Forms Of Neurodegenerative Diseases Research Articles

Hydrogen sulfide signalling in neurodegenerative diseases.

The gaseous neurotransmitter hydrogen sulfide (H2 S) exerts neuroprotective efficacy in the brain via post-translational modification of cysteine residues by sulfhydration, also known as persulfidation. This process is comparable in biological impact to phosphorylation and mediates a variety of signalling events. Unlike conventional neurotransmitters, H2 S cannot be stored in vesicles due to its gaseous nature. Instead, it is either locally synthesized or released from endogenous stores. Sulfhydration affords both specific and general neuroprotective effects and is critically diminished in several neurodegenerative disorders. Conversely, some forms of neurodegenerative disease are linked to excessive cellular H2 S. Here, we review the signalling roles of H2 S across the spectrum of neurodegenerative diseases, including Huntington's disease, Parkinson's disease, Alzheimer's disease, Down syndrome, traumatic brain injury, the ataxias, and amyotrophic lateral sclerosis, as well as neurodegeneration generally associated with ageing.

Multi-speed transformer network for neurodegenerative disease assessment and activity recognition

Background and objectiveNeurodegenerative diseases are the most frequent age-related diseases. This type of disease, if not discovered in the initial stage, will compromise the quality of life of the affected subject. Thus, a timely diagnosis is of paramount importance. One of the most used tasks from neurologists to detect and determine the severity of the disease is analysing human gait. This work presents the dataset named “Beside Gait” containing timeseries of coordinates of extracted body joints of people with neurodegenerative diseases in various stages of the disease as well as control subjects. In addition, the novel Multi-Speed transformer technique will be presented and benchmarked against several other techniques making use of deep learning and Shallow Learning. The objective is to recognize subjects affected by some form of neurodegenerative disease in early stage using a computer vision technique making use of deep learning that can be integrated into a smartphone app for offline inference with the aim of promptly initiate investigations and treatment to improve the patient's quality of life. MethodsThe recorded videos were processed, and the skeleton of the person in the video was extracted using pose estimation. The raw time-series coordinates of the joints extracted by the pose estimation algorithm were tested against novel deep neural network architectures and Shallow Learning techniques. In this work, the proposed Multi-Speed Transformer is benchmarked against other deep neural networks such as Temporal Convolutional Neural Networks, Transformers, as well as Shallow Learning techniques making use of feature extraction and different classifiers such as Random Forests, K Nearest Neighbours, Ada Boost, Linear and RBF SVM. The proposed Multi-Speed Transformer architecture has been developed to learn short and long-term patterns to model the various pathological gaits. ResultsThe Multi-Speed Transformer outperformed all other existing models reaching an accuracy of 96.9%, a sensitivity of 96.9%, a precision of 97.7%, and a specificity of 97.1% in binary classification. The accuracy in multi-class classification for detecting the presence of the disease in various stages is 71.6%, the sensitivity is 67.7%, and the specificity is 71.8%. In addition, tests have also been conducted against two other different activity recognition datasets, namely SHREC and JHMDB, in the exact same conditions. Multi-Speed Transformer has demonstrated to beat always all other tested techniques as well as the techniques reviewed in the state-of-the-art with respectively of accuracy 91.8% and 74%. Having those datasets more than two classes, specificity was not computed. ConclusionsThe Multi-Speed Transformer is a valuable technique for neurodegenerative disease assessment through computer vision. In addition, the novel dataset “Beside Gait” here presented is an important starting point for future research work on automatic recognition of neurodegenerative diseases using gait analysis.

Inhibitory Control of Saccadic Eye Movements and Cognitive Impairment in Mild Cognitive Impairment

AbstractBackgroundMild cognitive impairment (MCI) may occur due to several forms of neurodegenerative diseases and non‐degenerative conditions and is associated with cognitive impairment that does not affect everyday activities. For a timely diagnosis of MCI to prevent progression to dementia, a screening tool of fast, low‐cost and easy access is needed. Recent research on eye movement hints it a potential application for the MCI screening. However, the precise extent of cognitive function decline and eye‐movement control alterations in patients with MCI is still unclear.MethodPatients with MCI (n = 79) and age‐matched cognitively healthy controls (HC) (n = 170) completed four saccadic eye‐movement paradigms: prosaccade (PS)/antisaccade (AS), Go/No‐go, and a battery of neuropsychological tests.ResultThe findings revealed significantly longer latency in patients with MCI than in HC during the PS task. Additionally, patients with MCI had a lower proportion of correct responses and a marked increase in inhibition errors for both PS/AS and Go/No‐go tasks. Furthermore, when patients with MCI made errors, they failed to self‐correct many of these inhibition errors. In addition to the increase in inhibition errors and uncorrected inhibition errors, patients with MCI demonstrated a trend toward increased correction latencies. We also showed a relationship between neuropsychological scores and correct and error saccade responses.ConclusionOur results demonstrate that, similar to patients with Alzheimer’s dementia (AD), patients with MCI generate a high proportion of erroneous saccades toward the prepotent target and fail to self‐correct many of these errors, which is consistent with an impairment of inhibitory control and error monitoring.

Shen Qi Wan Ameliorates Learning and Memory Impairment Induced by STZ in AD Rats through PI3K/AKT Pathway

Alzheimer’s disease is the most common form of neurodegenerative disease, and increasing evidence shows that insulin signaling has crucial roles in AD initiation and progression. In this study, we explored the effect and underlying mechanism of SQW, a representative formula for tonifying the kidney and promoting yang, on improving the cognitive function in a streptozotocin-induced model of AD rats. We investigated memory impairment in the AD rats by using the Morris water test. HE and Nissl staining were employed to observe the histomorphological changes in the hippocampal. Expression levels of NeuN and proteins related to Tau and apoptosis were measured using immunohistochemistry and Western blotting, respectively. Additionally, we performed RNA sequencing, and the selected hub genes were then validated by qRT-PCR. Furthermore, the protein expression levels of PI3K/AKT pathway-related proteins were detected by Western blot. We found that SQW treatment significantly alleviated learning and memory impairment, pathological damage, and apoptosis in rats, as evidenced by an increased level of NeuN and Bcl-2, and decreased phosphorylation of Tau, Bax, and Caspase-3 protein expression. SQW treatment reversed the expression of insulin resistance-related genes (Nr4a1, Lpar1, Bdnf, Atf2, and Ppp2r2b) and reduced the inhibition of the PI3K/AKT pathway. Our results demonstrate that SQW could contribute to neuroprotection against learning and memory impairment in rats induced by STZ through activation of the PI3K/AKT pathway.

Inhibitory Control of Saccadic Eye Movements and Cognitive Impairment in Mild Cognitive Impairment.

BackgroundMild cognitive impairment (MCI) may occur due to several forms of neurodegenerative diseases and non-degenerative conditions and is associated with cognitive impairment that does not affect everyday activities. For a timely diagnosis of MCI to prevent progression to dementia, a screening tool of fast, low-cost and easy access is needed. Recent research on eye movement hints it a potential application for the MCI screening. However, the precise extent of cognitive function decline and eye-movement control alterations in patients with MCI is still unclear.ObjectiveThis study examined executive control deficits and saccade behavioral changes in patients with MCI using comprehensive neuropsychological assessment and interleaved saccade paradigms.MethodsPatients with MCI (n = 79) and age-matched cognitively healthy controls (HC) (n = 170) completed four saccadic eye-movement paradigms: prosaccade (PS)/antisaccade (AS), Go/No-go, and a battery of neuropsychological tests.ResultsThe findings revealed significantly longer latency in patients with MCI than in HC during the PS task. Additionally, patients with MCI had a lower proportion of correct responses and a marked increase in inhibition errors for both PS/AS and Go/No-go tasks. Furthermore, when patients with MCI made errors, they failed to self-correct many of these inhibition errors. In addition to the increase in inhibition errors and uncorrected inhibition errors, patients with MCI demonstrated a trend toward increased correction latencies. We also showed a relationship between neuropsychological scores and correct and error saccade responses.ConclusionOur results demonstrate that, similar to patients with Alzheimer’s dementia (AD), patients with MCI generate a high proportion of erroneous saccades toward the prepotent target and fail to self-correct many of these errors, which is consistent with an impairment of inhibitory control and error monitoring.SignificanceThe interleaved PS/AS and Go/No-go paradigms are sensitive and objective at detecting subtle cognitive deficits and saccade changes in MCI, indicating that these saccadic eye movement paradigms have clinical potential as a screening tool for MCI.

Effects of DISC1 on Alzheimer's disease cell models assessed by iTRAQ proteomics analysis.

Alzheimer’s disease (AD) is a form of neurodegenerative disease in the elderly with no cure at present. In a previous study, we found that the scaffold protein, disrupted in Schizophrenia 1 (DISC1) is down-regulated in the AD brains, and ectopic expression of DISC1 can delay the progression of AD by protecting synaptic plasticity and down-regulating BACE1. However, the underlying mechanisms remain not to be elucidated. In the present study, we compared the proteomes of normal and DISC1high AD cells expressing the amyloid precursor protein (APP) using isobaric tag for relative and absolute quantitation (iTRAQ) and mass spectrometry (MS). The differentially expressed proteins (DEPs) were identified, and the protein–protein interaction (PPI) network was constructed to identify the interacting partners of DISC1. Based on the interaction scores, NDE1, GRM3, PTGER3 and KATNA1 were identified as functionally or physically related to DISC1, and may therefore regulate AD development. The DEPs were functionally annotated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases with the DAVID software, and the Non-supervised Orthologous Groups (eggNOG) database was used to determine their evolutionary relationships. The DEPs were significantly enriched in microtubules and mitochondria-related pathways. Gene set enrichment analysis (GSEA) was performed to identify genes and pathways that are activated when DISC1 is overexpressed. Our findings provide novel insights into the regulatory mechanisms underlying DISC1 function in AD.

Is pseudoexfoliation glaucoma a neurodegenerative disorder?

Pseudoexfoliation (PEX) is a systemic age-related progressive disorder with ocular manifestations. The earlier stage of the disease, pseudoexfoliation syndrome (PEXS) involves deposition of white fibrillar aggregates on anterior and posterior eye tissues. It is also the cause of most common form of secondary glaucoma known as pseudoexfoliation glaucoma (PEXG). Studies in the past decade highlight the role of many genetic and environmental factors as the underlying cause of PEX pathogenesis. Latest research findings by various researchers and us present the view of PEX as a type of neurodegenerative disorder. Epidemiological studies have shown association of PEX with different forms of neurodegenerative diseases like Alzheimer's, agerelated macular degeneration and open angle glaucoma. Also, sharing of common genetic risk factors, abnormal protein aggregation and most importantly, progressive degeneration of neurons with age are some of the identifiable features seen in both PEX and other neurodegenerative diseases. In this review, we have compared the pathological symptoms and factors involved in the disease manifestation of PEXG with various forms of neurodegenerative disorders and categorized PEXG as a progressive neurodegenerative disorder.

A comparative and comprehensive study of prediction of Parkinson’s disease

Objectives: Parkinson's Disease (PD) is a form of neurodegenerative disease that is caused the progressive weakening of dopaminergic nerve cells that affects a large number of people around the world. The event of recent treatment methods principally depends upon the experimental data resulting from assessment balances and patients’ journals that take varied boundaries with reference to legitimacy, inter-rater inconsistency, and incessant monitoring. Methods: Nowadays various techniques and algorithms are utilized in predicting the accuracy in PD. A range of those techniques, including SVM, Artificial Neural Network, Naive Bayes, Kernel based extreme learning through subtractive clustering landscapes, Random Forest, The Multi-Layer Perceptron with Back-Propagation Learning Algorithm are widely applied to form the acceptable decision accurately. During this work, and in-depth review was administered on various techniques proposed by numerous researchers. a replacement system must be proposed which uses DL techniques and considers other attributes of paralysis agitans which can improve the prediction and be an advancement within the medical field. Result: It has been observed that many researches have been done in identifying the PD yet there is a need of suitable method or algorithm to improve the prediction of PD which will help in the clinical management. Conclusion and Future work: Most of the methods have used speech as a major attribute for their research and have produced substantial accuracy. In order to increase the precision approaches involving movements, facial expression and other attributes also be considered for evaluation

Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity

BackgroundMany neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained.ResultsAnalyzing single-cell RNA sequencing from Alzheimer’s disease (AD) and Huntington’s disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/− cells, a model for autism spectrum disorder.ConclusionsOverall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.

Contribution of TRPC Channels in Neuronal Excitotoxicity Associated With Neurodegenerative Disease and Ischemic Stroke.

The seven canonical members of transient receptor potential (TRPC) proteins form cation channels that evoke membrane depolarization and intracellular calcium concentration ([Ca2+]i) rise, which are not only important for regulating cell function but their deregulation can also lead to cell damage. Recent studies have implicated complex roles of TRPC channels in neurodegenerative diseases including ischemic stroke. Brain ischemia reduces oxygen and glucose supply to neurons, i.e., Oxygen and Glucose Deprivation (OGD), resulting in [Ca2+]i elevation, ion dyshomeostasis, and excitotoxicity, which are also common in many forms of neurodegenerative diseases. Although ionotropic glutamate receptors, e.g., N-methyl-D-aspartate receptors, are well established to play roles in excitotoxicity, the contribution of metabotropic glutamate receptors and their downstream effectors, i.e., TRPC channels, should not be neglected. Here, we summarize the current findings about contributions of TRPC channels in neurodegenerative diseases, with a focus on OGD-induced neuronal death and rodent models of cerebral ischemia/reperfusion. TRPC channels play both detrimental and protective roles to neurodegeneration depending on the TRPC subtype and specific pathological conditions involved. When illustrated the mechanisms by which TRPC channels are involved in neuronal survival or death seem differ greatly, implicating diverse and complex regulation. We provide our own data showing that TRPC1/C4/C5, especially TRPC4, may be generally detrimental in OGD and cerebral ischemia/reperfusion. We propose that although TRPC channels significantly contribute to ischemic neuronal death, detailed mechanisms and specific roles of TRPC subtypes in brain injury at different stages of ischemia/reperfusion and in different brain regions need to be carefully and systematically investigated.

Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro

BackgroundAlzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1, and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of a mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs).Methods iPSC lines from patients suffering from a familial form of Alzheimer’s disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporter activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1, and lysosomal acidification by acridine orange.ResultsiPSC-derived BMECs from the FAD patient presenting a mutation in the PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to the control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Aβ1–40 peptides compared to control-BMECs.ConclusionsOur study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMEC metabolism. In particular, mutation in the PSEN1 gene was associated with a more detrimental phenotype than mutation in PSEN2, as noted by a reduced barrier function, reduced drug efflux pump activity, and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.

Speech and language disorders as core diagnostic tools for differentiation of neurodegenerative diseases

AbstractBackgroundA patient suffering from a neurodegenerative disease may demonstrate various combinations of dysarthria, aphasia, and apraxia. Besides, a speech disorder can be a primary and dominant sign (primary progressive aphasia or apraxia), or can develop secondarily as part of general clinical picture. No unified approach to classification and diagnostics of various speech disorder forms has been developed to date. Aim: to study speech disorders in various forms of neurodegenerative diseases, to assess common structure, clinical‐neuroimaging heterogeneity, and to develop a unified algorithm for differential diagnosis.Method1008 patients with neurodegenerative diseases were included in the study by continuous sampling of consultant practice specializing in neurodegenerations: 234 AD, 118 DLB, 62 FTD (behavior and language variants), 366 PD, 22 PSP, 14 CBS, and 292 patients with unspecified and other forms of neurodegenerative pathology. All patients were screened for cortical speech disorders (pure dysarthria was not considered). Patients demonstrating speech and language disorders were tested using the speech disorder assessment test battery we have developed. Structural MRI was performed for all the patients with speech and language disorders to assess ROI.Resultspeech and language disorders were identified in 41% of patients in aggregate group, 78% of AD, 48% of DLB, 31% of PD, 82% of FTD, 64% of PSP, and 96% of CBS patients. Based on the detailed speech assessment battery in aggregate group of all the neurodegenerative diseases 7 subtypes of speech and language disorders were highlighted by means of cluster analysis (Figure 1), principal component method allowed to identify the most significant tests for differentiation of these forms. Aphasia forms and neurodegenerative diseases forms were matched using multinomial logistic regression (Figure 2). We identified the main ROI for all subtypes (Figure 3)Conclusionspeech disorders in patients with neurodegenerative diseases have a specific structure with clinical‐neuroimaging heterogeneity, which allowed to develop a unified algorithm for differential diagnosis.

Lipid Peroxidation and Antioxidant Supplementation in Neurodegenerative Diseases: A Review of Human Studies.

Being characterized by progressive and severe damage in neuronal cells, neurodegenerative diseases (NDDs) are the major cause of disability and morbidity in the elderly, imposing a significant economic and social burden. As major components of the central nervous system, lipids play important roles in neural health and pathology. Disturbed lipid metabolism, particularly lipid peroxidation (LPO), is associated with the development of many NDDs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), all of which show elevated levels of LPO products and LPO-modified proteins. Thus, the inhibition of neuronal oxidation might slow the progression and reduce the severity of NDD; natural antioxidants, such as polyphenols and antioxidant vitamins, seem to be the most promising agents. Here, we summarize current literature data that were derived from human studies on the effect of natural polyphenols and vitamins A, C, and E supplementation in patients with AD, PD, and ALS. Although these compounds may reduce the severity and slow the progression of NDD, research gaps remain in antioxidants supplementation in AD, PD, and ALS patients, which indicates that further human studies applying antioxidant supplementation in different forms of NDDs are urgently needed.

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases.

Neurons are particularly susceptible to microtubule (MT) defects and deregulation of the MT cytoskeleton is considered to be a common insult during the pathogenesis of neurodegenerative disorders. Evidence that dysfunctions in the MT system have a direct role in neurodegeneration comes from findings that several forms of neurodegenerative diseases are associated with changes in genes encoding tubulins, the structural units of MTs, MT-associated proteins (MAPs), or additional factors such as MT modifying enzymes which modulating tubulin post-translational modifications (PTMs) regulate MT functions and dynamics. Efforts to use MT-targeting therapeutic agents for the treatment of neurodegenerative diseases are underway. Many of these agents have provided several benefits when tested on both in vitro and in vivo neurodegenerative model systems. Currently, the most frequently addressed therapeutic interventions include drugs that modulate MT stability or that target tubulin PTMs, such as tubulin acetylation. The purpose of this review is to provide an update on the relevance of MT dysfunctions to the process of neurodegeneration and briefly discuss advances in the use of MT-targeting drugs for the treatment of neurodegenerative disorders.

The Neural Basis of Metaphor Comprehension: Evidence from Left Hemisphere Degeneration.

Despite the ubiquity of metaphor in cognition and communication, it is absent from standard clinical assessments of language, and the neural systems that support metaphor processing are debated. Previous research shows that patients with focal brain lesions can display selective impairments in processing metaphor, suggesting that figurative language abilities may be disproportionately vulnerable to brain injury. We hypothesized that metaphor processing is especially vulnerable to neurodegenerative disease, and that the left hemisphere is critical for normal metaphor processing. To evaluate these hypotheses, we tested metaphor comprehension in patients with left-hemisphere neurodegeneration, and in demographically matched healthy comparison participants. Stimuli consisted of moderately familiar metaphors and closely matched literal sentences sharing the same source term (e.g., The interview was a painful crawl / The infant's motion was a crawl). Written sentences were presented, followed by four modifier-noun answer choices (one target and three foils). Healthy controls, though reliably better at literal than metaphor trials, comprehended both sentence conditions well. By contrast, participants with left-hemisphere neurodegeneration performed disproportionately poorly on metaphor comprehension. Anatomical analyses show relationships between metaphor accuracy and patient atrophy in the left middle and superior temporal gyri, and the left inferior frontal gyrus, areas that have been implicated in supporting metaphor comprehension in previous imaging research. The behavioral results also suggest deficits of metaphor comprehension may be a sensitive measure of cognitive dysfunction in some forms of neurodegenerative disease.

P62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles.

p62 is a versatile protein involved in the delicate balance between cell death and survival, which is fundamental for cell fate decision in the context of both cancer and neurodegenerative diseases. As an autophagy adaptor, p62 recognizes polyubiquitin chains and interacts with LC3, thereby targeting the selected cargo to the autophagosome with consequent autophagic degradation. Beside this function, p62 behaves as an interactive hub in multiple signalling including those mediated by Nrf2, NF-κB, caspase-8, and mTORC1. The protein is thus crucial for the control of oxidative stress, inflammation and cell survival, apoptosis, and metabolic reprogramming, respectively. As a multifunctional protein, p62 falls into the category of those factors that can exert opposite roles in the cells. Chronic p62 accumulation was found in many types of tumors as well as in stress granules present in different forms of neurodegenerative diseases. However, the protein seems to have a Janus behaviour since it may also serve protective functions against tumorigenesis or neurodegeneration. This review describes the diversified roles of p62 through its multiple domains and interactors and specifically focuses on its oncoJanus and neuroJanus roles.

Metabolomic study of disease progression in scrapie prion infected mice; validation of a novel method for brain metabolite extraction.

Prion disease is a form of neurodegenerative disease caused by the misfolding and aggregation of cellular prion protein (PrPC). The neurotoxicity of the misfolded form of prion protein, PrPSc still remains understudied. Here we try to investigate this issue using a metabolomics approach. The intention was to identify and quantify the small-in-size and water-soluble metabolites extracted from mice brains infected with the Rocky Mountain Laboratory isolate of mouse-adapted scrapie prions (RML) and track changes in these metabolites during disease evolution. A total of 73 mice were inoculated with RML prions or normal brain homogenate control; brains were harvested at 30, 60, 90, 120 and 150days post-inoculation (dpi). We devised a high-efficiency metabolite extraction method and used nuclear magnetic resonance spectroscopy to identify and quantify 50 metabolites in the brain extracts. Data were analyzed using multivariate approach. Brain metabolome profiles of RML infected animals displayed continuous changes throughout the course of disease. Among the analyzed metabolites, the most noteworthy changes included increases in myo-inositol and glutamine as well as decreases in 4-aminobutyrate, acetate, aspartate and taurine. We report a novel metabolite extraction method for lipid-rich tissue. As all the major metabolites are identifiable and quantifiable by magnetic resonance spectroscopy, this study suggests that tracking of neurochemical profiles could be effective in monitoring the progression of neurodegenerative diseases and useful for assessing the efficacy of candidate therapeutics.

Effects of Boron Nitride Nanotube on the Secondary Structure of Aβ(1-42) Trimer: Possible Inhibitory Effect on Amyloid Formation.

Aggregation of amyloid-β (Aβ) peptides into prefibrillar toxic oligomers is responsible for Alzheimer's disease, which is one of the most commonly known forms of neurodegenerative diseases. It has been reported that the low-molecular weight Aβ(1-42) trimer and its higher order oligomers are responsible for the cytotoxicity in the neuronal cells, leading to their death. Various experimental studies have shown that boron nitride nanotube (BNNTs) are noncytotoxic for health and environment and biocompatible in living cells and can be used as delivery vehicles for brain anticancer drugs. Here, we investigate the effects of BNNT on the secondary structure of Aβ(1-42) in the amyloid oligomerization process. We have performed long atomistic molecular dynamics simulations of 4.0 μs in total to study the structural stability of Aβ(1-42) trimer both in presence and absence of BNNT in explicit solvent. It is found that in the absence of BNNT, Aβ(1-42) trimer aggregates, leading to α-helix to β-sheet transition, whereas BNNT provides structural stability to the peptides by keeping them separated and preserving the initial monomeric helical conformation of the Aβ(1-42) trimer. It is found through a free-energy decomposition analysis that the key residues (Lys28, Ile31, Ile32, Leu34, Val40, and Ile41) from the C-terminal that are more responsible for β-sheet fibril formation bind with the BNNT surface and block their structural conversion. Due to the presence of polar B-N bonds, BNNT is less hydrophobic as compared with the carbonaceous nanomaterials where large hydrophobicity of these carbonaceous nanomaterials mostly destabilizes the secondary structure of peptides. The current study reveals that the less hydrophobicity of BNNT provides stability of the initial secondary structure of the Aβ(1-42) trimer and hinders their aggregation. Hence, the secondary structure stabilization in presence of BNNT provides new possibilities for the design of different nanoparticles as therapeutic agents for different types of amyloidogenesis by tuning their hydrophobicity.

Toll-like Receptor 2 Facilitates Oxidative Damage-Induced Retinal Degeneration

SUMMARYRetinal degeneration is a form of neurodegenerative disease and is the leading cause of vision loss globally. The Toll-like receptors (TLRs) are primary components of the innate immune system involved in signal transduction. Here we show that TLR2 induces complement factors C3 and CFB, the common and rate-limiting factors of the alternative pathway in both retinal pigment epithelial (RPE) cells and mononuclear phagocytes. Neutralization of TLR2 reduces opsonizing fragments of C3 in the outer retina and protects photoreceptor neurons from oxidative stress-induced degeneration. TLR2 deficiency also preserves tight junction expression and promotes RPE resistance to fragmentation. Finally, oxidative stress-induced formation of the terminal complement membrane attack complex and Iba1+ cell infiltration are strikingly inhibited in the TLR2-deficient retina. Our data directly implicate TLR2 as a mediator of retinal degeneration in response to oxidative stress and present TLR2 as a bridge between oxidative damage and complement-mediated retinal pathology.

The contribution of multicellular model organisms to neuronal ceroid lipofuscinosis research

The NCLs (neuronal ceroid lipofuscinosis) are forms of neurodegenerative disease that affect people of all ages and ethnicities but are most prevalent in children. Commonly known as Batten disease, this debilitating neurological disorder is comprised of 13 different subtypes that are categorized based on the particular gene that is mutated (CLN1-8, CLN10-14). The pathological mechanisms underlying the NCLs are not well understood due to our poor understanding of the functions of NCL proteins. Only one specific treatment (enzyme replacement therapy) is approved, which is for the treating the brain in CLN2 disease. Hence there remains a desperate need for further research into disease-modifying treatments. In this review, we present and evaluate the genes, proteins and studies performed in the social amoeba, nematode, fruit fly, zebrafish, mouse and large animals pertinent to NCL. In particular, we highlight the use of multicellular model organisms to study NCL protein function, pathology and pathomechanisms. Their use in testing novel therapeutic approaches is also presented. With this information, we highlight how future research in these systems may be able to provide new insight into NCL protein functions in human cells and aid in the development of new therapies.