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INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.
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The distribution range of root-knot nematode Meloidogyne graminicola is rapidly expanding, posing a severe threat to rice production. In this study, the sequences of cytochrome oxidase subunit I (COI) genes of rice M. graminicola populations from all reported provinces in China were amplified and sequenced by PCR. The distribution pattern and phylogenetic tree showed that all 54 M. graminicola populations in China have distinct geographical distribution characteristics; specifically, cluster 1 (southern China), cluster 2 (central south and southwest China), and cluster 3 (central and eastern China). The high haplotype diversity (Hd = 0.646) and low nucleotide diversity (π = 0.00682), combined with the negative value of Tajima's D (-1.252) and Fu's Fs (-3.06764), suggested that all nematode populations were expanding. The existence of high genetic differentiation (Fst = 0.5933) and low gene flow (Nm = 0.3333) indicated that there was a block of gene exchange between most populations. Mutation accumulation with population expansion might be directly responsible for the high genetic differentiation; therefore, the tested nematode population showed high within-group genetic variation (96.30%). The haplotype Hap8 was located at the bottom of the network topology, with the widest distribution and the highest frequency (59.26%), indicating that it was the ancestral haplotype. The populations in cluster 3 were newly invasive according to the lowest frequency of occurrence of Hap8, the highest number of endemic haplotypes, and the highest total haplotype frequency (60%). In contrast, cluster 1 having the highest genetic diversity (Hd = 0.772, π = 0.01127) indicated that it was the most primitive. Interestingly, the highest gene flow (Nm > 1), lowest genetic differentiation (Fst ≤ 0.33), and closest genetic distance (0.000) only occurred between the Guangdong/Hainan population and others, which suggested that there might be channels for gene exchange between them and that long-distance dispersal occurred. This suggestion is further confirmed by the weak correlation between genetic distance and geographical distance. Based on these data, a hypothesis can be drawn that M. graminicola populations in China were spreading from south to north, specifically from Guangdong and Hainan Provinces to other regions. Natural selection (including anthropogenic) and genetic drift were the main drivers of their evolution. Coincidentally, this hypothesis was consistent with the gradual warming trend and the chronological order of reporting these populations. The main factors influencing current M. graminicola population expansion and distribution patterns might be geography, climate, long-distance seedling transport, interregional operations of agricultural machinery, and rotation mode. It reminds human beings of the necessity to be vigilant about preventing nematode disease according to local conditions all year round.
Subject(s)
Oryza , Tylenchoidea , Animals , Humans , Phylogeny , Tylenchoidea/genetics , Geography , Genetic Drift , ChinaABSTRACT
BACKGROUND: Vascular dementia is a common disorder resulting in considerable morbidity and mortality. Determining the extent to which genes play a role in disease susceptibility and their pathophysiological mechanisms could improve our understanding of vascular dementia, leading to a potential translation of this knowledge to clinical practice. DISCUSSION: In this review, we discuss what is currently known about the genetics of vascular dementia. The identification of causal genes remains limited to monogenic forms of the disease, with findings for sporadic vascular dementia being less robust. However, progress in genetic research on associated phenotypes, such as cerebral small vessel disease, Alzheimer's disease, and stroke, have the potential to inform on the genetics of vascular dementia. We conclude by providing an overview of future developments in the field and how such work could impact patients and clinicians. CONCLUSION: The genetic background of vascular dementia is well established for monogenic disorders, but remains relatively obscure for the sporadic form. More work is needed for providing robust findings that might eventually lead to clinical translation.
Subject(s)
Dementia, Vascular/diagnostic imaging , Dementia, Vascular/genetics , Apolipoproteins E/genetics , Aryldialkylphosphatase/genetics , Dementia/etiology , Disease Progression , Humans , Magnetic Resonance Imaging , Polymorphism, GeneticABSTRACT
Uranium is one of the important nuclear materials to nuclear industry. Because of the direct disposal of spent fuel, there is still a huge possibility that uranium migrates into the groundwater, causing water contamination. It is of great importance to understand the concentration and their species distribution in aqueous solutions. Surface-Enhanced Raman Scattering (SERS) technique has been widely used for the detection of uranium (â ¥). However, the interactions between uranium (â ¥) and SERS substrate cause the symmetric stretching vibration peak of uranium (â ¥) shift to low wave number direction, which is unfavorable for confirming the species of uranium (â ¥) in aqueous solution. For instance, the normal Raman bands of uranyl in nitric acid solution are 871 cm-1, which belongs to the symmetric stretching mode of UO2+2. However, it moves to 710 cm-1 on the surface of silver nanorods SERS substrtate. What's more, different SERS substrate causes different number of shift. Graphene has advantages of inertness and integrity as well as 2-dimensional thickness. In this paper, graphene-isolated SERS substrate which is silver nanoparticles (AgNPs)/graphene complex substrate, was designed to prevent the interaction between SERS substrate and it was analyzed by using the inert graphene layer. First of all, according to our previous work, AgNPs SERS substrate was fabricated on silicon wafer by using an ascorbic acid-actived self-assembly method. Then, AgNPs/graphene complex substrate was prepared by transfering monolayer graphene onto the self-assembly AgNPs substrate. The morphology of complex substrate was obtained by SEM. Some AgNPs link together closely to form nanochain structures. Nanochain structures were distributed evenly on the surface of silicon wafer. The 2-dimensional thickness of graphene did not affect the morphology of AgNPs. When using the complex substrate to detect uranyl nitrate (5×10-4 mol·L-1)ï¼the Raman peak that appeared around 771 cm-1 is considered to be the symmetric stretching mode of UO2+2, shifting back about 52 cm-1 to high wave number direction when compared with AgNPs substrate, which was about ~719 cm-1. The result indicates that graphene layer isolates the interaction between AgNPs substrate and uranyl in some degree.
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AIM: Oxymatrine (OMT) is the major quinolizidine alkaloid extracted from the root of Sophora flavescens Ait (the Chinese herb Kushen) and exhibits diverse pharmacological actions. In this work we investigated the effects of OMT on diabetes-associated cognitive decline (DACD) in a rat model of diabetes and explored the mechanisms of action. METHODS: Male Wistar rats were injected with streptozotocin (65 mg/kg, ip) once to induce diabetes. The rats were then treated with vehicle or OMT (60 or 120 mg/kg per day, ip) for 7 weeks. Memory function was assessed using Morris water maze test. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), NF-κB p65 unit, TNF-α, IL-1ß and caspase-3 in the cerebral cortex and hippocampus were quantified. RESULTS: The diabetic rats exhibited markedly reduced body weight and increased plasma glucose level. The memory function of the rats assessed using Morris water maze test showed significant reduction in the percentage of time spent in the target quadrant and the number of times crossing the platform, coupled with markedly prolongation of escape latency and mean path length. Moreover, the rats showed oxidative stress (significantly increased MDA, decreased SOD and reduced GSH levels), as well as significant increases of NF-κB p65 unit, TNF-α, IL-1ß and caspase-3 levels in the cerebral cortex and hippocampus. Chronic treatment with OMT dose-dependently reversed these behavioral, biochemical and molecular changes in the diabetic rats. However, the swimming speed had no significant difference among the control, diabetic and OMT-treated diabetic rats. CONCLUSION: Chronic treatment with OMT alleviates diabetes-associated cognitive decline in rats, which is associated with oxidative stress, inflammation and apoptotic cascades.
Subject(s)
Alkaloids/pharmacology , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Behavior, Animal/drug effects , Cerebral Cortex/drug effects , Cognition Disorders/prevention & control , Cognition/drug effects , Diabetes Mellitus, Experimental/drug therapy , Hippocampus/drug effects , Quinolizines/pharmacology , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , Body Weight/drug effects , Caspase 3/metabolism , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Cognition Disorders/blood , Cognition Disorders/chemically induced , Cognition Disorders/physiopathology , Cognition Disorders/psychology , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Experimental/psychology , Dose-Response Relationship, Drug , Glutathione/metabolism , Hippocampus/metabolism , Hippocampus/physiopathology , Inflammation Mediators/metabolism , Interleukin-1beta/metabolism , Male , Malondialdehyde/metabolism , Maze Learning/drug effects , Memory/drug effects , Motor Activity/drug effects , Oxidative Stress/drug effects , Rats, Wistar , Streptozocin , Superoxide Dismutase/metabolism , Time Factors , Transcription Factor RelA/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
INTRODUCTION: Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations. Nonetheless, research findings on VEGF in Alzheimer's disease (AD) and vascular dementia (VaD) are inconsistent across various studies. METHODS: We conducted a meta-analysis to elucidate relationships between VEGF and AD/VaD. RESULTS: Twenty-four studies were included. Pooled data showed that both blood and cerebrospinal fluid (CSF) VEGF levels were higher in VaD patients, whereas no significant difference was found between AD patients and healthy controls. However, the correlation between blood VEGF and AD was found among studies with AD pathology verification. And blood VEGF levels were higher in AD patients than controls in "age difference < 5 years" subgroup and CSF samples for European cohorts. DISCUSSION: This study highlights that VEGF is more effective for the diagnosis of VaD and vascular factors are also an important contributor in AD. Highlights: Vascular endothelial growth factor (VEGF) levels were higher in the vascular dementia group, but not in the overall Alzheimer's disease (AD) group.Correlation between VEGF and AD was found among studies with clear AD pathological verification.Elevated VEGF in the cerebrospinal fluid might be a diagnostic marker for AD in European populations.
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Amyloid-ß, tau pathology, and biomarkers of neurodegeneration make up the core diagnostic biomarkers of Alzheimer disease (AD). However, these proteins represent only a fraction of the complex biological processes underlying AD, and individuals with other brain diseases in which AD pathology is a comorbidity also test positive for these diagnostic biomarkers. More AD-specific early diagnostic and disease staging biomarkers are needed. In this study, we performed tandem mass tag proteomic analysis of paired cerebrospinal fluid (CSF) and serum samples in a discovery cohort comprising 98 participants. Candidate biomarkers were validated by parallel reaction monitoring-based targeted proteomic assays in an independent multicenter cohort comprising 288 participants. We quantified 3,238 CSF and 1,702 serum proteins in the discovery cohort, identifying 171 and 860 CSF proteins and 37 and 323 serum proteins as potential early diagnostic and staging biomarkers, respectively. In the validation cohort, 58 and 21 CSF proteins, as well as 12 and 18 serum proteins, were verified as early diagnostic and staging biomarkers, respectively. Separate 19-protein CSF and an 8-protein serum biomarker panels were built by machine learning to accurately classify mild cognitive impairment (MCI) due to AD from normal cognition with areas under the curve of 0.984 and 0.881, respectively. The 19-protein CSF biomarker panel also effectively discriminated patients with MCI due to AD from patients with other neurodegenerative diseases. Moreover, we identified 21 CSF and 18 serum stage-associated proteins reflecting AD stages. Our findings provide a foundation for developing blood-based tests for AD screening and staging in clinical practice.
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This study was conducted to investigate the relationship between the pattern of pathological plantar response (Babinski sign), and the focus of the lesions of pyramidal tract. We examined 107 subjects with definite lesions of the pyramidal tract recruited from inpatients at the Neurology Department of the Xuanwu Hospital of Capital Medical University (Beijing, China). We found that patients with sub-cortical lesions (corona radiata to spinal cord) showed different patterns of Babinski sign than those with lesions within the primary motor cortex. Specifically, dorsiflexion of the big toe without recruitment of the other toes was seen in 71.4 % of patients with cortical pyramidal tract lesions, while 93 patients with lesions lower than cortex (corona radiata to spinal cord) showed movement of other toes in addition to the big toe, which showed movement due to contraction of the extensor hallucis longus tendon in all patients. There were no differences in patterns of Babinski sign between the different sub-cortical lesion foci. We conclude that the patterns of Babinski sign can be used to predict cortical lesions of the pyramidal tract.
Subject(s)
Brain/pathology , Pyramidal Tracts/injuries , Reflex, Babinski/pathology , Reflex, Babinski/physiopathology , Adult , Aged , Aged, 80 and over , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Physical Stimulation/methodsABSTRACT
OBJECTIVE: To investigate clinical and imaging features of a patient with adult-onset Krabbe disease and to detect the underlying genetic mutations. METHODS: Clinical and cranial MRI features of the patient were analyzed. Pathogenesis, clinical manifestation, cranial MRI features and diagnostic criteria for the disease were discussed. RESULTS: The patient had presented asymmetric limb weakness and difficulty in walking. Electromyography suggested peripheral nerve demyelination. Cranial MRI showed increased signal intensity in white matter with involvement of the corticospinal tracts. Screening of GALC gene mutation has found the patient to be heterozygous for T1685C (Ile562Thr) and homozygous for A1921G (Thr641Ala), both of which were considered to be polymorphisms. In addition, he was heterozygous for G136T (Asp46Tyr), which had not been described previously. CONCLUSION: Clinical manifestations of adult-onset Krabbe disease may be atypical. Cranial MRI and galactocerebroside activity assay should be carried out for patients featuring chronic progressive corticospinal tract injury. An Asp46Tyr mutation probably underlies the disease in the current case.
Subject(s)
Leukodystrophy, Globoid Cell/genetics , Point Mutation , Adult , Base Sequence , Brain/diagnostic imaging , Female , Humans , Leukodystrophy, Globoid Cell/diagnosis , Leukodystrophy, Globoid Cell/diagnostic imaging , Magnetic Resonance Imaging , Molecular Sequence Data , RadiographyABSTRACT
OBJECTIVE: To explore different risk factors between anterior and posterior circulation affecting onset and prognosis in the North Chinese young ischemic stroke patients. METHODS: This study included 446 cases of young ischemic stroke patients in northern China. All patients were recruited from our department from 2001 to 2010, Among them, the lesion sites were anterior circulation infarction (n = 353), posterior circulation infarction (n = 56) and both anterior and posterior circulation infarction (n = 37). Non-conditional Logistic regression analysis was used to determine the risk factors of predicting the onset of either anterior or posterior or mixed stroke and their short-term prognosis. RESULTS: Advanced age and a higher white blood cell count (WBC) increased the risk of non-anterior circulation lesions (OR 0.951, P = 0.030; OR 0.876, P = 0.014). Patients with a history of alcohol drinking had an increased risk for simple posterior circulation lesions (OR 1.856, P = 0.047); Both high National Institute of Health stroke scale (NIHSS score) and high total cholesterol (TC) predicted a poor short-term prognosis for simple anterior circulation lesions (OR 1.884, P = 0.000; OR 1.792, P = 0.008). CONCLUSION: Age, WBC count, alcohol intake, NIHSS score and TC are closely correlated with different lesions of northern Chinese young patients with ischemic stroke and their poor short-term prognosis.
Subject(s)
Brain Ischemia/diagnosis , Brain Ischemia/physiopathology , Stroke/diagnosis , Stroke/physiopathology , Adult , Brain Ischemia/etiology , Cerebrovascular Circulation , Cholesterol/blood , Female , Humans , Logistic Models , Male , Middle Aged , Prognosis , Risk Factors , Stroke/etiologyABSTRACT
OBJECTIVE: To compare the cognitive functions and neuropsychiatric symptoms of Parkinson's disease dementia (PDD) versus Alzheimer's disease (AD). METHODS: Patients fulfilling the diagnostic and statistical manual of mental disorders, 4(th) edition (DSM-IV) dementia diagnosis criteria were recruited into this case-control study. AD patients were diagnosed with the criteria of National Institute of Neurologic and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) while PDD was based upon the standards of Movement Disorder Society (MDS) Task Force. According to clinical dementia rating (CDR) score, they were divided into mild dementia (CDR score = 0.5/1) and moderate-to-severe dementia groups (CDR score = 2/3). World Health Organization-University of California, Los Angeles, auditory verbal learning test (WHO-UCLA AVLT), clock drawing test (CDT) and neuropsychiatric inventory (NPI) were performed. RESULTS: No significant difference in immediate memory, delayed memory or long-delayed recognition score was observed between PDD and AD patients (P > 0.05). CDT score was significantly lower in PDD patients (mild dementia group: 0.9 ± 0.9; moderate-to-severe dementia group: 0.6 ± 0.9) than that of AD patients (mild dementia group: 1.5 ± 0.7, P < 0.001; moderate-to-severe dementia group: 1.1 ± 0.6, P = 0.027) and this difference was more significant in mild dementia group. More than 70% of PDD patients reported at least one neuropsychiatric symptom. And also, in mild dementia group, compared with AD patients (frequency: 43.2% (16/37), NPI score = 5.7 ± 11.9), a higher frequency of neuropsychiatric symptoms and higher NPI scores were observed in PDD patients (frequency: 71.40% (25/35), NPI score = 8.4 ± 9.8). CONCLUSION: More severe impairment in visuospatial ability and executive function was present in PDD patients compared with AD patients. And neuropsychiatric symptoms were more common and severe in PDD patients.
Subject(s)
Alzheimer Disease/psychology , Cognition , Parkinson Disease/psychology , Aged , Aged, 80 and over , Alzheimer Disease/physiopathology , Female , Humans , Male , Middle Aged , Neuropsychological Tests , Parkinson Disease/physiopathologyABSTRACT
OBJECTIVE: To explore the efficacy and safety of intravenous thrombolysis (IVT) directed by whole-brain computed tomographic perfusion (CTP). METHODS: A total of 65 patients with acute ischemic stroke at our hospital during the period of April 2011 to April 2013, selected in accordance with the established CTP or TTW standard (0 to 3.0 h and 3.0 to 4.5 h) for IVT were included for analysis. The primary endpoint events were Barthel index (BI) and the rate of serious adverse events at 14 days post-onset. The latter included mortality and symptomatic intracerebral hemorrhage (ICH). And secondary indicators included the incidence of reperfusion, recanalization, ICH and neurological improvement at Day 14, as well as time indicators, such as onset-to-door time (ODT), door-to-treatment time (DTT) and onset-to-treatment time (OTT). Statistical calculations for continuous variables were compared with t or Mann-Whitney U test. And other comparisons were made with Pearson Chi-square or Fisher's exact test. RESULTS: Twenty-five and 40 cases with acute ischemic stroke were enrolled according to CTP or TTW standard for IVT respectively. Baseline characteristics, including age, gender, risk factors, blood pressure, blood sugar, National Institute of Health stroke scale (NIHSS) and drug dose showed no significant difference among groups. DTT and OTT in CTP group were significantly longer than those of the 0 to 3.0 h subgroup, while similar with those of the 3.0 to 4.5 h subgroup. Interestingly, consistent with a significant higher rate of transferring for consultation in the CTP group comparing with the TTW group (52.0% vs 25.0%, P = 0.03), the rate was also significantly higher than the 0 to 3.0 h subgroup (52.0% vs 7.7%, P = 0.02), but not significantly higher than the 3.0 to 4.5 subgroup. Both primary endpoint events and secondary outcome measures among three groups showed no significant differences. As for secondary outcome measures, CTP group had a higher recanalization than the 3.0 to 4.5 h subgroup (52.0% vs 37.0%, P = 0.28) and there was a trend toward significance. CTP excluded 58 cases, including 20 proved cases of malignant infarction on magnetic resonance imaging. CONCLUSION: CTP is able to select reasonable candidates for IVT in an extended time window with effectiveness and safety comparable to TTW standard. Furthermore, it is quicker and more sensitive than TTW standard in detecting malignant infarction.
Subject(s)
Brain Ischemia/prevention & control , Thrombolytic Therapy/methods , Tomography, X-Ray Computed , Adult , Aged , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Thrombolytic Therapy/adverse effectsABSTRACT
By comprehensive review and analysis of post-marketing clinical research on the efficacy and safety,we concluded that Fufang Zaoren capsule has certain therapeutic effects for insomnia, although current clinical research design needs improving. The post-marketing clinical studies also showed that it causes several adverse reactions at the recommended doses, such as chills, fever, dizziness, nausea, shortness of breath, chest tightness and palpitations, whereas high doses of Fufang Zaoren capsule can cause delayed extrapyramidal symptoms. Health Canada government website also prompted the L-tetrahydropalmatine in Fufang Zaoren capsule caused liver damage in pregnant women. The authors summarized the risk points, factors and risk control in the clinical use of Fufang Zaoren capsule and also present their perspective on the research status, existing problems and corresponding countermeasures in the post-marketing clinical re-evaluation of traditional Chinese medicine.
Subject(s)
Drug Evaluation , Drugs, Chinese Herbal/adverse effects , Product Surveillance, Postmarketing , Capsules/economics , China , Drug Evaluation/economics , Drugs, Chinese Herbal/economics , Female , Humans , Male , Marketing , Product Surveillance, Postmarketing/economicsABSTRACT
Neuronal death and synaptic loss are principal pathological features of Alzheimer's disease (AD). Amyloid beta oligomers (AßOs) constitute the main neurotoxin underscoring AD pathology. AßOs interact with N-methyl-D-aspartate receptors (NMDARs), resulting in neurotoxic events, including activation of apoptosis and synaptic impairment. Carnosic acid (CA), extracted from Salvia rosmarinus, has been verified its neuroprotective effects in AD. However, the precise mechanisms by which CA induces synaptic protection remain unclear. In this study, we established an in vitro AD model using SH-SY5Y human neuroblastoma cells. We observed that CA improved neuronal survival by suppressing apoptosis. Moreover, CA restored synaptic impairments by increasing expression levels of brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), and synaptophysin (Syn). Furthermore, we found these protective effects were dependent on inhibiting the phosphorylation of NMDAR subtype 2B (NMDAR2B), which further suppressed calcium overload and promoted activation of the extracellular signal-regulated kinase (ERK)-cAMP response element-binding protein (CREB) pathway. Administration of N-methyl-D-aspartic acid (NMDA), an agonist of NMDARs, abolished these effects of CA. Our findings demonstrate that CA exerts neuroprotective effects in an in vitro model of AD by regulating NMDAR2B and its downstream cascades, highlighting the therapeutic potential of CA as a NMDARs-targeted candidate in the treatment of AD.
Subject(s)
Abietanes , Alzheimer Disease , Neuroblastoma , Neuroprotective Agents , Receptors, N-Methyl-D-Aspartate , Humans , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Apoptosis , Neuroblastoma/pathology , Neuroprotective Agents/pharmacology , Receptors, N-Methyl-D-Aspartate/metabolism , Abietanes/pharmacologyABSTRACT
BACKGROUND: Alzheimer's disease (AD) is the most common form of neurodegenerative dementia among the elderly. Excitotoxicity has been implicated as playing a dominant role in AD, especially related to the hyperactivation of excitatory neurons. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent kinase and involved in the pathogenesis of AD, but the roles and mechanisms of DAPK1 in excitotoxicity in AD are still uncertain. OBJECTIVE: We mainly explored the underlying mechanisms of DAPK1 involved in the excitotoxicity of AD and its clinical relevance. METHODS: Differentiated SH-SY5Y human neuroblastoma cells, PS1 V97âL transgenic mice, and human plasma samples were used. Protein expression was assayed by immunoblotting, and intracellular calcium and neuronal damage were analyzed by flow cytometry. Plasma DAPK1 was measured by ELISA. RESULTS: We found that DAPK1 was activated after amyloid-ß oligomers (AßOs) exposure in differentiated SH-SY5Y cells. Besides, we found the phosphorylation of GluN2B subunit at Ser1303 was increased, which contributing to excitotoxicity and Ca2+ overload in SH-SY5Y cells. Inhibiting DAPK1 activity, knockdown of DAPK1 expression, and antagonizing GluN2B subunits could effectively prevent AßOs-induced activation of GluN2B subunit, Ca2+ overload, and neuronal apoptosis. Additionally, we found that DAPK1 was elevated in the brain of AD transgenic mouse and in the plasma of AD patients. CONCLUSION: Our finding will help to understand the mechanism of DAPK1 in the excitotoxicity in AD and provide a reference for the diagnosis and therapy of AD.
Subject(s)
Alzheimer Disease , Neuroblastoma , Aged , Animals , Humans , Mice , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Calcium/metabolism , Death-Associated Protein Kinases/genetics , Mice, Transgenic , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
AIMS: This study investigated the relationship between plasma Wnt2b levels and Alzheimer's disease (AD), and explored the effect of Wnt2b on mitochondrial dysfunction in AD. METHODS: Healthy and AD subjects, AD transgenic mice, and in vitro models were used to investigate the roles of Wnt2b in abnormalities in canonical Wnt signaling and mitochondria in AD. RT-qPCR, immunoblotting, and immunofluorescence analysis were performed to assay canonical Wnt signaling. Mitochondrial structure was analyzed by electron microscopy. Flow cytometry was used to examine the intracellular calcium and neuronal apoptosis. RESULTS: Plasma Wnt2b levels were lower in AD patients and positively correlated with cognitive performance. Similarly, Wnt2b was reduced in the hippocampus of AD mice and in vitro models. Next, Wnt2b overexpression and recombinant Wnt2b were used to endogenously and exogenously upregulate Wnt2b levels. Upregulation of Wnt2b could effectively prevent downregulation of canonical Wnt signaling, mitochondrial dysfunction in in vitro AD models. Subsequently, intracellular calcium overload and neuronal damage were ameliorated. CONCLUSIONS: Our study highlights that Wnt2b decline is associated with cognitive impairment in AD, and upregulation of Wnt2b can exert neuroprotective effects in AD, particularly in ameliorating mitochondrial dysfunction.
Subject(s)
Alzheimer Disease , Mitochondria , Neuroprotective Agents , Animals , Mice , Amyloid beta-Peptides/metabolism , Calcium , Disease Models, Animal , Mice, Transgenic , Mitochondria/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Up-Regulation , HumansABSTRACT
Alzheimer's disease (AD) is the most common form of neurodegenerative disease and most anti-AD drugs have failed in clinical trials; hence, it is urgent to find potentially effective drugs against AD. DL-3-n-butylphthalide (NBP) is a compound extracted from celery seed and is a multiple-target drug. Several studies have demonstrated the neuroprotective effects of NBP on cognitive impairment, but the mechanisms of NBP remains relatively unexplored. In this study, we found that NBP could alleviated the increase of intracellular Ca2+ and reversed down-regulation of Ca2+/calmodulin-dependent protein kinase alpha (CaMKIIα) signaling and rescued neuronal apoptosis in SH-SY5Y cells treated by Aß oligomers. However, these neuroprotective effects of NBP on neuronal damage and CaMKIIα signaling were abolished when CaMKIIα expression was knocked down or its activity was inhibited. Thus, our findings suggested that CaMKIIα signaling was required for the neuroprotective effects of NBP in AD and provided an improved basis for elucidating the mechanism and treatment of NBP in AD.
Subject(s)
Alzheimer Disease , Benzofurans , Neurodegenerative Diseases , Neuroprotective Agents , Alzheimer Disease/metabolism , Benzofurans/pharmacology , Benzofurans/therapeutic use , Humans , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic useABSTRACT
OBJECTIVE: To explore the diagnostic valves of computed tomography perfusion imaging (CTP) in hyperacute cerebral infarction patients and examine the correlation of time period from symptom onset to examination and CTP parameters. METHODS: Non-enhancement CT and CTP were performed on 75 patients with acute cerebral infarction of internal carotid system within 8 hours of symptom onset at our department from January 2006 to May 2008. National Institute of Health Stroke Scale score (NIHSS), Barthel index (BI) and modified Rankin scale (mRS) were assessed at the same day, days 14 and 90 after stroke onset respectively for neurological function impairment, activity of daily living and extent of disability in prognosis. RESULTS: (1) All CTP parameters in ischemic region had no correlation with time period from symptom onset to examination (P > 0.05). No significant differences were found between the patients with > 3 hours and < 3 hours after stroke onset in terms of the above parameters; (2) the areas of CBF (cerebral blood flow) on ischemic region significantly correlated with NIHSS at the day of symptom onset (r = 0.391, P < 0.001), Day 14 (r = 0.564, P < 0.001) and Day 90 (r = 0.549, P < 0.001) after symptom onset. CBV (cerebral blood volume) and TTP (time-to-peak) on ischemic region significantly correlated with the evaluation indices of predicting clinical outcomes at the day of symptom onset, Days 14 and 90 (P < 0.01). CBF, CBV, rCBF (regional CBF) and rCBV (regional CBV) correlated only with some of the clinical outcome scores. CONCLUSION: Time period after symptom onset can not reflect the ischemic extent and volume of cerebral infarction. But CTP may evaluate the severity and prognosis of acute cerebral infarction patients. The area of abnormal perfusion is the most sensitive parameter.
Subject(s)
Cerebral Infarction/diagnostic imaging , Perfusion Imaging , Tomography, X-Ray Computed/methods , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Prognosis , Time FactorsABSTRACT
BACKGROUND: Alterations in levels of peripheral insulin-like growth factor-1 (IGF-1) in Alzheimer's disease (AD) have been reported in several studies, and results are inconsistent. OBJECTIVE: We conducted a meta-analysis to investigate the relationship between peripheral and cerebrospinal fluid IGF-1 levels and AD or mild cognitive impairment (MCI). METHODS: A systematic search in PubMed, Medline, Web of Science, Embase, and Cochrane Library was conducted and 18 studies were included. RESULTS: Results of random-effects meta-analysis showed that there was no significant difference between AD patients and healthy control (17 studies; standard mean difference [SMD], -0.01; 95%CI, -0.35 to 0.32) and between MCI patients and healthy control (6 studies; SMD, -0.20; 95%CI, -0.52 to 0.13) in peripheral IGF-1 levels. Meta-regression analyses identified age difference might explain the heterogeneity (pâ=â0.017). However, peripheral IGF-1 levels were significantly decreased in AD subjects (9 studies; SMD, -0.44; 95%CI, -0.81 to -0.07) and MCI subjects exhibited a decreasing trend (4 studies; SMD, -0.31; 95%CI, -0.72 to 0.11) in studies with sample size≥80. Cerebrospinal fluid IGF-1 levels also significantly decreased in AD subjects (3 studies; SMD, -2.40; 95%CI, -4.36 to -0.43). CONCLUSION: These findings suggest that decreased peripheral and cerebrospinal fluid IGF-1 levels might be a potential marker for the cognitive decline and progression of AD.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnosis , Insulin-Like Growth Factor I/cerebrospinal fluid , Alzheimer Disease/epidemiology , Biomarkers/cerebrospinal fluid , HumansABSTRACT
A patient with migraine-induced stroke with risk factors involving both anterior cerebral artery and posterior cerebral artery territory was presented. To better explain the symptom, the mechanisms of the migraine-induced stroke with risk factors were assessed and a hypothesis was raised.