Forms Of Neurodegenerative Diseases Research Articles

Chronic traumatic encephalopathy: the nature, mechanisms and stages of development

The survey provides data on the history of discovery and the epidemiology of chronic traumatic encephalopathy, which can occur after a single or repeated mild traumatic brain injury. Chronic traumatic encephalopathy has a nearly century-long history and was first identified in boxing veterans. Initially, signs of progressive neurological disease (punch-drunk), which occurred after repeated multiple traumatic brain injury in boxers, were described. Other sport activities alongside with box, associated with repeated mild brain injuries may cause dementia and neurodegenerative diseases. That led to the use of the term “chronic traumatic encephalopathy” (CTE). The features of the disease are defined, namely, that it occurs many years after the injury and develops in very small percentage of persons experienced a head injury, and clinically it resembles such neurodegenerative disorders as Parkinson’s and Alzheimer’s diseases. The paper deals with the pathogenesis associated with the accumulation of beta amyloid, tau protein, the development of neuro-inflammation and immune-associated reactions, including intracerebral local and systemic immune processes. The review indicates the role of genetic susceptibility, resistance to injury, gender, physiological stress, environmental exposure and age in the development of CTE.The significance of immune responses and inflammation in the development of various forms of neurodegenerative diseases and CTE is widely recognized, but the mechanisms of the immunoprotective and immunodegenerative actions are still not well understood and require special experimental studies. The review notes different role of immune responses in the pathogenesis at certain stages of development of CTE.The protective and immunopathological mechanisms of chronic traumatic encephalopathy are analyzed in detail; three main periods of its development have been identified, and new approaches to the study and treatment have been outlined.

Parkinson’s disease: Etiopathogenesis, molecular basis and potential treatment opportunities

Neurodegenerative diseases affect the life quality and lifespan of aging populations. Among all forms of neurodegenerative diseases, Parkinson’s disease (PD) has a massive impact on the elderly. Oxidative stress and mitochondrial dysfunction are the main causes of neurodegeneration and progression of PD. Oxidative stress, which plays a vital role in the pathophysiology of PD, is related to the dysfunction of cellular antioxidant mechanisms as a result of enhanced production of reactive oxygen species. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of neurodegeneration and medications are available, but these only treat the symptoms. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases, using suitable animal models. The review focuses on the role of oxidative stress in the pathogenesis of Parkinson’s disease and the protective potential of natural products against neurodegeneration.

An exTREMe disruption in Alzheimer's cleanup

Partial loss-of-function variants in the TREM2 immune receptor are associated with increased risk for Alzheimer's disease (AD) and other forms of neurodegenerative disease, but the molecular bases for these connections are unknown. Three new structures of WT and R47H mutant TREM2 immunoglobulin-like (Ig-like) domain now reveal that R47 functions to correctly position elements of the ligand-binding surface. Intriguingly, the authors also demonstrate a disruption of receptor oligomerization by the R47H mutation, suggesting a role for ligand-induced clustering in receptor signaling and resultant plaque clearance.

The axon degeneration gene SARM1 is evolutionarily distinct from other TIR domain-containing proteins.

Many forms of neurodegenerative disease are characterized by Wallerian degeneration, an active program of axonal destruction. Recently, the important player which enacts Wallerian degeneration was discovered, the multidomain protein SARM1. Since the SARM1 protein has classically been thought of as an innate immune molecule, its role in Wallerian degeneration has raised questions on the evolutionary forces acting on it. Here, we synthesize a picture of SARM1's evolution through various organisms by examining the molecular and genetic changes of SARM1 and the genes around it. Using proteins that possess domains homologous to SARM1, we established distances and Ka/Ks values through 5671 pairwise species-species comparisons. We demonstrate that SARM1 diverged across species in a pattern similar to other SAM domain-containing proteins. This is surprising, because it was expected that SARM1 would behave more like its TIR domain relatives. Going along with this divorce from TIR, we also noted that SARM1's TIR is under stronger purifying selection than the rest of the TIR domain-containing proteins (remaining highly conserved). In addition, SARM1's synteny analysis reveals that the surrounding gene cluster is highly conserved, functioning as a potential nexus of gene functionality across species. Taken together, SARM1 demonstrates a unique evolutionary pattern, separate from the TIR domain protein family.

Promotion of behavior and neuronal function by reactive oxygen species in C. elegans

Reactive oxygen species (ROS) are well known to elicit a plethora of detrimental effects on cellular functions by causing damages to proteins, lipids and nucleic acids. Neurons are particularly vulnerable to ROS, and nearly all forms of neurodegenerative diseases are associated with oxidative stress. Here, we report the surprising finding that exposing C. elegans to low doses of H2O2 promotes, rather than compromises, sensory behavior and the function of sensory neurons such as ASH. This beneficial effect of H2O2 is mediated by an evolutionarily conserved peroxiredoxin-p38/MAPK signaling cascade. We further show that p38/MAPK signals to AKT and the TRPV channel OSM-9, a sensory channel in ASH neurons. AKT phosphorylates OSM-9, and such phosphorylation is required for H2O2-induced potentiation of sensory behavior and ASH neuron function. Our results uncover a beneficial effect of ROS on neurons, revealing unexpected complexity of the action of oxidative stressors in the nervous system.

Stratifying Heterogeneous Dimension of Neurodegenerative Diseases: Intervention for Stipulating Epigenetic Factors to Combat Oxidative Stress in Human Brain

Neurodegenerative diseases affect the neurons of the human brain and decline the neural activities causing neurocognitive dysfunctions and brain and behavioral disorders. An intensive immunotherapy is used to alter the course of multiple sclerosis, a common form of neurodegeneration, by controlling oxidative stress, recovering mitochondrial injury, and rehabilitating channelopathy dysfunctions. However, little is known about how the epigenetic factors can regulate atrophy genesis at hippocampal region, which prevents neurodegeneration. Further, traumatic brain injury leads to neurodegeneration. However, the onset of the later is not yet successfully monitored. Simultaneously, discrimination between neurodegeneration due to ageing and traumatic brain injury has not been addressed in the existing literature. Therefore, we present different forms of traumatic brain injury that trigger neurotoxicity, leading to the classification of onset stage of neurodegenerative pathways. We discuss how the immune system orchestrates changes in neurogenesis in presence of physiological stimuli. In our view, the epigenetic mode of treatment successfully intervenes all forms of neurodegenerative disease in both ageing and traumatic condition. Here, we establish a cross talk between epigenetic factors and neural immunology to balance oxidative stress at hippocampal regions.

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling.

In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3–stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1564-y) contains supplementary material, which is available to authorized users.

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.

Amyloid-β in mitochondrial disease: mutation in a human metallopeptidase links amyloidotic neurodegeneration with mitochondrial processing.

There is increasing evidence that common molecular pathways in neurons are closely linked with mitochondrial function and that mitochondrial dysfunction is connected to various forms of neurodegenerative diseases. For instance, mitochondria are involved in amyloid‐β (Aβ) deposition in Alzheimer9s disease, although the exact molecular pathways remain largely unknown. Brunetti et al (2015) in this issue of EMBO Molecular Medicine provide a novel link between Aβ accumulation and mitochondria. A pathogenic mutation in a Norwegian family in the mitochondrial metallopeptidase PITRM1 is found to underlie a novel mitochondrial neurodegenerative phenotype associated with Aβ accumulation.

The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease: A Mini Review

Neurodegenerative diseases affect not only the life quality of aging populations, but also their life spans. All forms of neurodegenerative diseases have a massive impact on the elderly. The major threat of these brain diseases includes progressive loss of memory, Alzheimer's disease (AD), impairments in the movement, Parkinson's disease (PD), and the inability to walk, talk, and think, Huntington's disease (HD). Oxidative stress and mitochondrial dysfunction are highlighted as a central feature of brain degenerative diseases. Oxidative stress, a condition that occurs due to imbalance in oxidant and antioxidant status, has been known to play a vital role in the pathophysiology of neurodegenerative diseases including AD, PD, and HD. A large number of studies have utilized oxidative stress biomarkers to investigate the severity of these neurodegenerative diseases and medications are available, but these only treat the symptoms. In traditional medicine, a large number of medicinal plants have been used to treat the symptoms of these neurodegenerative diseases. Extensive studies scientifically validated the beneficial effect of natural products against neurodegenerative diseases using suitable animal models. This short review focuses the role of oxidative stress in the pathogenesis of AD, PD, and HD and the protective efficacy of natural products against these diseases.

Cell Cycle Proteins and Retinal Degeneration: Evidences of New Potential Therapeutic Targets.

During different forms of neurodegenerative diseases, including the retinal degeneration, several cell cycle proteins are expressed in the dying neurons from Drosophila to human revealing that these proteins are a hallmark of neuronal degeneration. This is true for animal models of Alzheimer's, and Parkinson's diseases, Amyotrophic Lateral Sclerosis and for Retinitis Pigmentosa as well as for acute injuries such as stroke and light damage. Longitudinal investigation and loss-of-function studies attest that cell cycle proteins participate to the process of cell death although with different impacts, depending on the disease. In the retina, inhibition of cell cycle protein action can result to massive protection. Nonetheless, the dissection of the molecular mechanisms of neuronal cell death is necessary to develop adapted therapeutic tools to efficiently protect photoreceptors as well as other neuron types.

Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis.

KIF1A gene encodes the kinesin 1a protein, an axonal motor protein working in cargo transport along neurites. Variants in KIF1A were identified in different forms of neurodegenerative diseases with dominant and recessive inheritance. Homozygous recessive mutations were found in the hereditary sensory and autonomic neuropathy type 2, HSAN2 and in a recessive subtype of hereditary spastic paraparesis, SPG30. De novo heterozygous dominant variants were found both in a dominant form of SPG30 (AD-SPG30) with one single family reported and in patients with different forms of progressive neurodegenerative diseases. We report the results of a genetic screening of 192 HSP patients, with the identification of four heterozygous variants in KIF1A in four cases, two of whom with family history for the disease. Three of the four variants fall within the motor domain, a frequent target for variants related to the AD-SPG30 subtype. The fourth variant falls downstream the motor domain in a region lacking any functional domain. The KIF1A-related patients show clinical pictures overlapping the known AD-SPG30 phenotype including pure and complicated forms with few differences. Of note, one of the families, originating from the Sicily island, carries the same variant p.S69L detected in the first AD-SPG30 family of Finnish origin reported; differently from the first one, the latter family shows a wide intra-familial phenotype variability. Overall, these data reveal a very low frequency of the AD-SPG30 subtype while confirming the presence of amino acid residues in the motor domain representing preferential targets for mutations, thereby supporting their functional relevance in kinesin 1a activity.

R-Ras contributes to LTP and contextual discrimination

The ability to discriminate between closely related contexts is a specific form of hippocampal-dependent learning that may be impaired in certain neurodegenerative disorders such as Alzheimer’s and Down Syndrome. However, signaling pathways regulating this form of learning are poorly understood. Previous studies have shown that the calcium-dependent exchange factor Ras-GRF1, an activator of Rac, Ras and R-Ras GTPases, is important for this form of learning and memory. Moreover, the ability to discriminate contexts was linked to the ability of Ras-GRF1 to promote high-frequency stimulation long-term potentiation (HFS-LTP) via the activation of p38 Map kinase. Here, we show that R-Ras is involved in this form of learning by using virally-delivered miRNAs targeting R-Ras into the CA1 region of the dorsal hippocampus and observing impaired contextual discrimination. Like the loss of GRF1, knockdown of R-Ras in the CA1 also impairs the induction of HFS-LTP and p38 Map kinase. Nevertheless, experiments indicate that this involvement of R-Ras in HFS-LTP that is required for contextual discrimination is independent of Ras-GRF1. Thus, R-Ras is a novel regulator of a form of hippocampal-dependent LTP as well as learning and memory that is affected in certain forms of neurodegenerative diseases.

Extending technology-aided leisure and communication programs to persons with spinal cord injury and post-coma multiple disabilities

Purpose: These two studies extended technology-aided programs to promote leisure and communication opportunities to a man with cervical spinal cord injury and a post-coma man with multiple disabilities. Method: The studies involved the use of ABAB designs, in which A and B represented baseline and intervention phases, respectively. The programs focused on enabling the participants to activate songs, videos, requests, text messages, and telephone calls. These options were presented on a computer screen and activated through a small pressure microswitch by the man with spinal cord injury and a special touch screen by the post-coma man. To help the latter participant, who had no verbal skills, with requests and telephone calls, series of words and phrases were made available that he could activate in those situations. Results: Data showed that both participants were successful in managing the programs arranged for them. The man with spinal cord injury activated mean frequencies of above five options per 10-min session. The post-coma man activated mean frequencies of about 12 options per 20-min session. Conclusions: Technology-aided programs for promoting leisure and communication opportunities might be successfully tailored to persons with spinal cord injury and persons with post-coma multiple disabilities.Implications for RehabilitationTechnology-aided programs may be critical to enable persons with pervasive motor impairment to engage in leisure activities and communication events independently.Persons with spinal cord injury, post-coma extended brain damage, and forms of neurodegenerative disease, such as amyotrophic lateral sclerosis, may benefit from those programs.The programs could be adapted to the participants’ characteristics, both in terms of technology and contents, so as to improve their overall impact on the participants’ functioning and general mood.

Mitochondrial-Targeted Protective Properties of Isolated Diterpenoids from Sideritis spp. in Response to the Deleterious Changes Induced by H2O2

Mitochondrial impairment and oxidative stress are considered widely to be central events in many forms of neurodegenerative disease. The current study has evaluated for the first time the potential protective role of three diterpenoids [andalusol (1), conchitriol (2), and lagascatriol (3)] in response to the deleterious H2O2-induced changes on mitochondrial function. U373-MG human astrocytoma cells and PC12 rat adrenal pheochromocytoma cells were used as models for evaluating the cytoprotective potential of these compounds. In the absence of diterpenoids 1-3, H2O2 compromised mitochondrial function, decreasing mitochondrial membrane potential and ATP levels, increasing caspase-3 activity, and disrupting cytosolic and mitochondrial calcium homeostasis. However, treatment with the diterpenoids, prior to H2O2, prevented these mitochondrial perturbations. In particular, 1 and 3 were the most effective compounds in protecting mitochondrial function against H2O2-induced oxidative stress in U373-MG, whereas all three diterpenoids studied were significantly active against PC12 cells. Since consistent evidence has demonstrated the contribution of H2O2 on both progression and pathological development of several human diseases associated with mitochondrial function and oxidative stress responses, compounds 1-3 are worthy of further investigation.

Apathy and Related Executive Syndromes in Dementia Associated with Parkinson’s Disease and in Alzheimer’s Disease

Apathy is defined as a lack of motivation and has been reported to be common in Alzheimer’s disease (AD) and Parkinson's disease (PD). To explore the neuropsychological correlates of apathy in patients with PD related dementia (PDD) and AD and to identify the specific cognitive profile of apathy in the two forms of neurodegenerative disease, 61 non-depressed patients (29 PDD and 32 AD) were selected. Out of these, 29 patients (47.5%) were detected as apathetic (14 PDD-A+ and 15 AD-A+), and 32 patients as non-apathetic (15 PDD-A- and 17 AD-A-). All patients underwent cognitive tasks tapping memory, visuospatial and executive functions, behavioral rating scales and Clinical Judgment for Apathy Syndrome (CJ-AS), an inventory developed to measure severity of apathy.The four subgroups differed significantly on memory and frontal tasks. The PDD-A+ performed significantly worse than PDD-A- on frontal tasks. The AD-A+ had poorer performance than AD-A- on frontal tasks. Last, PDD-A+ achieved significantly higher scores than AD-A+ on memory tasks. The four groups differed significantly on CJ-AS and behavioral rating scales.The results showed that apathetic patients with both forms of dementia showed a common neuropsychological and behavioral picture, characterized by defects on frontal tasks, thus strongly supporting the existence of an ‘apathetic syndrome’, characterized by specific cognitive and psychological symptoms.

Apathy and related executive syndromes in dementia associated with Parkinson's disease and in Alzheimer's disease.

Apathy is defined as a lack of motivation and has been reported to be common in Alzheimer’s disease (AD) and Parkinson's disease (PD). To explore the neuropsychological correlates of apathy in patients with PD related dementia (PDD) and AD and to identify the specific cognitive profile of apathy in the two forms of neurodegenerative disease, 61 non-depressed patients (29 PDD and 32 AD) were selected. Out of these, 29 patients (47.5%) were detected as apathetic (14 PDD-A+ and 15 AD-A+), and 32 patients as non-apathetic (15 PDD-A- and 17 AD-A-). All patients underwent cognitive tasks tapping memory, visuospatial and executive functions, behavioral rating scales and Clinical Judgment for Apathy Syndrome (CJ-AS), an inventory developed to measure severity of apathy.The four subgroups differed significantly on memory and frontal tasks. The PDD-A+ performed significantly worse than PDD-A- on frontal tasks. The AD-A+ had poorer performance than AD-A- on frontal tasks. Last, PDD-A+ achieved significantly higher scores than AD-A+ on memory tasks. The four groups differed significantly on CJ-AS and behavioral rating scales.The results showed that apathetic patients with both forms of dementia showed a common neuropsychological and behavioral picture, characterized by defects on frontal tasks, thus strongly supporting the existence of an ‘apathetic syndrome’, characterized by specific cognitive and psychological symptoms.

Interaction of Heme Proteins with Anionic Polyfluorene: Insights into Physiological Effects, Folding Events, and Inhibition Activity

Because of the toxicity caused by the heme redox-active iron proteins, their elevated levels, localization, and accumulation in the brain, many forms of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, occur as a result of which the brain becomes vulnerable to oxidative stress, ultimately resulting in neuronal death. An anionic water-soluble conjugated polyfluorene derivative poly(9,9-bis(6-sulfate hexyl) fluorene-alt-1,4-phenylene) sodium salt (P1) that binds Fe³⁺ proteins with very high selectivity and sensitivity is reported here. The photophysical properties of P1 were modified by the interaction with ferric heme-containing proteins cytochrome c (Cc), methemoglobin (MetHb), and hemin. P1 was found to be highly sensitive toward Fe³⁺ heme proteins as compared to nonmetalloproteins. We observed that the respective activities of ferric heme proteins were inhibited and proteins were unfolded, due to modification in their heme microenvironment in the presence of the polymer P1. The observations reported in this article provide the first example for the use of a water-soluble conjugated polymer in applications, such as (1) to detect small quantities of iron proteins in aqueous medium/physiological condition with the highest K(sv) values of 2.27 × 10⁸ M⁻¹ for Cc, 3.81 × 10⁷ M⁻¹ for MetHb, and 5.31 × 10⁷ M⁻¹ for hemin; (2) to study the physiological effects of heme metalloproteins; (3) to visualize the folding events in real time; and (4) the inhibition activity of metalloproteins can be selectively studied using a conjugated polymer based assay system rapidly without interference from nonmetalloproteins at biological pH. All this is achieved by generating optical events, taking advantage of the bright fluorescence of anionic polyfluorene P1 in this case, that can be observed and monitored by modification in the absorption and emission color in real time.

Clinical and laboratory features of progressive supranuclear palsy: five cases retrospective analysis

Progressive supranuclear palsy (PSP) is a form of neurodegenerative disease which affects the brainstem and basal ganglia. Patients present supranuclear ophthalmoplegia, postural instability and mild dementia. We analyzed five cases of PSP from 1 January 2005 to 31 December 2009. All patients underwent a memory test, autonomic examination, brain magnetic resonance imaging (MRI) and they evaluated by formal neurologic examination. All were taking L-dopa or dopamine agonists. At the onset of PSP the initial diagnosis was Parkinson’s disease in all patients. The brain MRI findings were revealed severe midbrain atrophy, while mini-mental state examination disclosed cognitive impairment, with predominant subcorticalfrontal involvement. Autonomic tests were failure in three of the patients. We emphasize the still obvious current difficulty in diagnosing PSP at an early stage in clinical practice. Therefore it is essential to formulate better clinical diagnostic criteria, to permit correct management of the disease.

Neuroprotective role of estrogens: relationship with insulin/IGF-1 signaling

Postmenopausal women have an elevated risk of developing a neurodegenerative disease. These clinical observation supported by basic research, suggest that estrogens are neuroprotective. Insulin resistance represents an independent factor in the etiology of age-associated disease and metabolic syndrome should be considered as a contributing factor to the higher post-menopausal vulnerability to neurological disorders. Elucidating the relationship between insulin resistance associated with aging in females, and the cross-talk between estradiol, insulin, and insulin-like growth factor (IGF-1) signaling pathways, will lead to a more complete understanding of the mechanism underlying estradiol-mediated neuroprotection. In past decades, estrogen replacement therapy (ERT) was commonly used as a palliative therapy during menopause, but the mid-term and long-term effects of estrogen as possible promoters of breast cancer and the increased risk of coronary illness or stroke, has limited current usage. A deeper understanding of the molecular mechanisms common to all forms of neurodegenerative diseases may hasten the development of protective strategies against chronic age-related deterioration and acute illness, ultimately providing a better quality of life for the elderly.