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  • 1.

    【2hr】Early age-related progression of AD-like neuropathology in Down’s syndrome

    包量

    机译 唐氏综合征中与AD相关的神经病理学与年龄相关的早期进展
    摘要：We have previously reported that increased numbers of Alz-50-reactive (apoptotic) neurons occurred in young DS subjects compared to controls, but increased in density with increasing age, and in advance of identifiable senile plaques (SP) in DS. The purpose of the study was to determine if there are further differences in Alzheimer’s disease (AD)-like neuropathology with increasing age among individuals with Down’s syndrome (DS) compared to cognitively normal age-matched controls. The two populations compared were age-matched normal controls (N = 14) between 11 months and 61 years of age and individuals with DS (N = 8) between 1 and 54 years of age. There were 7 cognitively intact DS and 10 control subjects under 35 years of age. The single demented 54 year old DS subject was compared to 4 non-demented controls between 48 and 61 years of age. 50 μm Vibratome sections of formalin fixed hippocampal formations were immunohistochemically stained for amyloid-β (6E10), APP (22C11) and phosphorylated tau (AT8) using standard methods. AT8 immunoreactive features were found only in the oldest DS subject. In contrast, the number and intensity of amyloid-β-immunoreactive neurons were maximal in the youngest DS subjects (1-24 years), reduced in the young adults (25-35 years) synchronous with the appearance of only diffuse-form SP, and were further reduced in the 54 year-old DS subject exhibiting abundant multiform SP. Distribution of APP immunoreactivity (22C11) was distinct from amyloid-β (6E10) in appearance and by location and age in both DS and normal controls. The data indicates that the earliest observable neuropathologic feature in DS may be neuronal accumulation of amyloid-β. Such accumulation of amyloid-β occurs decades in advance of deposition as SP, which in turn occurs decades before cognitive decline.
  • 2.

    【2hr】Tocilizumab infusion therapy normalizes inflammation in sporadic ALS patients

    包量

    机译 Tocilizumab输注疗法可使散发性ALS患者的炎症正常化
    摘要：Patients with sporadic amyotrophic lateral sclerosis (sALS) show inflammation in the spinal cord and peripheral blood. The inflammation is driven by stimulation of macrophages by aggregated superoxide dismutase 1 (SOD1) through caspase1, interleukin 1 (IL1), IL6 and chemokine signaling. Inflammatory gene activation is inhibited in vitro by tocilizumab, a humanized antibody to IL6 receptor (IL6R). Tocilizumab inhibits global interleukin-6 (IL6) signaling, a key mechanism in chronic rheumatoid disorders. Here we studied in vivo baseline inflammatory gene transcription in peripheral blood mononuclear cells (PBMCs) of 10 sALS patients, and the effects of tocilizumab (ActemraR) infusions. At baseline, one half of ALS subjects had strong inflammatory activation (Group 1) (8 genes up regulated >4-fold, P<0.05 vs. controls) and the other half (Group 2) had weak activation. All patients showed greater than four-fold up regulation of MMP1, CCL7, CCL13 and CCL24. Tocilizumab infusions in the Group 1 patients resulted in down regulation of inflammatory genes (in particular IL1β), whereas in the Group 2 patients in up regulation of inflammatory genes. Post-infusion serum and CSF concentrations of tocilizumab inhibited caspase1 activation in vitro. Three of 5 patients receiving tocilizumab infusions showed time-limited attenuation of clinical progression. In conclusion, inflammation of sALS patients at baseline is up- or down-regulated in comparison to controls, but is partially normalized by tocilizumab infusions.
  • 3.

    【2hr】Clinical outcomes and serum uric acid levels in elderly patients with amyotrophic lateral sclerosis aged ≥ 70 years

    包量

    机译 ≥70岁老年肌萎缩性侧索硬化患者的临床结局和血清尿酸水平
    摘要：Background: Amyotrophic lateral sclerosis is a slowly progressive fetal neurodegenerative disease in which clinical phenotype and nutritional status are considered prognostic factors. Advanced age has also been reported to carry a poor prognosis in amyotrophic lateral sclerosis. The elderly population is expected to increase in Japan, as well as in other countries in the near future. Whether late-onset amyotrophic lateral sclerosis affects the average lifespan or survival of patients and the nutritional status was related to survival remains an open question. Methods: We studied the survival of elderly 34 patients with clinically definite amyotrophic lateral sclerosis aged ≥ 70 years and investigated serum triglycerides, cholesterol, LDL/HDL ratio, and glucose. Serum uric acid was examined. Results: The average age at respiratory disorders or death as a whole was 77.5 ± 4.3 years. Survival did not differ significantly between different clinical phenotypes or between patients with and those without riluzole usage. Survival differed significantly between patients with and those without other complications. No biochemical parameter is correlated with outcome in this series, including elevated triglyceride or cholesterol levels and an increased LDL/HDL ratio. The survival correlated with the serum uric acid level (r = 0.407, p = 0.017). Conclusions: The onset of amyotrophic lateral sclerosis at ≥ 70 years of age might not be the key determinant of survival in patients with amyotrophic lateral sclerosis.
  • 4.

    【2hr】Protein aggregation and degradation mechanisms in neurodegenerative diseases

    包量

    机译 神经退行性疾病中的蛋白质聚集和降解机制
    摘要：Neurodegenerative diseases are characterized by selective neuronal vulnerability and neurodegeneration in specific brain regions. The pathogenesis of these disorders centrally involves abnormal accumulation and aggregation of specific proteins, which are deposited in intracellular inclusions or extracellular aggregates that are characteristic for each disease. Increasing evidence suggests that genetic mutations or environmental factors can instigate protein misfolding and aggregation in these diseases. Consequently, neurodegenerative diseases are often considered as conformational diseases. This idea is further supported by studies implicating that impairment of the protein quality control (PQC) and clearance systems, such as the ubiquitin-proteasome system and autophagosome-lysosome pathway, may lead to the abnormal accumulation of disease-specific proteins. This suggests that similar pathological mechanisms may underlie the pathogenesis of the different neurodegenerative disorders. Interestingly, several proteins that are known to associate with neurodegenerative diseases have been identified as important regulators of PQC and clearance systems. In this review, we summarize the central features of abnormal protein accumulation in different common neurodegenerative diseases and discuss some aspects of specific disease-associated proteins regulating the PQC and clearance mechanisms, such as ubiquilin-1.
  • 5.

    【2hr】Comparable dimerization found in wildtype and familial Alzheimer’s disease amyloid precursor protein mutants

    包量

    机译 在野生型和家族性阿尔茨海默氏病淀粉样蛋白前体蛋白突变体中发现可比的二聚化
    摘要：Alzheimer’s disease (AD) is a progressive and fatal neurodegenerative disorder marked by memory impairment and cognitive deficits. A major component of AD pathology is the accumulation of amyloid plaques in the brain, which are comprised of amyloid beta (Aβ) peptides derived from the amyloidogenic processing of the amyloid precursor protein (AβPP) by β- and γ-secretases. In a subset of patients, inheritance of mutations in the AβPP gene is responsible for altering Aβ production, leading to early onset disease. Interestingly, many of these familial mutations lie within the transmembrane domain of the protein near the GxxxG and GxxxA dimerization motifs that are important for transmembrane interactions. As AβPP dimerization has been linked to changes in Aβ production, it is of interest to know whether familial AβPP mutations affect full-length APP dimerization. Using bimolecular fluorescence complementation (BiFC), blue native gel electrophoresis, and live cell chemical cross-linking, we found that familial Alzheimer’s disease (FAD) mutations do not affect full-length AβPP dimerization in transfected HEK293 and COS7 cells. It follows that changes in AβPP dimerization are not necessary for altered Aβ production, and in FAD mutations, changes in Aβ levels are more likely a result of alternative proteolytic processing.
  • 6.

    【2hr】The impact of DaTscan on the diagnosis and management of movement disorders: A retrospective study

    包量

    机译 DaTscan对运动障碍的诊断和处理的影响：一项回顾性研究
    摘要：Background: The diagnosis of Parkinson’s disease remains a challenge in patients who have abnormal symptoms or show a lack of response to medication. The imaging technique, DaTscan, can be used to visualize dopamine degeneration in the nigro-striatum, which is associated with Parkinsonian Syndrome. We examined the use of the DaTscan in diagnosis, confidence in diagnosis, and clinical management. Methods: Physicians of 125 patients were contacted to fill out a brief survey about changes in diagnosis, confidence of diagnosis, and clinical management after assessment with the DaTscan. Results: There was an overall increase in confidence of diagnosis with the results of the DaTscan. Physicians also stated that the DaTscan impacted their diagnosis in 68% of the patients, as well as an impact in the clinical management of 58% of the patients. Conclusion: The DaTsan can be used as a tool to help diagnose Parkinsonian Syndrome in patients with unclear symptoms.
  • 7.

    【2hr】Convenient diagnosis of spinal and bulbar muscular atrophy using a microchip electrophoresis system

    包量

    机译 使用微芯片电泳系统方便诊断脊髓和延髓性肌萎缩
    摘要：Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive motor neuron disease. Lower and primary sensory neuronopathy is one of the major neuropathological changes that occurs in SBMA. However, many sings are common to SBMA and amyotrophic lateral sclerosis (ALS), and SBMA patients are sometimes diagnosed with ALS. Leuprorelin may be used to treat SBMA, but an accurate diagnosis is necessary for treatment and care. Genetic diagnosis can be performed to detect the expansion of a CAG repeat in the androgen receptor gene in SBMA patients. To screen for this expansion, we used a microchip electrophoresis system. The discrepancy between the actual repeat length and that found by the microchip electrophoresis system was roughly dependent on the repeat length. The mean difference was –6.8 base pairs (bp) in SBMA patients, –0.30 bp in controls. The microchip electrophoresis results were approximately 2 CAG repeats shorter than the actual repeat length in SBMA patients. Using this method, we screened our ALS samples (31 were familial, 271 were sporadic): 4 subjects were diagnosed with SBMA; 2 had familial ALS, and 2 had sporadic ALS (0.7%). The microchip electrophoresis system is semi-quantitative, convenient and useful for screening a large number of samples.
  • 8.

    【2hr】Multiplex assessment of a panel of 16 serum molecules for the differential diagnosis of Alzheimer’s disease

    包量

    机译 一组16种血清分子的多重评估以鉴别诊断阿尔茨海默氏病
    摘要：One of the current challenge in Alzheimer’s disease (AD) is the identification of reliable biomarkers that might improve diagnostic accuracy, possibly correlating with the disease progression and patient’s response to therapy. As the clinically validated AD biomarkers evaluate cerebrospinal fluid (CSF) parameters, the need for less invasive diagnostic markers is well evident. To this respect, blood circulating cytokines or growth factors have provided some encouraging results, even though no clinically validated to date. In 2007 Ray et al suggested a panel of 18 circulating molecules that might increase AD diagnostic accuracy. In an attempt of replicating their data, we designed a multiplex fluorimetric assay comprising 16 independent analytes and covering 15 out of the 18 described proteins. We collected serum samples from three diagnostic groups: probable AD (n=33), matched healthy controls (CNT, n=23) and non AD demented (NAD, n=14). After correction for age, we found an increased level of EGF-1 in AD in comparison to CNT and NAD, while an increase of TRAIL-R4 was found in NAD. However, evaluation of specificity/sensitivity by ROC curve analysis gave weak evidence of diagnostic accuracy (area under the curve = 0.63 and 0.66 for EGF and TRAIL-R4, respectively). Finally, we tried to find a diagnostic classifier by a multivariate algorithm. We found indication of diagnostic evidence for AD only, while NAD samples did not show a diagnostic pattern.
  • 9.

    【2hr】Microglial chemotactic signaling factors in Alzheimer’s disease

    包量

    机译 小胶质细胞趋化信号转导因子与阿尔茨海默氏病
    • 作者：James G McLarnon
    • 刊名：American Journal of Neurodegenerative Disease
    • 2012年第3期
    摘要：The net migration of microglia induced by deposits of amyloid beta (Aβ) constitutes a chemotactic response of resident neuroimmune brain cells. This process serves to localize clusters of microglia nearby Aβ deposits preparatory to cellular activation and functional responses. Microglial responses to Aβ deposits localized in brain parenchyma and in blood vessels lead to acute and chronic neuroinflammation in Alzheimer’s disease (AD) brain. This review summarizes studies on the prominent chemotactic factors MCP-1, MIP-1α and IL-8 and also includes recent work indicating VEGF and fractalkine as chemotactic agents. The possibility that microglial release of MCP-1 may play a role in mediating chemotactic responses of neural progenitor cells is also considered. The plethora of chemotactic factors and their cognate receptors suggests the utility in testing pharmacological modulation of chemotaxis for effects to inhibit chronic neuroinflammation and confer neuroprotection in AD animal models.
  • 10.

    【2hr】Advances in designs for Alzheimer’s disease clinical trials

    包量

    机译 阿尔茨海默氏病临床试验设计的进展
    摘要：There is an urgent need to identify new treatments for the rapidly growing population of people with Alzheimer’s disease (AD). Innovations in clinical trial designs many help to reduce development time, provide more definitive answers regarding drug efficacy, and facilitate prioritizing compounds to be advanced to Phase III clinical trials. Standard designs compare drug and placebo changes from baseline on a rating scale. Baysian adaptive clinical trials allow the use of data collected in the trial to modify doses, sample size, trial duration, and entry criteria in an ongoing way as the data are collected. Disease-modification is supported by findings on staggered start and delayed withdrawal designs. Futility designs can use historical controls and may shorten trial duration. Combination therapy designs may allow investigation of additive or synergistic treatment effects. Novel trial selection criteria allow investigation of treatment effects in asymptomatic or minimally symptomatic, prodromal AD populations. The Clinical Dementia Rating-Sum of Boxes (CDR-SOB) can be considered as a single trial outcome in early disease populations. Alternate forms of the Alzheimer’s Disease Assessment Scale-Cognitive Portion (ADAS-cog), computerized measures, and pharmacoeconomic scales provide new and relevant information on drug effects. Comparative dose strategies are used in trials of symptomatic agents, and novel methods including withdrawal designs, symptom emergence analyses, and sequential designs are being utilized to assess the efficacy of putative psychotropic agents. The choice of trial design is driven by the question to be answered by the clinical trial; an increasing number of design approaches are available and may be useful in accelerating and refining AD drug development.
  • 11.

    【2hr】Exosomes-associated neurodegeneration and progression of Parkinson’s disease

    包量

    机译 外泌体相关的神经变性和帕金森氏病进展
    摘要：Growing evidence indicates the role of exosomes in a variety of physiological pathways as conveyors of biological materials from cell-to-cell. However the molecular mechanism(s) of secretion and their interaction with receiving cells are yet unclear. Recently, it is emerging that exosomes are involved in pathological processes as potential carriers in the progression of neurodegenerative pathologies associated with misfolded proteins. In the current review we will discuss some recent findings on the key role of exosomes in the spreading of the aggregated products of α-synuclein from neuron-to-neuron and of inflammatory response propagation from immune cell-to-cell; we will highlight the implication of exosomes in the neurodegeneration and progression of the disease and the their potential interplay with genes related to Parkinson’s disease. Increasing our knowledge on the cell-to-cell transmissions might provide new insights into mechanism of disease onset and progression and identify novel strategies for diagnosis and therapeutic intervention in Parkinson and other neurodegenerative diseases.
  • 12.

    【2hr】Brain angiotensin and dopaminergic degeneration: relevance to Parkinson’s disease

    包量

    机译 脑血管紧张素和多巴胺能变性：与帕金森氏病的相关性
    摘要：The pathogenic mechanism of Parkinson’s disease (PD) appears to be multifactorial. However, oxidative stress and neuroinflammation, including activation of NADPH-dependent oxidases, play a major role in the progression of dopaminergic cell death. The renin-angiotensin system (RAS) was described as a circulating humoral system that regulates blood pressure and water homeostasis. However, there exist local RAS in many tissues, and locally formed angiotensin activates NADPH-dependent oxidases, which are a major source of superoxide and are upregulated in major aging-related diseases such as hypertension, diabetes and atherosclerosis. Furthermore, an intracellular or intracrine RAS, with still unknown functions, has been identified in several cell types. The brain has an independent local RAS, which has been involved in several brain disorders, including neurodegenerative diseases. It is particularly interesting for PD the important interaction observed between angiotensin and dopamine, which counterregulate each other in renal cells and also in the striatum and substantia nigra. In recent studies, we have observed both a local and an intracellular RAS in the rodent, monkey and human substantia nigra, and that dopamine depletion induced RAS upregulation possibly as a compensatory mechanism. However, RAS hyperactivation also exacerbated oxidative stress and neuroinflammation, which contributed to progression of dopaminergic degeneration. In addition, we observed increased RAS activity in the nigra of animals with higher vulnerability of dopaminergic neurons to degeneration, such as aged males, menopausal females and rats subjected to chronic brain hypoperfusion. RAS activity and dopaminergic vulnerability were significantly reduced by treatment with angiotensin type I receptor antagonists. Manipulation of the brain RAS may constitute an effective neuroprotective strategy against dopaminergic degeneration in PD.
  • 13.

    【2hr】Leptin signaling and Alzheimer’s disease

    包量

    机译 瘦素信号传导和阿尔茨海默氏病
    摘要：Leptin, an adipocytokine produced in the peripheral system as well as in the brain, is implicated in obesity, food intake, glucose homeostasis, and energy expenditure. Leptin expression levels and signaling pathways may also be linked to the pathophysiology of neurodegenerative diseases including Alzheimer’s disease. Epidemiological studies have demonstrated that higher circulating leptin levels are associated with lower risk of dementia including Alzheimer’s disease, and lower circulating levels of leptin have been reported in patients with Alzheimer’s disease. Leptin receptors are highly expressed in the hippocampus, a brain area involved in learning and memory and severely affected during the course of Alzheimer’s disease. In laboratory studies, several in vivo and in vitro studies have shown that leptin supplementation decreases amyloid-β (Aβ) production and tau phosphorylation, two major biochemical events that play a key role in the pathogenesis of Alzheimer’s disease. In this review, we will review the structure of leptin, the type of receptors of leptin in the brain, the various biological functions attributed to this adipocytokine, the signaling pathways that govern leptin actions, and the potential role of leptin in the pathophysiology of Alzheimer’s disease. Leptin exerts its functions by binding to the leptin receptor (ObR). This binding can involve several signaling pathways including JAK/STAT pathway, ERK pathway and the PI3K/Akt/mTOR Pathway. Modulation of these pathways leads to the regulation of a multitude of functions that define the intricate involvement of leptin in various physiological tasks. In this review, we will specifically relate the potential involvement of leptin signaling in Alzheimer’s disease based on work published by several laboratories including ours. All this work points to leptin as a possible target for developing supplementation therapies for reducing the progression of Alzheimer’s disease.
  • 14.

    【2hr】Interactions between oestrogen and the renin angiotensin system - potential mechanisms for gender differences in Alzheimer’s disease

    包量

    机译 雌激素和肾素血管紧张素系统之间的相互作用-阿尔茨海默氏病性别差异的潜在机制
    摘要：Interactions between oestrogen and the renin angiotensin system (RAS) are reviewed and explored from the perspective where these interactions may modulate risk of developing Alzheimer’s disease (AD). AD is more prevalent in women than men, partly attributed to women’s increased life expectancy; however underlying vascular differences may also contribute to AD risk. The RAS is a key regulator of blood pressure (BP). Pharmacological inhibition of angiotensin converting enzyme (ACE) and blockade of angiotensin II type 1 receptors (AT1R) are widely used to treat hypertension. Variation in components of the RAS such as ACE, neprilysin (NEP) and AT1R have been reported in AD, some of which may also directly alter AD neuropathology with changes in amyloid beta (Aβ) levels, cognitive decline and neuroinflammation. Recently, RAS inhibiting drugs have been shown to attenuate the incidence, progression and pathology of AD. Oestrogen is also thought to prevent hypertension by reducing the vasoconstrictive actions of the RAS. Reduced oestrogen levels in women during the menopausal transition may therefore increase their risk of hypertension and/or RAS-mediated changes to cerebrovascular or AD pathology. Specifically, oestrogen prevents the production and action of angiotensin II (Ang II), thought to exert harmful effects of the RAS in both hypertension and AD, while also potentially facilitating RAS-mediated Aβ degradation. These oestrogen-RAS interactions may partly explain current conflicting findings regarding oestrogen depletion and hormone therapy with respect to AD risk. Clinical trials targeting either the RAS or oestrogen systems for AD prevention and treatment should perhaps give closer attention to key biochemical components of these pathways as potential confounders to primary and secondary outcome measures.
  • 15.

    【2hr】Therapeutic application of melatonin in mild cognitive impairment

    包量

    机译 褪黑素在轻度认知障碍中的治疗应用
    摘要：Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome defined by cognitive impairment in advance of dementia. We previously reported in a retrospective analysis that daily 3 - 9 mg of a fast-release melatonin preparation given p. o. at bedtime for up to 3 years significantly improved cognitive and emotional performance and daily sleep/wake cycle in MCI patients. In a follow up of that study we now report data from another series of 96 MCI outpatients, 61 of who had received daily 3 - 24 mg of a fast-release melatonin preparation p. o. at bedtime for 15 to 60 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin exhibited significantly better performance in Mini–Mental State Examination and the cognitive subscale of the Alzheimer’s disease Assessment Scale. After application of a neuropsychological battery comprising a Mattis´ test, Digit-symbol test, Trail A and B tasks and the Rey´s verbal test, better performance was found in melatonin-treated patients for every parameter tested. Abnormally high Beck Depression Inventory scores decreased in melatonin-treated patients, concomitantly with the improvement in the quality of sleep and wakefulness. The comparison of the medication profile in both groups of MCI patients indicated that 9.8% in the melatonin group received benzodiazepines vs. 62.8% in the non-melatonin group. The results further support that melatonin can be a useful add-on drug for treating MCI in a clinic environment.
  • 16.

    【2hr】Audio representations of multi-channel EEG: a new tool for diagnosis of brain disorders

    包量

    机译 多通道脑电图的音频表示：诊断脑部疾病的新工具
    摘要：Objective: The objective of this paper is to develop audio representations of electroencephalographic (EEG) multichannel signals, useful for medical practitioners and neuroscientists. The fundamental question explored in this paper is whether clinically valuable information contained in the EEG, not available from the conventional graphical EEG representation, might become apparent through audio representations. Methods and Materials: Music scores are generated from sparse time-frequency maps of EEG signals. Specifically, EEG signals of patients with mild cognitive impairment (MCI) and (healthy) control subjects are considered. Statistical differences in the audio representations of MCI patients and control subjects are assessed through mathematical complexity indexes as well as a perception test; in the latter, participants try to distinguish between audio sequences from MCI patients and control subjects. Results: Several characteristics of the audio sequences, including sample entropy, number of notes, and synchrony, are significantly different in MCI patients and control subjects (Mann-Whitney p < 0.01). Moreover, the participants of the perception test were able to accurately classify the audio sequences (89% correctly classified). Conclusions: The proposed audio representation of multi-channel EEG signals helps to understand the complex structure of EEG. Promising results were obtained on a clinical EEG data set.
  • 17.

    【2hr】Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling

    包量

    机译 托珠单抗通过抑制IL6受体信号传导减轻ALS患者的炎症
    摘要：Patients with amyotrophic lateral sclerosis (ALS) have evidence of chronic inflammation demonstrated by infiltration of the gray matter by inflammatory macrophages, IL17A-positive T cells, and mast cells. Increased serum levels of IL6 and IL17A have been detected in sporadic ALS (sALS) patients when compared to healthy controls. Herein we investigate, in peripheral blood mononuclear cells (PBMCs), the baseline transcription of genes associated with inflammation in sALS and control subjects and the impact of the IL6 receptor (IL6R) antibody (tocilizumab) on the transcription and/or secretion of inflammation factors (e.g. cytokines) stimulated by the apo-G37R superoxide dismutase (SOD1) mutant. At baseline, PBMCs of four sALS patients (Group 1) showed significantly increased expression of TLR2 and CD14; ALOX5, PTGS2 and MMP1; IL1α, IL1β, IL6, IL36G, IL8 and TNF; CCL3, CCL20, CXCL2, CXCL3 and CXCL5. In four other sALS patients (Group 2), most of the genes just mentioned were expressed at near control levels and a significant decrease in the expression of PPARG, PPARA, RARG, HDAC4 and KAT2B; IL6R, IL6ST and ADAM17; TNFRSF11A; MGAT2 and MGAT3; PLCG1; CXCL3 were detected. Apo-G37R SOD1 up regulated the transcription of cytokines (e.g. IL1α/β, IL6, IL8, IL36G), chemokines (e.g. CCL20; CXCL3, CXCL5), and enzymes (e.g. PTGS2 and MMP1). In vitro, tocilizumab down regulated the transcription of many inflammatory cytokines, chemokines, enzymes, and receptors, which were up regulated by pathogenic forms of SOD1. Tocilizumab also reduced the secretion of the pro-inflammatory cytokines IL1β, IL6, TNFα, GM-CSF, IFNγ, and IL17A by Group 1 PBMCs. Finally, sALS patients had significantly higher concentrations of IL6, sIL6R and C-reactive protein in the cerebrospinal fluid when compared to AD patients. This pilot study demonstrates that in vitro tocilizumab suppresses many factors that drive inflammation in sALS patients, with possible increased efficacy in Group 1 ALS patients.
  • 18.

    【2hr】Multiple mechanisms of extracellular tau spreading in a non-transgenic tauopathy model

    包量

    机译 非转基因tauopathy模型中细胞外tau扩散的多种机制
    摘要：While the interneuronal propagation of neurofibrillary lesions in Alzheimer’s disease and other tauopathies now appears to involve the spreading of tau-associated toxicity, little is known about its mechanism. We characterized the movement of human tau through the brain of a non-transgenic lower vertebrate tauopathy model in which full-length wild type and mutant human tau isoforms were expressed in identified neurons, thus permitting the identification and localization of EC tau sources. We describe two distinct patterns of tau spreading that correspond to tau species that lack (MTBR-) and contain (MTBR+) the tau microtubule-binding region. These patterns illustrate the production, migration and uptake of EC tau and resemble some of the extracellular tau deposits typically seen in human brain after repeated traumatic injury in cases of chronic traumatic encephalopathy (CTE). We propose that misprocessed human tau can spread between CNS neurons via a variety of non-synaptic mechanisms as well as synaptically mediated mechanisms.
  • 19.

    【2hr】Neuroprotection against iron-induced cell death by perineuronal nets - an in vivo analysis of oxidative stress

    包量

    机译 神经保护作用防止铁通过神经周神经网死亡-体内氧化应激分析
    摘要：Perineuronal nets (PNs) are a specialized form of extracellular matrix, surrounding different types of neurons and mainly consist of chondroitin sulfate proteoglycans connected to hyaluronan, stabilized by link protein and cross-linked via tenascin-R. Due to their polyanionic character, caused by the highly charged chondroitin sulfate glycosaminoglycan and hyaluronan components, PNs might be involved in local ion homeostasis. They are able to scavenge and bind redox-active ions and thus reduce the local oxidative potential. We investigated whether netenwrapped neurons are less vulnerable against iron-induced oxidative processes. Oxidative stress is a key factor in the development and progression of neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Iron is believed to contribute to oxidative stress in Alzheimer brains by catalyzing the generation of free radicals. For examining potential neuroprotective effects of PNs, mice were microinjected with 0.2μl of a 20mM solution of FeCl3 into the barrel field while the control group received an equal volume of 0.9% NaCl. Brains were analyzed after time intervals of 24h and 72h. Neuronal degeneration was visualized using Fluoro-Jade B staining. The presence of PNs was assessed by Wisteria floribunda agglutinin histochemistry or aggrecan immunocytochemistry. The analysis showed a significant lower degeneration rate of net-ensheathed neurons in comparison to neurons without PNs. The results suggest a neuroprotective mechanism associated with the presence of PNs against iron-induced cell death.
  • 20.

    【2hr】Retinoid signaling alterations in amyotrophic lateral sclerosis

    包量

    机译 类肌萎缩性侧索硬化的类维生素A信号改变
    摘要：Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease for which effective therapeutic interventions and an understanding of underlying disease mechanism are lacking. A variety of biochemical pathways are believed to contribute to the pathophysiology of ALS that are common to both sporadic and familial forms of the disease. Evidence from both human and animal studies indicates that expression of retinoid signaling genes is altered in ALS and may contribute to motor neuron loss. Our goals were to examine the expression and distribution of proteins of the retinoid signaling pathway in spinal cord samples from patients with sporadic and familial ALS and to evaluate the role of these proteins in motor neuron cell survival. In sporadic ALS, the cytoplasmic binding protein that facilitates nuclear translocation of retinoic acid, cellular retinoic acid binding protein-II (CRABP-II), was localized to the nucleus and retinoic acid receptor β (RARβ) was significantly increased in motor neuron nuclei when compared to either familial ALS patients or non-neurologic disease controls. Motor neurons with increased nuclear RARβ were negative for markers of apoptosis. Pre-treatment of primary motor neuron-enriched cultures with a pan-RAR or RARβ-specific agonist decreased motor neuron cell death associated with oxidative injury/stress while a RARβ-specific antagonist enhanced cell death. Our data suggest retinoid signaling is altered in ALS and increased nuclear RARβ occurs in motor neurons of sporadic ALS patients. Activation of RARβ protects motor neurons from oxidative-induced cell death.
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