Intermittent Theta-Burst Stimulation for Stroke: Primary Motor Cortex Versus Cerebellar Stimulation: A Randomized Sham-Controlled Trial.

BACKGROUND: Stroke survivors with impaired balance and motor function tend to have relatively poor functional outcomes. The cerebellum and primary motor cortex (M1) have been suggested as targets for neuromodulation of balance and motor recovery after stroke. This study aimed to compare the efficacy and safety of intermittent theta-burst stimulation (iTBS) to the cerebellum or M1 on balance and motor recovery in patients with stroke. METHODS: In this randomized, double-blind, sham-controlled clinical trial, patients with subacute stroke were randomly divided into 3 groups: M1-, cerebellar-, and sham-iTBS (n=12 per group; 15 sessions, 3 weeks). All outcomes were evaluated before intervention (T0), after 1 week of intervention (T1), after 3 weeks of intervention (T2), and at follow-up (T3). The primary outcome was the Berg balance scale score at T2. Secondary outcomes include the Fugl-Meyer assessment scale for lower extremities, the trunk impairment scale, the Barthel index, the modified Rankin Scale, the functional ambulation categories, and cortical excitability. RESULTS: A total of 167 inpatients were screened, 36 patients (age, 57.50±2.41 years; 10 women, 12 ischemic) were enrolled between December 2020 and January 2023. At T2, M1- or cerebellar-iTBS significantly improved Berg balance scale scores by 10.7 points ([95% CI, 2.7-18.6], P=0.009) and 14.2 points ([95% CI, 1.2-27.2], P=0.032) compared with the sham-iTBS group. Moreover, the cerebellar-iTBS group showed a significantly greater improvement in Fugl-Meyer assessment scale for lower extremities scores by 5.6 points than the M1-iTBS ([95% CI, 0.3-10.9], P=0.037) and by 7.8 points than the sham-iTBS ([95% CI, 1.1-14.5], P=0.021) groups at T2. The motor-evoked potential amplitudes of the M1- and cerebellar-iTBS groups were higher than those of the sham-iTBS group (P<0.001). CONCLUSIONS: Both M1- and cerebellar-iTBS could improve balance function. Moreover, cerebellar-iTBS, but not M1-iTBS, induced significant effects on motor recovery. Thus, cerebellar-iTBS may be a valuable new therapeutic option in stroke rehabilitation programs. REGISTRATION: URL: https://www.chictr.org.cn/; Unique identifier: ChiCTR2100047002.

Neurotrophin receptor p75 mediates amyloid ß-induced tau pathology.

Neurofibrillary tangles of hyperphosphorylated tau protein (p-tau) are a key pathological feature of Alzheimer's disease (AD). Tau phosphorylation is suggested to be secondary to amyloid-beta (Aß) accumulation. However, the mechanism by which Aß induces tau phosphorylation in neurons remains unclear. Neurotrophin receptor p75 (p75NTR) is a receptor for Aß and mediates Aß neurotoxicity, implying that p75NTR may mediate Aß-induced tau phosphorylation in AD. Here, we showed that Aß-induced tau hyperphosphorylation and neurodegeneration, including tau phosphorylation, synaptic disorder and neuronal loss, in the brains of both male wild-type (Wt) mice and male P301L transgenic mice (a mouse model of human tauopathy) were alleviated by genetic knockout of p75NTR in the both mouse models. We further confirmed that the activation or inhibition of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase-3ß (GSK3ß) significantly changed Aß/p75NTR-mediated p-tau levels in neurons. Treatment of male P301L mice with soluble p75NTR extracellular domain (p75ECD-Fc), which antagonizes the binding of Aß to p75NTR, suppressed tau hyperphosphorylation. Taken together, our findings suggest that p75NTR meditates Aß-induced tau pathology and is a potential druggable target for AD and other tauopathies.

The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau.

Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3ß pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3ß pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.

Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model.

Clearance of amyloid-beta (Aß) from the brain is an important therapeutic strategy for Alzheimer's disease (AD). Current studies mainly focus on the central approach of Aß clearance by introducing therapeutic agents into the brain. In a previous study, we found that peripheral tissues and organs play important roles in clearing brain-derived Aß, suggesting that the peripheral approach of removing Aß from the blood may also be effective for AD therapy. Here, we investigated whether peritoneal dialysis, a clinically available therapeutic method for chronic kidney disease (CKD), reduces brain Aß burden and attenuates AD-type pathologies and cognitive impairments. Thirty patients with newly diagnosed CKD were enrolled. The plasma Aß concentrations of the patients were measured before and after peritoneal dialysis. APP/PS1 mice were subjected to peritoneal dialysis once a day for 1 month from 6 months of age (prevention study) or 9 months of age (treatment study). The Aß in the interstitial fluid (ISF) was collected using microdialysis. Behavioural performance, long-term potentiation (LTP), Aß burden and other AD-type pathologies were measured after 1 month of peritoneal dialysis. Peritoneal dialysis significantly reduced plasma Aß levels in both CKD patients and APP/PS1 mice. Aß levels in the brain ISF of APP/PS1 mice immediately decreased after reduction of Aß in the blood during peritoneal dialysis. In both prevention and treatment studies, peritoneal dialysis substantially reduced Aß deposition, attenuated other AD-type pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, and synaptic dysfunction, and rescued the behavioural deficits of APPswe/PS1 mice. Importantly, the Aß phagocytosis function of microglia was enhanced in APP/PS1 mice after peritoneal dialysis. Our study suggests that peritoneal dialysis is a promising therapeutic method for AD, and Aß clearance using a peripheral approach could be a desirable therapeutic strategy for AD.

An overview of potential molecular mechanisms involved in VSMC phenotypic modulation.

The fully differentiated medial vascular smooth muscle cells (VSMCs) of mature vessels keep quiescent and contractile. However, VSMC can exhibit the plasticity in phenotype switching from a differentiated and contractile phenotype to a dedifferentiated state in response to alterations in local environmental cues, which is called phenotypic modulation or switching. Distinguishing from its differentiated state expressing more smooth muscle (SM)-specific/selective proteins, the phenotypic modulation in VSMC is characterized by an increased rate of proliferation, migration, synthesis of extracellular matrix proteins and decreased expression of SM contractile proteins. Although it has been well demonstrated that phenotypic modulation of VSMC contributes to the occurrence and progression of many proliferative vascular diseases, little is known about the details of the molecular mechanisms of VSMC phenotypic modulation. Growing evidence suggests that variety of molecules including microRNAs, cytokines and biochemical factors, membrane receptors, ion channels, cytoskeleton and extracellular matrix play important roles in controlling VSMC phenotype. The focus of the present review is to provide an overview of potential molecular mechanisms involved in VSMC phenotypic modulation in recent years. To clarify VSMC differentiation and phenotypic modulation mechanisms will contribute to producing cell-based therapeutic interventions for aberrant VSMC differentiation-related diseases.

Impaired SIRT1 promotes the migration of vascular smooth muscle cell-derived foam cells.

The formation of fat-laden foam cells, contributing to the fatty streaks of the plaques of atheroma, is the critical early process in atherosclerosis. The previous study demonstrated that vascular smooth muscle cells (VSMCs) contain a much larger burden of the excess cholesterol in comparison with monocyte-derived macrophages in human coronary atherosclerosis, as the main origin of foam cells. It is noteworthy that VSMC-derived foam cells are deposited in subintima but not media, where VSMCs normally deposit in. Therefore, migration from media to intima is an indispensable step for a VSMC to accrue neutral lipids and form foam cell. Whether this migration occurs paralleled with or prior to the formation of foam cell is still unclear. Herein, the present study was designed to test the VSMC migratory capability in the process of foam cell formation induced by oxidized low-density lipoprotein (oxLDL). In conclusion, we provide evidence that oxLDL induces the VSMC-derived foam cells formation with increased migration ability and MMP-9 expression, which were partly attributed to the impaired SIRT1 and enhanced nuclear factor-kappa B (NF-κB) activity. As activation of transient receptor potential vanilloid type 1 (TRPV1) has been reported to have anti-atherosclerotic effects, we investigated its role in oxLDL-treated VSMC migration. It is found that activating TRPV1 by capsaicin inhibits VSMC foam cell formation and the accompanied migration through rescuing the SIRT1 and suppressing NF-κB signaling. The present study provides evidence that SIRT1 may be a promising intervention target of atherosclerosis, and raises the prospect of TRPV1 in prevention and treatment of atherosclerosis.

Telmisartan-induced PPARγ activity attenuates lipid accumulation in VSMCs via induction of autophagy.

Foam cell formation is the hallmark of atherosclerosis. Both telmisartan and autophagy protect against the development of atherosclerosis. However, it has yet to be elucidated whether telmisartan prevents vascular smooth muscle cell (VSMC)-derived foam cell formation. Vascular smooth muscle cells isolated from the thoracic aorta of male C57BL/6J mice were used for this study. To induce foam cell formation, primary VSMCs were incubated in 80 µg/ml oxLDL for 24 h. LC3, beclin-1, PPARγ, AMPK, p-AMPK, mTOR and p-mTOR expression were determined via Western blot. Lipid accumulation was evaluated via oil red O staining and intracellular total cholesterol level measurement. Our study demonstrated that telmisartan dose-dependently increased the expression of beclin-1, the LC3II/LC3I ratio and the quantity of GFP-labeled autophagosomes, displaying a peak effect at 10 µM. In control siRNA-transfected VSMCs, telmisartan (10 µM) decreased lipid droplet accumulation and the total cholesterol level significantly. In contrast, in Atg7 siRNA-transfected VSMCs, telmisartan failed to attenuate lipid accumulation. In addition, telmisartan dose-dependently increased the expression of PPARγ and p-AMPK and decreased the expression of p-mTOR. GW9662 attenuated the telmisartan-induced increase in PPARγ expression, the LC3-II/LC3-I ratio and p-AMPK expression and the telmisartan-induced decrease in p-mTOR expression. Compound C restored mTOR activity and abolished the increase in the LC3-II/LC3-I ratio. Rapamycin significantly reduced p-mTOR expression and increased the LC3-II/LC3-I ratio. In conclusion, this study provides evidence that the chronic pharmacological activation of the PPARγ-mediated autophagy pathway using telmisartan may represent a promising therapeutic strategy for atherosclerosis.

The association between leukoaraiosis and carotid atherosclerosis: a systematic review and meta-analysis.

The association between large-artery atherosclerosis and leukoaraiosis (LA) has been increasingly reported with inconsistent conclusion. This systematic review examines the relationship between LA and carotid atherosclerosis, manifested as atherosclerotic stenosis, plaques and increased intima-media thickness (IMT). PubMed, Embase, and Web of Science were searched for articles published up to February 2014. Thirty-two studies that examined the relationship between LA and carotid atherosclerosis were included. All statistical analysis was conducted with Review Manager 5.2.4. Finally, 32 studies including 17,721 patients were identified. There were 7 (30%) out of 23 studies reporting significant association between LA and carotid stenosis; 11 (79%) out of 14 studies reporting significant association between LA and carotid plaque; all 9 studies reporting significant association between LA and carotid IMT; one study showing an association between LA and CAWT (similar to the role of the IMT). The quantitative meta-analysis of 10 studies showed that carotid atherosclerosis was not associated with LA (OR: 1.10; 95% CI: 0.61-1.98). A significant association was found between LA and carotid plaque (OR = 3.53; 95% CI = 1.83-6.79), and the result of IMT group showed that IMT increased risk of LA (MD = 0.11; 95% CI = 0.01-0.22). This systematic review suggested that LA has a tendency of association with carotid plaques but no association with simple carotid stenosis.

Association between intercellular adhesion molecule-1 gene K469E polymorphism and the risk of stroke in a Chinese population: a meta-analysis.

Several epidemiologic studies have evaluated the association between intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism and stroke, but the results were inconsistent. The present meta-analysis was performed to investigate the relationship between K469E polymorphism and stroke in the Chinese population. A comprehensive search for related studies from the electronic databases of PubMed, Embase, Web of Science, CBMdisc and CNKI as well as a manual search of the references of identified articles was performed. Data were extracted to calculate for allelic, additive, dominant and recessive models using pooled odds ratios (ORs) along with 95% confidence intervals (CIs) by Review Manager 5.0 and Stata 11.0. Different effect models, subgroup analysis, sensitivity analysis, publication bias and power calculations were used to improve the comprehensive analysis. Finally, a total of 12 studies containing 1593 cases and 1555 controls were included in the final meta-analysis. No evidence of significant association between ICAM-1 gene K469E polymorphism and stroke was found in all four models (allelic model: OR = 1.07, 95%CI = 0.78-1.47; additive model: OR = 1.21, 95% CI = 0.67-2.16 (EE vs. KK); OR = 1.04, 95%CI = 0.75-1.45 (EK vs. KK); dominant model: OR = 1.07, 95% CI = 0.73-1.56; and recessive model: OR = 1.18, 95% CI = 0.77-1.83, respectively) based on the overall population, as well as subgroup analysis and sensitivity analysis. In conclusion, the present meta-analysis showed no evidence of significant association between ICAM-1 gene K469E polymorphism and stroke in the Chinese population. Nonetheless, this conclusion should be interpreted cautiously due to the low statistical power and considerable heterogeneity. Therefore, larger sample-size studies with homogeneous cases and well-matched controls are needed to further address this correlation.

A meta-analysis of the relationship between MTHFR gene A1298C polymorphism and the risk of adult stroke.

BACKGROUND: The association between methylenetetrahydrofolate reductase (MTHFR) gene A1298C polymorphism and adult stroke remains controversial. The present article was designed to clarify this relationship through pooled analysis of the numerous epidemiological studies focusing on this association. METHODS: We comprehensively searched all published papers in electronic database including PubMed, Embase, Web of Science, Chinese Biomedical Literature on disc (CBMdisc) and China National Knowledge Infrastructure (CNKI) up to 2013. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) for allelic (C allele vs. A allele), additive (CC vs. AA), dominant (CC+AC vs. AA), and recessive (CC vs. AA+AC) models were calculated. Subgroup and sensitivity analyses were performed to detect the heterogeneity and examine the reliability of results, respectively. Begg's funnel plots and Egger's regression test were used to assess the potential publication bias. RESULTS: A total of fifteen studies containing 2,361 cases and 2,653 controls were included in the final meta-analysis. The combined results of overall analysis showed that there was significant association between MTHFR gene A1298C polymorphism and adult stroke (allelic model: OR=1.36, 95% CI=1.11-1.67; additive model: OR=1.88, 95% CI=1.12-3.18; dominant model: OR=1.33, 95% CI=1.08-1.65 and recessive model: OR=1.77, 95% CI=1.07-2.94, respectively). On subgroup analysis by ethnicity of study population, significant association was shown in meta-analysis based on Asian population (allelic model: OR=1.40, 95% CI=1.19-1.65; additive model: OR=2.58, 95% CI=1.34-4.96; dominant model: OR=1.44, 95% CI=1.20-1.73 and recessive model: OR=2.12, 95% CI=1.20-3.76, respectively), but not in Caucasian population (allelic model: OR=1.30, 95% CI=0.93-1.82; additive model: OR=1.65, 95% CI=0.81-3.33; dominant model: OR=1.17, 95% CI=0.86-1.61 and recessive model: OR=1.70, 95% CI=0.83-3.50, respectively). In addition, the heterogeneity was effectively removed or decreased by limiting the included studies with population of Asian ethnicity. Furthermore, the corresponding pooled ORs were not materially changed in all genetic models of meta-analysis after limiting the included studies with population-based controls. However, except the recessive model, publication bias presented in the allelic, additive, dominant models identified by the Begg's funnel plots and Egger's regression test. CONCLUSIONS: In conclusion, the overall analysis suggests that MTHFR gene A1298C polymorphism plays an important role in the development of adult stroke. Genotype CC of MTHFR-1298A/C could increase the risk of stroke and may act as a predictor for clinical evaluation, especially in the Asian population. More studies with large-scale and different ethnicities are required to further confirm our findings.

Toll-like receptor 4 gene Asp299Gly polymorphism in ischemic cerebrovascular disease: a meta-analysis.

Epidemiological studies have evaluated the association between Toll-like receptor 4 (TLR4) gene Asp299Gly (rs4986790) polymorphism and the risk of ischemic cerebrovascular disease, but the results are inconsistent. In an effort to clarify earlier inconclusive results, a meta-analysis was performed. We searched the PubMed, Web of Science, Embase, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, CNKI, CBMdisc, Chinese Clinical Trial Registry and Google Scholar until up to 20 July 2013. Additionally, hand searching of the references of identified articles was performed. Original observational studies investigating the association between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk were included. All statistical analyses were performed using Stata 11.0. The search strategy identified 1038 potentially relevant articles, seven of which were included in the final meta-analysis, covering a total of 1767 cases and 2785 controls. Overall, no significant association was found between TLR4 gene Asp299Gly polymorphism and ischemic cerebrovascular disease risk (for G allele versus A allele: OR = 0.95, 95% CI = 0.75-1.21, p = 0.69; for G/G+A/G versus A/A: OR = 0.96, 95% CI = 0.75-1.22, p = 0.73). In addition, the similar results were obtained in the sensitivity analysis based on studies with the high quality. In summary, the present meta-analysis indicates that TLR4 gene Asp299Gly polymorphism is not associated with increased ischemic cerebrovascular disease risk.

Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer's Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice.

Intermittent theta burst stimulation (iTBS), a time-saving and cost-effective repetitive transcranial magnetic stimulation regime, has been shown to improve cognition in patients with Alzheimer's disease (AD). However, the specific mechanism underlying iTBS-induced cognitive enhancement remains unknown. Previous studies suggested that mitochondrial functions are modulated by magnetic stimulation. Here, we showed that iTBS upregulates the expression of iron-sulfur cluster assembly 1 (ISCA1, an essential regulatory factor for mitochondrial respiration) in the brain of APP/PS1 mice. In vivo and in vitro studies revealed that iTBS modulates mitochondrial iron-sulfur cluster assembly to facilitate mitochondrial respiration and function, which is required for ISCA1. Moreover, iTBS rescues cognitive decline and attenuates AD-type pathologies in APP/PS1 mice. The present study uncovers a novel mechanism by which iTBS modulates mitochondrial respiration and function via ISCA1-mediated iron-sulfur cluster assembly to alleviate cognitive impairments and pathologies in AD. We provide the mechanistic target of iTBS that warrants its therapeutic potential for AD patients.

Inhibition of reactive oxygen species generation attenuates TLR4-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells.

Reactive oxygen species (ROS) are associated with inflammation and vasculature dysfunction. This study aimed to investigate the potential role of the ROS on vascular Toll-like receptor 4 (TLR4)-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells (VSMCs). A wire-induced carotid injury model was used in male TLR4-deficient (TLR4(-/-)) and wild-type C57BL/6J mice to induce neointima formation. In the presence or absence of the ROS scavenger apocynin for 14 days, increased TLR4 and proinflammatory cytokines were observed in wire injury-induced carotid neointima and in platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs. The TLR4(-/-) protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to PDGF-BB. Apocynin attenuated intimal hyperplasia. Pre-treatment with apocynin significantly inhibited intracellular ROS generation, accompanied by a significant suppression of TLR4 and proinflammatory cytokines expression, and VSMC proliferation and migration. However, the results were not obvious in TLR4(-/-) condition. These findings highlight the importance of ROS inhibition in TLR4-mediated proinflammatory and proliferative phenotype of VSMCs, and suggest ROS as an essential therapeutic target for TLR4-associated vascular inflammation and vascular diseases.

Association between interleukin-1α C(-889)T polymorphism and Alzheimer's disease: a meta-analysis including 12,817 subjects.

Epidemiological studies have evaluated the association between interleukin-1 (IL-1)α C(-889)T polymorphism and Alzheimer's disease (AD), but the results remain inconclusive. This meta-analysis was, therefore, designed to clarify these controversies. Systematic searches of electronic databases Embase, PubMed, and Web of Science as well as hand searching of the references of identified articles and the meeting abstracts were performed. Statistical analyses were performed using software Review Manager (Version 5.1.2) and Stata (Version 11.0). The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were calculated. A total of 28 publications including 29 studies were involved. There was a significant association between IL-1α C(-889)T polymorphism and AD (for T allele vs. C allele: OR = 1.14, 95 % CI = 1.07-1.21; for T/T vs. C/C: OR = 1.39, 95 % CI = 1.18-1.63; for dominant model: OR = 1.13, 95 % CI = 1.04-1.22; and for recessive model: OR = 1.39, 95 % CI = 1.20-1.60). Significant association was found for Asians, Caucasians, and early-onset Alzheimer's disease (EOAD) but for late-onset Alzheimer's disease (LOAD). This meta-analysis indicates that there is a significant association between IL-1α C(-889)T polymorphism and AD as well as EOAD.

Prevalence and clinical predictors of spasticity after intracerebral hemorrhage.

BACKGROUND: Spasticity is a common complication of intracerebral hemorrhage (ICH). However, no consensus exists on the relation between spasticity and initial clinical findings after ICH. METHODS: This retrospective study enrolled adult patients with a history of ICH between January 2012 and October 2020. The modified Ashworth scale was used to assess spasticity. A trained image analyst traced all ICH lesions. Multivariable logistic regression was used to examine the association between ICH lesion sites and spasticity. RESULTS: We finally analyzed 304 patients (mean age 54.86 ± 12.93 years; 72.04% men). The incidence of spasticity in patients with ICH was 30.92%. Higher National Institutes of Health stroke scale (NIHSS) scores were associated with an increased predicted probability for spasticity (odds ratio, OR = 1.153 [95% confidence interval, CI 1.093-1.216], p < .001). Logistic regression analysis revealed that lower age, higher NIHSS scores, and drinking were associated with an increased risk of moderate-to-severe spasticity (OR = 0.965 [95% CI 0.939-0.992], p = .013; OR = 1.068 [95% CI 1.008-1.130], p = .025; OR = 4.809 [95% CI 1.671-13.840], p = .004, respectively). However, smoking and ICH in the thalamus were associated with a reduced risk of moderate-to-severe spasticity (OR = 0.200 [95% CI 0.071-0.563], p = .002; OR = 0.405 [95% CI 0.140-1.174], p = .046, respectively) compared with ICH in the basal ganglia. CONCLUSIONS: Our results suggest that ICH lesion locations are at least partly associated with post-stroke spasticity rather than the latter simply being a physiological reaction to ICH itself. The predictors for spasticity after ICH were age, NIHSS scores, past medical history, and ICH lesion sites.

p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain.

Accumulation of toxic amyloid-ß (Aß) in the cerebral cortex and hippocampus is a major pathological feature of Alzheimer's disease (AD). The neurotrophin receptor p75NTR has been proposed to mediate Aß-induced neurotoxicity; however, its role in the development of AD remains to be clarified. The p75NTR/ExonIII-/- mice and APPSwe/PS1dE9 mice were crossed to generate transgenic AD mice with deletion of p75NTR gene. In APPSwe/PS1dE9 transgenic mice, p75NTR expression was localized in the basal forebrain neurons and degenerative neurites in neocortex, increased with aging, and further activated by Aß accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Aß levels in the brain and serum, but increased the accumulation of insoluble Aß and Aß plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or α-, ß-, and γ-secretase activities, or in levels of BACE1, neprilysin (NEP), and insulin-degrading enzyme (IDE) proteins. Aß production by cortical neurons of APPSwe/PS1dE9 mice was reduced by deletion of p75NTR gene in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Aß(42) peptide in vitro, and reduced local Aß plaques after hippocampus injection in vivo. In addition, deletion of p75NTR attenuated microgliosis but increased the microhemorrhage profiles in the brain. The deletion of p75NTR did not significantly change the cognitive function of the mice up to the age of 9 months. Our data suggest that p75NTR plays a critical role in regulating Aß levels by both increasing Aß production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology.

Association between paraoxonase 2 Ser311Cys polymorphism and ischemic stroke risk: a meta-analysis involving 5,008 subjects.

Epidemiological studies have evaluated the association between paraoxonase 2 (PON2) Ser311Cys polymorphism and ischemic stroke risk which developed inconsistent conclusions. The aim of this study was to perform a meta-analysis to investigate a more authentic association between PON2 Ser311Cys polymorphism and ischemic stroke. Systematic searches in PUBMED, EMBASE, CBM, and CNKI databases were performed. Data analyses were carried out by Review Manager 5.1.2 and Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used for additive model (Cys/Cys vs. Ser/Ser), dominant model (Ser/Cys+Cys/Cys vs. Ser/Ser), recessive model (Cys/Cys vs. Ser/Cys+Ser/Ser), and allelic model (Cys allele vs. Ser allele), respectively. Publication bias was analyzed by Begg's funnel plot and Egger's test. A total of 7 studies including 2,046 cases and 2,962 controls were involved. Overall, no significant association was found between PON2 Ser311Cys polymorphism and ischemic stroke risk when all studies were pooled into the meta-analysis (for additive model: OR = 0.87, 95% CI = 0.67-1.14; for dominant model: OR = 1.05, 95% CI = 0.91-1.22; for recessive model: OR = 0.90, 95% CI = 0.77-1.05; and for allelic model: OR = 1.17, 95% CI = 0.86-1.59). In the subgroup analysis by ethnicity, significant association was found among Europeans (for recessive model: OR = 0.83, 95% CI = 0.69-0.99). However, due to the small number of studies included in subgroup analysis, the result for European population should be interpreted cautiously.

Association between estrogen receptor alpha c.454-397T>C and c.454-351A>G and ischemic stroke risk: a systematic review and meta-analysis.

The association between estrogen receptor alpha (ESR1) c.454-397T>C and c.454-351A>G polymorphism and ischemic stroke remains controversial. The aim of this study was to perform a meta-analysis to investigate a more authentic association between c.454-397T>C and c.454-351A>G mutation and ischemic stroke. Systematic searches of electronic databases Embase, PubMed, Web of Science as well as hand-searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were performed using software Stata 11.0. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were performed. Different effect models were used according to the difference in heterogeneity. Publication bias was tested by Begg's funnel plot and Egger's regression test. For c.454-397T>C mutation, five studies were combined. Significant association was found in allelic model (OR = 1.12, 95 % CI = 1.01-1.25, p = 0.03), additive model (OR = 1.25, 95 % CI = 1.01-1.54, p = 0.04), and recessive model (OR = 1.23, 95 % CI = 1.02-1.49, p = 0.03), whereas no evidence of association was found for dominant model (OR = 1.10, 95 % CI = 0.85-1.42, p = 0.47). For c.454-351A>G mutation, no evidence of association was found for all genetic models. Our meta-analysis suggests that ESR1 c.454-397T>C mutation is significantly associated with increased risk of ischemic stroke, whereas no evidence of association was found for ESR1 c.454-351A>G mutation.

[Role of toll like receptor 4 in low shear stress-induced intimal hyperplasia].

OBJECTIVE: To determine the role of toll like receptor 4 (TLR4) in intimal hyperplasia induced by low shear stress (LSS). METHODS: TLR4(-/-) mice and control mice C57BL/6J were used. Polyethylene cuff was placed on murine carotid to establishing a LSS model. Cultured vascular endothelial cells under LSS condition were used as an in vitro LSS cell model. Intimal hyperplasia was evaluated pathologically. TLR4 was tested by Western blot and the expression of IL-1ß, IL-6 and TNF-α mRNA were detected using RT-PCR. Cell proliferation was determined by detecting DNA synthesis. RESULTS: LSS elicited significant carotid intimal hyperplasia in normal mice but a slight neointima formation in TLR4(-/-) mice (42.67 ± 16.46 vs 7.03 ± 2.95, P < 0.05). LSS upregulated the expression of TLR4 (2.30 ± 0.66 vs 0.16 ± 0.10, P < 0.05), as well as the mRNA of IL-1ß (6.52 ± 3.15 vs 1.65 ± 0.45, P < 0.01), IL-6 (16.17 ± 7.49 vs 6.50 ± 1.84, P < 0.01) and TNF-α(9.98 ± 3.77 vs 2.72 ± 1.03, P < 0.01) in normal mice. However, only moderate increases in IL-6 and TNF-α mRNA were observed in TLR4(-/-) mice. LSS induced the proliferation in cultured endothelial cells. And it was further enhanced by TLR4 overexpression (177 ± 33 vs 83 ± 15, P < 0.05) but attenuated by TLR4 silencing (40 ± 8 vs 83 ± 15, P < 0.05). CONCLUSION: TLR4 plays an important role in LSS-induced intimal hyperplasia. It is likely that LSS induces the proliferation of endothelial cells through TLR4-mediated inflammatory reaction and ultimately promotes intimal hyperplasia.

Activation of Dopamine D2 Receptors Alleviates Neuronal Hyperexcitability in the Lateral Entorhinal Cortex via Inhibition of HCN Current in a Rat Model of Chronic Inflammatory Pain.

Functional changes in synaptic transmission from the lateral entorhinal cortex to the dentate gyrus (LEC-DG) are considered responsible for the chronification of pain. However, the underlying alterations in fan cells, which are the predominant neurons in the LEC that project to the DG, remain elusive. Here, we investigated possible mechanisms using a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. We found a substantial increase in hyperpolarization-activated/cyclic nucleotide-gated currents (Ih), which led to the hyperexcitability of LEC fan cells of CFA slices. This phenomenon was attenuated in CFA slices by activating dopamine D2, but not D1, receptors. Chemogenetic activation of the ventral tegmental area -LEC projection had a D2 receptor-dependent analgesic effect. Intra-LEC microinjection of a D2 receptor agonist also suppressed CFA-induced behavioral hypersensitivity, and this effect was attenuated by pre-activation of the Ih. Our findings suggest that down-regulating the excitability of LEC fan cells through activation of the dopamine D2 receptor may be a strategy for treating chronic inflammatory pain.