Rationale: Absent in melanoma 2 (AIM2) inflammasome-mediated effector plays critical roles in multiple disease pathologies. While nanotechnology has revolutionized therapeutic development through novel approaches, the potential regulatory effects of nanoparticles on AIM2 inflammasome activity remain unexplored. Here, guided by clinical patient data and computational modeling, we developed an AIM2 inflammasome-targeting biomimetic mineralization inhibitor for vascular dementia (VaD) therapy. Methods: GEO datasets were analyzed to compare AIM2 inflammasome component expression in VaD patient brains versus controls. Molecular dynamics simulations identified high-affinity binding between manganese ferrocyanide and the AIM2 protein. We synthesized hollow manganese Prussian blue nanoparticles (HMPB) via biomineralization and functionalized them with M2 macrophage-derived extracellular vesicles (M2exo@HMPB). Therapeutic efficacy was evaluated in a VaD rat model through intravenous and intracerebroventricular administration, employing behavioral assessments, histopathological analysis, and inflammatory cytokine profiling. AIM2 inflammasome assembly and pyroptosis were investigated through protein immunoblotting, scanning electron microscopy/transmission electron microscopy (SEM/TEM) imaging of microglial cells, and primary microglia cultures under hypoxic-hypoglycemic conditions. Results: Gene expression analysis demonstrated significantly elevated levels of AIM2 inflammasome components in VaD patients compared to normal controls. Molecular dynamics simulations revealed effective binding of manganese ferrocyanide to AIM2. M2exo@HMPB targeted central inflamed sites and were ultimately phagocytosed by microglia. In an in vitro sustained hypoxic-hypoglycemic model, M2exo@HMPB inhibited AIM2 inflammasome assembly and pyroptosis in primary microglia, thereby reducing IL-18/IL-1β release and promoting neuronal survival. In VaD rat models, M2exo@HMPB alleviated neuronal loss and white matter lesions while improving learning and executive functions. Additionally, M2exo@HMPB demonstrated favorable in vivo biosafety. Conclusions: Integrating clinical bioinformatics with computational drug design, this study establishes a translational paradigm for nanomaterial development. M2exo@HMPB serves not only as an AIM2 inflammasome-targeting biomimetic mineralization inhibitor for VaD therapy but also provides new insights for treating AIM2-mediated cell death pathologies.

BACKGROUND: Whether it is effective and safe to extend the time window of intravenous thrombolysis up to 24 hours after the last known well is unknown. We aimed to determine the efficacy and safety of tenecteplase in Chinese patients with acute ischemic stroke due to large/medium vessel occlusion within an extended time window. METHODS: Patients with ischemic stroke presenting 4.5 to 24 hours from the last known well, with a favorable penumbral profile and an associated large/medium vessel occlusion, were randomized 1:1 to either 0.25 mg/kg tenecteplase or the best medical treatment. A favorable penumbral profile was defined as a hypoperfusion lesion volume to infarct core volume ratio >1.2, with an absolute volume difference >10 mL, and an ischemic core volume <70 mL. The primary outcome was the achievement of major reperfusion without symptomatic intracranial hemorrhage within 24 to 48 hours post-randomization. Major reperfusion was defined as the restoration of blood flow of >50% of the involved ischemic territory. Secondary outcomes included recanalization, infarct growth, major neurological improvements, change in the National Institutes of Health Stroke Scale score, hemorrhagic transformation within 24 to 48 hours, systemic bleeding at discharge, and modified Rankin Scale (score 0–1, score 0–2, score 5–6, and modified Rankin Scale distribution) at 90 days. The comparison of the primary outcome between groups was conducted using modified Poisson regression with a log-link function and robust error variance, adjusted for time from the last known well to randomization, the site of vessel occlusion, and planned endovascular treatment. RESULTS: Among 224 enrolled patients, 111 were assigned to receive tenecteplase and 113 to receive the best medical treatment (including 23% [n=26] of participants who received intravenous tissue-type plasminogen activator). The mean (SD) age of the tenecteplase group and the best medical treatment group was 64.2 (10.4) and 63.6 (11.0) years old, with 72.1% (n=80) and 70.8% (n=80) male enrolled, respectively. A proportion of 54.9% (n=123) of patients were transferred to the catheter room for preplanned endovascular treatment. The primary outcome occurred in 33.3% (n=37) of the tenecteplase group versus 10.8% (n=12) in the best medical treatment group (adjusted relative risk, 3.0 [95% CI, 1.6–5.7]; P =0.001). Tenecteplase significantly increased the recanalization rate compared with the best medical treatment (35.8% [n=39] versus 14.3% [n=16], adjusted relative risk, 2.5 [95% CI, 1.4–4.4]; P =0.002). There were no significant differences in clinical efficacy outcomes or rates of hemorrhagic transformation between the groups. CONCLUSIONS: Administered at a dose of 0.25 mg/kg intravenously, tenecteplase increased reperfusion without symptomatic intracranial hemorrhage in patients with ischemic stroke selected by imaging in late-time window treatment but did not change clinical outcomes at 90 days. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04516993.

BACKGROUND:Chronic cerebral hypoperfusion (CCH) serves as a critical pathological mechanism that contributes to the development of vascular dementia (VaD). NLRP3 inflammasome activation is a pivotal factor in promoting cognitive decline in CCH. Farrerol, a dihydroflavonoid derived from Rhododendron and other Ericaceae species, possesses anti-inflammatory, antioxidant, and neuroprotective properties. However, its role in regulating pyroptosis triggered by the NLRP3 inflammasome in CCH remains unclear. METHODS:A permanent CCH rat model was generated by occluding the bilateral common carotid arteries (BCCAO), and cellular models of sustained hypoxia were used to mimic CCH in vitro. Eight weeks post-surgery, rats received farrerol treatment. Behavioral tests were conducted after four weeks of treatment. Brain tissues were analyzed via histological staining, immunofluorescence, qRT-PCR, ELISA, and Western blot. The anti-pyroptosis effects and mechanisms of farrerol were also tested in BV2 cells and primary microglia subjected to hypoglycemia and hypoxia conditions. RESULTS:Farrerol markedly alleviated cognitive impairments and neural damage caused by CCH. In CCH rats, farrerol suppressed the activation of the NLRP3 inflammasome, decreased the levels of IL-1β and IL-18, and reduced pyroptosis. The in vitro experiments also demonstrated that farrerol could reduce chronic hypoxia-induced pyroptosis by inhibiting the NLRP3 inflammasome pathway. The cellular study further showed that the beneficial effects of farrerol in CCH are via modulating the MAPK-NF-κB pathway. CONCLUSION:Farrerol mitigates CCH-induced cognitive dysfunction by inhibiting NLRP3 inflammasome-associated pyroptosis via modulating the MAPK-NF-κB signaling cascade. These findings underscore the potential of farrerol as a therapeutic candidate for CCH.

Background:Atrial fibrillation (AF) represents a major risk factor of ischemic stroke recurrence with serious management implications. However, it often remains undiagnosed due to lack of standard or prolonged cardiac rhythm monitoring. We aim to create a novel end-to-end artificial intelligence (AI) model that uses MRI data to rapidly identify high AF risk in patients who suffer from an acute ischemic stroke. Methods:This study comprises an internal retrospective cohort and a prospective cohort from Shanghai sixth people's hospital to train and validate an MRI-based AI model. Between January 1, 2018 and December 31, 2021, 510 patients were retrospectively enrolled for algorithm development and performance was measured using fivefold cross-validation. Patients from this trial were registered with http://www.chictr.org.cn, ChiCTR2200056385. Between September 1, 2022 and July 31, 2023, 73 patients were prospectively enrolled for algorithm test. An external cohort of 175 patients from Huashan Hospital, Minhang Hospital, and Shanghai Tenth People's Hospital was also enrolled retrospectively for further model validation. A combined classifier leveraging pre-defined radiomics features and de novo features extracted by convolutional neural network (CNN) was proposed to identify underlying AF in acute ischemic stroke patients. Area under the curve (AUC), sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were calculated for model evaluation. Findings:The top-performing combined classifier achieved an AUC of 0.94 (95% CI, 0.90-0.98) in the internal retrospective validation group, 0.85 (95% CI, 0.79-0.91) in the external validation group, and 0.87 (95% CI, 0.90-0.98) in the prospective test group. Based on subgroup analysis, the AI model performed well in female patients, patients with NIHSS > 4 or CHA2DS2-VASc ≤ 3, with the AUC of 0.91, 0.94, and 0.90, respectively. More importantly, our proposed model identified all the AF patients that were diagnosed with Holter monitoring during index stroke admission. Interpretation:Our work suggested a potential association between brain ischemic lesion pattern on MR images and underlying AF. Furthermore, with additional validation, the AI model we developed may serve as a rapid screening tool for AF in clinical practice of stroke units. Funding:This work was supported by grants from the National Natural Science Foundation of China (NSFC, Grant Number: 81871102 and 82172068); Shanghai Jiao Tong University School of Medicine, Two-Hundred Talent Program as Research Doctor (Grant Number: SBR202204); Municipal Science and Technology Commission Medical Innovation Project of Shanghai, (Grant/Award Number: 20Y11910200); Research Physician Program of Shanghai Shen Kang Hospital Development Center (Grant Number: SHD2022CRD039) to Dr. Dong Huang and the SJTU Trans-med Awards Research (No. 20220101) to Dahong Qian.

Alzheimer's disease (AD) stands as the most prevalent neurodegenerative condition worldwide, and its correlation with microglial function is notably significant. Dl-3-n-butylphthalide (NBP), derived from the seeds of Apium graveolens L. (Chinese celery), has demonstrated the capacity to diminish Aβ levels in the brain tissue of Alzheimer’s transgenic mice. Despite this, its connection to neuroinflammation and microglial phagocytosis, along with the specific molecular mechanism involved, remains undefined. In this study, NBP treatment exhibited a substantial improvement in learning deficits observed in AD transgenic mice (APP/PS1 transgenic mice).Furthermore, NBP treatment significantly mitigated the total cerebral Aβ plaque deposition. This effect was attributed to the heightened presence of activated microglia surrounding Aβ plaques and an increase in microglial phagocytosis of Aβ plaques. Transcriptome sequencing analysis unveiled the potential involvement of the AGE (advanced glycation end products) -RAGE (receptor for AGE) signaling pathway in NBP’s impact on APP/PS1 mice. Subsequent investigation disclosed a reduction in the secretion of AGEs, RAGE, and proinflammatory factors within the hippocampus and cortex of NBP-treated APP/PS1 mice.In summary, NBP alleviates cognitive impairment by augmenting the number of activated microglia around Aβ plaques and ameliorating AGE-RAGE-mediated neuroinflammation. These findings underscore the related mechanism of the crucial neuroprotective roles of microglial phagocytosis and anti-inflammation in NBP treatment for AD, offering a potential therapeutic target for the disease.

目的 利用多导睡眠图(PSG)监测技术分析主观认知下降(SCD)患者的睡眠结构特点.方法 选择2019年4月-2022年9月上海市第六人民医院神经内科记忆障碍门诊和老年病科认知障碍诊治中心所有以主观认知下降为主诉就诊的患者116例为研究对象,记录患者的性别、年龄、文化程度、既往史等基线资料.运用MMSE、MoCA等神经心理量表进行认知评估,匹兹堡睡眠质量指数(PSQI)评估患者的睡眠质量,根据结果分为睡眠正常(0～5分)组44例,睡眠障碍(6～21分)组72例.其中85例患者(睡眠正常者29例,睡眠障碍者56例)进行PSG监测,评估其睡眠结构特点.结果 与睡眠正常组比较,睡眠障碍组患者总睡眠时间明显缩短,睡眠效率降低,入睡后觉醒时间增加,REM期占比明显缩短,差异有统计学意义(P<0.01).结论 SCD伴睡眠障碍患者睡眠结构紊乱,可能导致主观认知下降.

Neuroinflammation plays critical roles in vascular dementia (VaD), the second leading cause of dementia, which can be induced by chronic cerebral hypoperfusion (CCH). NLRP3 inflammasome-induced pyroptosis, the inflammatory programmed cell death, has been reported to contribute to the development of VaD. ChemR23 is a G protein-coupled receptor that has emerging roles in regulating inflammation. However, the role of ChemR23 signalling in NLRP3 inflammasome-induced pyroptosis in CCH remains elusive. In this study, a CCH rat model was established by permanent bilateral common carotid artery occlusion (BCCAO) surgery. Eight weeks after the surgery, the rats were intraperitoneally injected with the ChemR23 agonist Resolvin E1 (RvE1) or chemerin-9 (C-9). Additionally, primary rat hippocampal neurons and SH-SY5Y cells were adopted to mimic CCH injury in vitro. Our results showed that the levels of ChemR23 expression were decreased from the 8th week after BCCAO, accompanied by significant cognitive impairment. Further analysis revealed that CCH induced neuronal damage, synaptic injury and NLRP3-related pyroptosis activation in hippocampal neurons. However, pharmacologic activation of ChemR23 with RvE1 or C-9 counteracted these changes. In vitro experiments also showed that ChemR23 activation prevented primary neuron pyroptosis induced by chronic hypoxia. In addition, manipulating ChemR23 expression markedly regulated NLRP3 inflammasome-induced neuronal pyroptosis through PI3K/AKT/Nrf2 signalling in SH-SY5Y cells under hypoglycaemic and hypoxic conditions. Collectively, our data demonstrated that ChemR23 activation inhibits NLRP3 inflammasome-induced neuronal pyroptosis and improves cognitive function via the PI3K/AKT/Nrf2 signalling pathway in CCH models. ChemR23 may serve as a potential novel therapeutic target to treat CCH-induced cognitive impairment.

衰老是随着年龄的增长,机体生理功能下降的自然过程.这是一切生物的普遍规律,其生理特征表现为皮肤松弛、血压升高、视力听力下降、平衡能力变差、反应变慢等等;其社会特征表现为社交范围变小、社会功能减弱、自我评价降低等等.衰老本身并不可怕,可怕的是人们对于衰老存在很多的误解.

目的 探讨梓醇-川芎嗪方(CT方)对阿尔茨海默病(AD)模型小鼠的作用及对水通道蛋白4表达的影响.方法 将β-淀粉样前体蛋白swe基因/早老蛋白1dE9基因(APPswe/PS1dE9)双转基因模型小鼠50只随机分为模型组、盐酸多奈哌齐片(安理申)组、梓醇-川芎嗪方低剂量组(CT-L组)、梓醇-川芎嗪方中剂量组(CT-M组)、梓醇-川芎嗪方高剂量组(CT-H组),每组10只.同月龄C57BL/6J小鼠10只为对照组.安理申组、CT-L组、CT-M组及CT-H组小鼠每天给予相应剂量的安理申及梓醇-川芎嗪方灌胃.对照组和模型组小鼠每天给予等体积的生理盐水灌胃,各组均为每天1次,连续灌胃8周,进行Morris水迷宫行为学检测,测定丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)及总抗氧化能力(T-AOC)水平,测定脑内β-淀粉样蛋白(Aβ)水平,检测水通道蛋白-4(AQP4)表达水平.结果 梓醇-川芎嗪方可以明显缩短APPswe/PS1dE9双转基因小鼠的逃避潜伏期、游泳距离、首次到达平台时间,增加穿越平台次数,降低脑内可溶性及不可溶性Aβ1-40、Aβ1-42水平,升高海马体和血清SOD、CAT和T-AOC水平,降低MDA水平,上调室周脑组织AQP4蛋白表达水平(P<0.05).结论 梓醇-川芎嗪方可以有效提高AD模型小鼠的认知和记忆能力,作用优于安理申.其作用机制可能与降低AD模型小鼠脑组织中Aβ沉积、调节氧化应激、上调AD模型小鼠室周脑组织AQP4蛋白表达水平有关.

Although diabetic cognitive impairment is one of the most common complications of type 2 diabetes mellitus (T2DM), optimized therapeutic strategies are not available yet. Astragalosides IV (AS-IV) is a traditional Chinese medicine possessing diverse pharmacological properties including anti-inflammatory and antioxidant effects. However, the effects of AS-IV on diabetes-related cognitive impairment and its precise mechanisms remain largely unknown. T2DM mice, induced by a high-fat diet (HFD) and an intraperitoneal injection of low-dose streptozotocin (STZ) were administrated with AS-IV every other day for eight consecutive weeks. Learning and memory abilities were assessed subsequently using the Ymaze test and the anxious behavior was evaluated using an open field test. Then, the morphology and number of neurons and microglia were observed by HE staining or immunohistochemistry. Oxidative stress biomarkers and pro-inflammatory cytokines were determined using relevant kits. In addition, the expression levels of Nrf2, Keap1, HO-1, and NQO1 were determined by Western blot analyses. The results indicated that AS-IV administration significantly improved neuronal damage and cognitive deficit in T2DM mice. Meanwhile, oxidative stress and neuroinflammation were also ameliorated in T2DM mice, which might be attributed to the regulation of Nrf2/Keap1/HO-1/NQO1 pathway in T2DM mice. Taken together, these data suggested that AS-IV ameliorates cognitive impairment in T2DM mice by attenuating oxidative stress and neuroinflammation, possibly through modulating the Nrf2/Keap1/HO1/NQO1 pathway.

目的 评价基于CanMEDS框架的住培新模式的效果.方法 将2016年7月至2020年6月进入神经内科住培基地的医学生223名,分为两组:新模式组117名基于CanMEDS框架内容进行规范化培训,传统模式组116名继续沿用传统的培训模式.对两组学员出基地时的各项考核成绩和培训满意度进行比较.结果 从专业知识[(84.07±6.93)分vs.(74.85±9.99)分]、临床技能[(85.26±6.08)vs.(76.38±8.17)分]、病史质量[(85.97±4.83)vs.(76.10±7.02)分]、科研能力[(79.84±8.40)分vs.(66.15±6.14)分]、卫生法规[(87.28±5.16)分vs.(79.20±7.42)分]等考核指标进行比较,新培训模式明显优于传统模式(P<0.01);培训满意度调查显示,在基地条件、带教师资相同前提下,对基地管理[(4.44±0.65)vs.(4.06±0.84)分]、培训内容[(4.61±0.54)分vs.(3.95±0.96)分]、培训效果[(4.54±0.56)分vs.(3.98±0.83)分]等指标的满意度,新培训模式组高于传统模式组(P<0.01).结论 基于CanMEDS框架的住培新模式,培训效果优于传统培训模式,可以提高住院医生的综合能力.

Vascular cognitive impairment (VCI) is the second most common form of dementia. Andrographolide (Andro) shows potential effects in anti-inflammation, anti-oxidative stress, and anti-apoptosis. We have obtained 48 potential genes related to the effect of Andro on VCI through network pharmacology analysis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to reveal significant enriched pathway of potential genes, and the mitogen-activated protein kinase (MAPK) pathway was screened out. To verify the results of network pharmacology, we tested the effects of Andro in VCI model induced by bilateral common carotid artery occlusion (BCCAO) surgery. The results showed that Andro treatment ameliorated the cognitive impairment induced by BCCAO. Immunohistochemistry study revealed that Andro could reduce neuronal damage and activation of microglia in the cortex and hippocampus in BCCAO rats. To test the MAPK pathway changes, we analyzed the expression of JNK, p38 and ERK and found that Andro reduced the levels of phosphorylated-ERK (p-ERK) and phosphorylated-p38 (p-p38) in BCCAO rats. In conclusion, Andro could improve neuronal survival, reduce neuroinflammation and ameliorate cognitive impairment in VCI. The underlying mechanisms of Andro treatment may be through the inhibition of MAPK pathway.

目的:探讨恒清Ⅰ号方联合盐酸多奈哌齐对血管性痴呆(vascular dementia,VD)患者的作用及其机制.方法:将VD患者132例按随机数字表法分为治疗组65例及对照组67例.两组患者均给予基础治疗.对照组同时给予盐酸多奈哌齐治疗,治疗组在对照组基础上给予恒清I号方,两组疗程均为3个月.比较治疗前后两组患者日常生活能力量表(activity of daily living,ADL)评分、长谷川痴呆量表(hasegawa dementia scale,HDS)评分、简易精神状态量表(minimum mental state examination,MMSE)评分、血液流变学指标水平(红细胞压积、血浆黏度、全血低切还原黏度与高切还原黏度)、白细胞介素6(interleukin-6,IL-6)和肿瘤坏死因子α(tumor necrosis factorα,TNF-α)、同型半胱氨酸(homocysteine,Hcy)、超敏C反应蛋白(high-sensitivity C-reactive protein,hs-CRP)、D-二聚体(D-Dimer)水平及总有效率.结果:治疗后治疗组HDS、MMSE与ADL评分均高于对照组(P<0.01);血液流变学指标与IL-6、TNF-α水平及Hcy、hs-CRP、D-Dimer水平均低于对照组(P<0.05);总有效率治疗组为84.6％,高于对照组的68.7％,差异有统计学意义(P<0.05).结论:恒清I号方与多奈哌齐联用可以提高VD患者HDS、MMSE与ADL评分.其作用机制可能为改善VD患者血液流变学指标,减轻炎症反应,降低氧化损伤,改善微循环,修复神经元细胞,保护中枢神经元,从而改善VD患者的日常生活能力及认知功能.

Background Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline in vascular dementia (VaD). We have previously shown that diabetes mellitus (DM) synergistically promotes CCH-induced cognitive dysfunction via exacerbating neuroinflammation. Furthermore, curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. However, the effects of curcumin on CCH-induced cognitive impairments in DM have remained unknown. Methods Rats were fed with a high-fat diet (HFD) and injected with low-dose streptozotocin (STZ), followed by bilateral common carotid artery occlusion (BCCAO), to model DM and CCH in vivo . After BCCAO, curcumin (50 mg/kg) was administered intraperitoneally every two days for eight weeks to evaluate its therapeutic effects. Additionally, mouse BV2 microglial cells were exposed to hypoxia and high glucose to model CCH and DM pathologies in vitro . Results Curcumin treatment significantly improved DM/CCH-induced cognitive deficits and attenuated neuronal cell death. Molecular analysis revealed that curcumin exerted protective effects via suppressing neuroinflammation induced by microglial activation, regulating the triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, alleviating apoptosis, and reducing nod-like receptor protein 3 (NLRP3)-dependent pyroptosis. Conclusions Taken together, our findings suggest that curcumin represents a promising therapy for DM/CCH-induced cognitive impairments.

何老师退休5年了,自从退休后自觉记忆力大不如以前,经常丢三落四,造成了很大的麻烦,也引起了自己和家人的担忧.何老师怀疑自己是不是得了老年性痴呆,于是来到了记忆障碍专病门诊.听了何老师的主诉,医生针对病情开了脑磁共振、血液生化全套检测和记忆力评估等检查.结果脑磁共振提示轻度老年脑,血液检测基本处于正常范围,简单的记忆力测试也在正常范围.医生诊断为主观认知下降.

阿尔茨海默病(AD)是一种进行性发展的神经退行性疾病,是导致老年人痴呆最主要的原因.AD的病理学主要表现为细胞外β淀粉样蛋白(Aβ)聚集和细胞内神经纤维缠结(NFT)形成.髓样细胞触发受体2(TREM2)主要在小胶质细胞和星形胶质细胞的细胞膜上表达,其突变可提高AD的发病风险,与配体结合可激活下游信号通路,调节小胶质细胞的存活、吞噬、增殖,并参与AD的病理发展过程.近年来,TREM2基因突变增加AD发病风险受到广泛重视.文中简要总结TREM2的相关信号通路,并讨论TREM2对Aβ沉积、tau蛋白的作用及其与AD的最强风险位点基因载脂蛋白E之间联系的研究进展.

Abstract Background Microglial-mediated neuroinflammation plays an important role in vascular dementia, and modulating neuroinflammation has emerged as a promising treatment target. Nicotinamide adenine dinucleotide (NAD+) shows anti-inflammatory and anti-oxidant effects in many neurodegenerative disease models, but its role in the chronic cerebral hypoperfusion (CCH) is still unclear. Methods The bilateral common carotid artery occlusion (BCCAO) was performed to establish CCH models in Sprague-Dawley rats. The rats were given daily intraperitoneal injection of NAD+ for 8 weeks. The behavioral test and markers for neuronal death and neuroinflammation were analyzed. Mitochondrial damage and ROS production in microglia were also assessed. RNA-seq was performed to investigate the mechanistic pathway changes. For in vitro studies, Sirt1 was overexpressed in BV2 microglial cells to compare with NAD+ treatment effects on mitochondrial injury and neuroinflammation. Results NAD+ administration rescued cognitive deficits and inhibited neuroinflammation by protecting mitochondria and decreasing ROS production in CCH rats. Results of mechanistic pathway analysis indicated that the detrimental effects of CCH might be associated with decreased gene expression of PPAR-γ co-activator1α (PGC-1α) and its upstream transcription factor Sirt1, while NAD+ treatment markedly reversed their decrease. In vitro study confirmed that NAD+ administration had protective effects on hypoxia-induced neuroinflammation and mitochondrial damage, as well as ROS production in BV2 microglia via Sirt1/PGC-1α pathway. Sirt1 overexpression mimicked the protective effects of NAD+ treatment in BV2 microglia. Conclusions NAD+ ameliorated cognitive impairment and dampened neuroinflammation in CCH models in vivo and in vitro, and these beneficial effects were associated with mitochondrial protection and ROS inhibition via activating Sirt1/PGC-1α pathway.

慢性脑低灌注(CCH)是血管性痴呆的危险因素之一,其相关机制涉及氧化应激、自噬、炎症反应等多个方面,其中神经炎症贯穿于CCH所致动物认知障碍的病理变化过程.被激活的小胶质细胞和其他神经胶质细胞产生大量的炎症因子,参与神经元损伤、脑白质病变、海马区损伤和β-淀粉样蛋白沉积等,这些损伤最终导致认知障碍的发生发展.深入研究CCH中神经炎症的意义以及小胶质细胞的促炎或抑炎作用,可为CCH引起的认知障碍提供新的治疗思路.

Alzheimer's disease is a devastating neurodegenerative disorder, with no disease-modifying treatment available yet. There is increasing evidence that neuroinflammation plays a critical role in the pathogenesis of AD. Andrographolide (Andro), a labdane diterpene extracted from the herb Andrographis paniculata, has been reported to exhibit neuroprotective property in central nervous system diseases. However, its effects on Aβ and Aβ-induced neuroinflammation have not yet been studied. In the present study, we found that Andro administration significantly alleviated cognitive impairments, reduced amyloid-β deposition, inhibited microglial activation, and decreased the secretion of proinflammatory factors in APP/PS1 mice. Furthermore, transcriptome sequencing analysis revealed that Andro could significantly decrease the expression of Itgax, TLR2, CD14, CCL3, CCL4, TLR1, and C3ar1 in APP/PS1 mice, which was further validated by qRT-PCR. Our results suggest that Andro might be a potential therapeutic drug for AD by regulating neuroinflammation.

目的 探讨血管性痴呆(VaD)患者血同型半胱氨酸(Hcy)、超敏C反应蛋白(hs-CRP)、D-二聚体、脑源性神经营养因子(BDNF)和碱性成纤维细胞生长因子(bFGF)水平及其临床意义.方法 选取231例急性缺血性脑卒中患者,分为VaD组175例和非血管性痴呆(NVaD)组56例.同时选取52例健康志愿者为健康组.比较3组血Hcy、hs-CRP、D-二聚体、BDNF及bFGF水平,分析VaD患者认知功能与上述指标的关系.结果 VaD组的血Hcy、hs-CRP及D-二聚体水平均高于健康组和NVaD组(均P<0.05),血BDNF及bFGF水平均低于健康组和NVaD组(均P<0.05).轻度VaD组、中度VaD组、重度VaD组的血Hcy、hs-CRP和D-二聚体水平依次升高,血BDNF及bFGF水平依次降低(均P<0.05).VaD患者的痴呆程度与血Hcy、hs-CRP、D-二聚体水平呈正相关,与血BDNF及bFGF水平呈负相关(均P<0.05).结论 VaD患者血Hcy、hs-CRP、D-二聚体升高,而BDNF及bFGF降低;以上指标可能与VaD的发生发展有关,或可用于VaD预测以及疗效评估.