged as a potential contributor to immune dysregulation, particularly in neuroinflammation and neurodegenerative diseases, where trained immunity is the epigenetic reprogramming of innate immune responses following an initial inflammatory stimulus, which increases responses to subsequent exposures. In parallel, although the brain has traditionally been viewed as an immune-privileged organ, growing evidence indicates that peripheral immune activity exerts significant influence on neuroinflammation in the brain. A major driver of peripheral immunity is the microbiome. Therefore, this perspective aims to present a conceptual framework for a relationship between the microbiome, trained immunity, and neurodegenerative diseases. We first summarize evidence of trained immunity in the brain and its role in neurodegeneration. Next, we highlight the role of the microbiome in peripheral immune modulation and in trained immunity. Finally, we propose potential mechanisms through which the microbiome may induce or modulate trained immunity in the brain. These include: 1) immunogenic microbial metabolites that cross the blood-brain barrier and alter host cell epigenetics; 2) migration of peripherally trained myeloid cells into the brain; 3) viral infection-induced trained immunity that may predispose to neurodegeneration. Together, this perspective suggests that microbiome-induced trained immunity offers a novel mechanism linking peripheral immune regulation with neuroinflammation and neurodegeneration with implications for therapeutic targeting of epigenetic modification as a molecular prevention strategy for progression of neurodegeneration.
Humans↗
Can flies help humans treat neurodegenerative diseases?
Neurodegenerative diseases are becoming increasingly common as life expectancy increases. Recent years have seen tremendous progress in the identification of genes that cause these diseases. While mutations have been found and cellular processes defined that are altered in the disease state, the identification of treatments and cures has proven more elusive. The process of finding drugs and therapies to treat human diseases can be slow, expensive and frustrating. Can model organisms such as Drosophila speed the process of finding cures and treatments for human neurodegenerative diseases? We pose three questions, (1) can one mimic the essential features of human diseases in an organism like Drosophila, (2) can one cure a model organisms of human disease and (3) will these efforts accelerate the identification of useful therapies for testing in mice and ultimately humans? Here we focus on the use of Drosophila to identify potential treatments for neurodegenerative diseases such as Huntington's and we discuss how well these therapies translate into mammalian systems.
Animals↗
Genetic dissection of primary neurodegenerative diseases.
Neurodegenerative diseases have traditionally been defined as clinico-pathological entities. The clinician observes characteristic clusters of symptoms that relate to the anatomical distribution of the lesion. Typically, these symptoms progress in a characteristic sequence allowing the clinician to make a provisional diagnosis. At autopsy, the pathologist examines the nature and distribution of the lesions, reads the clinical report and makes a definitive diagnosis. This structure is so deeply embedded in our concepts of neurodegenerative disease that we are hardly aware of it. It has become deeply embedded because it has been a useful construct that allows grouping of patients for research, especially in treatment trials. However this success has served to hide its limitations and molecular genetic analysis has clearly shown that there are other ways of thinking about neurodegenerative disease. In this review, I will summarize the limitations of the clinicopathological approach, and discuss how molecular genetics offers an alternative way of thinking about neurodegeneration. My intention is not to suggest that we should replace the clinicopathological approach (Newtonian physics is a perfectly good way of thinking about the world on a day-to-day basis even though we know it is only an approximation to the truth) but rather, to suggest that future treatments for these most devastating diseases may come from a deeper understanding of their related pathogenesis.
Alzheimer Disease↗
Natural antioxidants and neurodegenerative diseases.
Neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD) diseases are defined by a progressive neuronal dysfunction and an ensuing behavioral dysfunction. Although protein aggregation (i.e beta-amyloid and alpha-synuclein) plays a pivotal role in both AD and PD, there is increasing evidence that excessive accumulation of reactive oxygen species (ROS) that occurs during normal and pathological brain aging contributes to neuronal losses and dysfunction. Based on these observations, it has been hypothesized that natural antioxidants derived from food, beverages and natural extracts may be beneficial to prevent or delay the occurrence of age-related cognitive deficits and neurodegenerative diseases. We will summarize in this review the role of oxidative stress in pathological brain aging, and provide evidence for a role for antioxidant molecules as therapeutic agents. We will also focus on the various mechanisms underlying their neuroprotective effects in in vivo and in vitro models of neurotoxicity.
Acetylcarnitine↗
Differential vulnerability to excitatory amino acid-induced toxicity and selective neuronal loss in neurodegenerative diseases.
Neurodegenerative diseases are characterized by selective degeneration of certain biochemically distinct subpopulations of central neurons. Studies of the intrinsic vulnerability of such neurons to injury by excitatory amino acids in vitro, as well as study of neurologic syndromes produced in animals or humans by ingestion of environmental excitatory amino acid neurotoxins may suggest a link between excitotoxicity, and the pathogenesis of certain neurodegenerative diseases.
Amino Acids↗
Issues for clinical drug development in neurodegenerative diseases.
Neurodegenerative diseases pose specific challenges for drug development. These diseases typically have a slow and variable clinical course, an insidious onset, and symptom expression is only observed when a significant proportion of neurons are already lost. It is important to identify vulnerability factors and other determinants of clinical course in order to be able in the future to select patient populations for clinical trials with a predictable prognosis. The neurodegenerative process itself is not amenable to direct observation and, thus, cannot be monitored in clinical trials. For this reason, surrogate biomarkers are required for use as outcome parameters. In this respect, magnetic resonance imaging has proved valuable for assessing disease activity and progression in multiple sclerosis. Rating scales are of use as outcome measures but, as these generally measure symptom severity, they are most appropriate for use in assessing symptomatic treatments. Survival has been used with success as an outcome measure in trials in amyotrophic lateral sclerosis, where disease progression is rapid. The optimal outcome measure, the sample size required and the treatment duration need to be chosen in relation to the phase of the disease. Potential new treatments can be chosen based upon new knowledge of the genetics and physiopathology of neurodegenerative diseases and, in some cases, screened in transgenic mouse models, although it should be recognised that the validity of these models in terms of treatment response has yet to be established empirically.
Animals↗
Role of oxidative stress and antioxidants in neurodegenerative diseases.
Neurodegenerative diseases (NDD) are a group of illness with diverse clinical importance and etiologies. NDD include motor neuron disease such as amyotrophic lateral sclerosis (ALS), cerebellar disorders, Parkinson's disease (PD), Huntington's disease (HD), cortical destructive Alzheimer's disease (AD) and Schizophrenia. Numerous epidemiological and experimental studies provide many risk factors such as advanced age, genetic defects, abnormalities of antioxidant enzymes, excitotoxicity, cytoskeletal abnormalities, autoimmunity, mineral deficiencies, oxidative stress, metabolic toxicity, hypertension and other vascular disorders. Growing body of evidence implicates free radical toxicity, radical induced mutations and oxidative enzyme impairment and mitochondrial dysfunction due to congenital genetic defects in clinical manifestations of NDD. Accumulation of oxidative damage in neurons either primarily or secondarily may account for the increased incidence of NDD such as AD, ALS and stroke in aged populations. The molecular mechanisms of neuronal degeneration remain largely unknown and effective therapies are not currently available. Recent interest has focused on antioxidants such as carotenoids and in particular lycopene, a potent antioxidant in tomatoes and tomato products, flavonoids and vitamins as potentially useful agents in the management of human NDD. The pathobiology of neurodegenerative disorders with emphasis on genetic origin and its correlation with oxidative stress of neurodegenerative disorders will be reviewed and the reasons as to why brain constitutes a vulnerable site of oxidative damage will be discussed. The article will also discuss the potential free radical scavenger, mechanism of antioxidant action of lycopene and the need for the use of antioxidants in the prevention of NDD.
Alzheimer Disease↗
[Therapeutic potential of fetal neuron grafts in neurodegenerative diseases].
Neurodegenerative diseases are a major public health problem since they affect as a mean 1% of the people in industrialized countries, and will progress along with the ageing of the population. For ten years, a major research endeavor aims at developing new therapeutics against these diseases. These new approaches are based either on the substitution of affected neurons by homogous neuroblasts that are able to replace them anatomically and functionally (fetal neural grafts), or on the use of neuroprotective proteins (by gene therapy) that are able to promote natural defenses of neural cells. Clinical results have been obtained with fetal neural transplants over the past decade, in patients with Parkinson's and, more recently, Huntington's disease. The neuroprotective approach is under evaluation.
Embryo, Mammalian↗
Protein aggregation and neurodegenerative disease.
Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.
Amyloid beta-Peptides↗
[Experimentation in persons wtih a neurodegenerative disease].
Neurodegenerative diseases, of which the Alzheimer's disease, are more and more frequently the object of researches and new experiments. One wishes these experiments to be promising. Experiment with persons affected by a degenerative disease can begin at a moment when the subject is capable, and can be pursued beyond his incapacity. Law authorizes that a person of full age incapable of giving consent be subject of experiment. On the other hand, from the report of the incapacity, consent has to come from the legal representative: the mandatary, tutor or curator. The mandate given in anticipation of the mandator's incapacity empowers another person (the mandatary) to represent her. The use of this mandate confines the inconveniences of the mandator's incapacity to an interruption of the experiment for a duration of some weeks.
Clinical Trials as Topic↗
14-3-3 protein, total tau and phosphorylated tau in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease and neurodegenerative disease in Japan.
1. Sporadic Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and fatal disease. Patients with CJD usually become akinetic mutism within approximately 6 months. In addition, clinical signs and symptoms at early stage of sporadic CJD may not be easy to distinguish from other neurodegenerative diseases by neurological findings. However, diagnostic biochemical parameters including 14-3-3 protein, S100, neuron-specific enorase in cerebrospinal fluid (CSF) have been used as diagnostic markers, elevated titers of these markers can also be observed in CSF in other neurodegenerative diseases. Therefore, we examined other biochemical markers to discriminate CJD from other neurodegenerative diseases in CSF. 2. We analyzed CSF samples derived from 100 patients with various neurodegenerative disorders by Western blot of 14-3-3 protein, quantification of total tau (t-tau) protein, and phosphorylated tau (p-tau) protein. All patients with CJD in this study showed positive 14-3-3 protein and elevated t-tau protein (>1000 pg/mL) in CSF. We also detected positive 14-3-3 protein bands in two patients in non-CJD group (patients with dementia of Alzheimer's type; DAT) and also detected elevated t-tau protein in three patients in non-CJD group. Elevated t-tau protein levels were observed in two patients with DAT and in one patient with cerevrovascular disease in acute phase. 3. To distinguish patients with CJD from non-CJD patients with elevated t-tau protein in CSF, we compared the ratio of p-tau and t-tau proteins. The p-/t-tau ratio was dramatically and significantly higher in DAT patients rather than in CJD patients. 4.Therefore, we concluded that the assay of t-tau protein may be useful as 1st screening and the ratio of p-tau protein/t-tau protein would be useful as 2nd screening to discriminate CJD from other neurodegenerative diseases.
14-3-3 Proteins↗
Apoptosis as a general cell death pathway in neurodegenerative diseases.
Neurodegenerative processes are generally characterized by the long-lasting course of neuronal death and the selectivity of the neuronal population or brain structure involved in the lesion. Two main common forms of cell death that have been described in neurons as in other vertebrate tissues i.e., necrosis and apoptosis. Necrosis is the result of cellular "accidents", such as those occurring in tissues subjected to chemical trauma. The necrotizing cells swell, rupture and provoke an inflammatory response. Apoptosis, on the other hand, is dependent on the cell's "decision" to commit suicide and die, and therefore is referred to as "programmed cell death" (PCD). The course of apoptotic death is characterized by a massive morphological change, including cell shrinkage, nuclear (chromosome) condensation and DNA degradation. Activation of PCD in an individual cell is based on its own internal metabolism, environment, developmental background and its genetic information. Such a situation occurs in most of the neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis (ALS). In these pathological situations, specific neurons undergo apoptotic cell death characterized by DNA fragmentation, increased levels of pro-apoptotic genes and "apoptotic proteins" both, in human brain and in experimental models. It is of utmost importance to conclusively determine the mode of cell death in neurodegenerative diseases, because new "anti-apoptotic" compounds may offer a means of protecting neurons from cell death and of slowing the rate of cell degeneration and illness progression.
Alzheimer Disease↗
Transglutaminase-catalyzed reactions responsible for the pathogenesis of celiac disease and neurodegenerative diseases: from basic biochemistry to clinic.
Transglutaminases (TGases) are enzymes which catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate with the formation of an N-gamma-(epsilon-L-glutamyl)-L-lysine [GGEL] cross link (isopeptidic bond) and the concomitant release of ammonia. Such cross-linked proteins are often highly insoluble. The TGases are closely related enzymes and can also catalyze other important reactions for cell life. Recently, several findings concerning the relationships between the biochemical activities of the TGases and the basic molecular mechanisms responsible for some human diseases, have been reported. For example, some neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), supranuclear palsy, etc., are characterized in part by aberrant cerebral TGase activity and by increased cross-linked proteins in affected brains. Our article describes the biochemistry and the physio-pathological roles of the TGase enzymes, with particular reference to human pathologies in which the molecular mechanism of disease can be due to biochemical activities of the tissue TGase enzyme (tTGase, type 2), such as in a very common human disease, Celiac Disease (CD), and also in certain neuropsychiatric disorders.
Brain↗
Dental treatment of patients with neurodegenerative disease.
Neurodegenerative disorders are among the most challenging and devastating illnesses in medicine. A heterogeneous group of chronic and progressive diseases, they include Alzheimer's, Parkinson's, and Huntington's diseases. Dentists faced with patients affected by one of these disorders are confronted with the major problems of cognition, mobility, and behaviour, as well as of dental maintenance. While treatment of patients with progressive neurodegeneration remains daunting, increased knowledge of the aetiology and pathogenesis of these diseases has provided new opportunities and a new understanding of their treatment needs. In this article, we briefly describe the effects of ageing on the brain, and introduce two of the major neurodegenerative disorders, Alzheimer's and Parkinson's diseases. The dental problems associated with these conditions include a decrease in oral hygiene, difficulty in controlling and retaining dentures, and purposeless chewing. Medications can result in xerostomia and consequent root caries and recurrent decay. Where possible, individuals with neurodegenerative disorders should always be treated by the same dentist.
Aging↗