Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

Jiaohong pills attenuate neuroinflammation and amyloid-βprotein-induced cognitive deficits by modulating the mitogen-activated protein kinase/nuclear factor kappa-B pathway

Background:Jiaohong pills(JHP)consist of Pericarpium Zanthoxyli(PZ)and Radix Rehmanniae,two herbs that have been extensively investigated over many years due to their potential protective effects against cognitive decline and memory impairment.However,the precise mechanisms underlying the beneficial effects remain elusive.Here,research studies were conducted to investigate and validate the therapeutic effects of JHP on Alzheimer's disease.Methods:BV-2 cell inflammation was induced by lipopolysaccharide.AD mice were administered amyloid-β(Aβ).Behavioral experiments were used to evaluate learning and memory ability.The levels of nitric oxide(NO),tumor necrosis factor-alpha(TNF-α),interleukin-1β(IL-1β),and interleukin-10(IL-10)were detected using enzymelinked immunosorbent assay(ELISA).The protein expressions of inducible nitric oxide synthase(iNOS)and the phosphorylation level of mitogen-activated protein kinase(MAPK)and nuclear factor kappa-B(NF-κB)were detected using Western blot.Nissl staining was used to detect neuronal degeneration.Results:The results demonstrated that an alcoholic extract of PZ significantly decreased the levels of NO,IL-1β,TNF-α,and iNOS;increased the expression level of IL-10;and significantly decreased the phosphorylation levels of MAPK and NF-κB.These inhibitory effects were further confirmed in the AD mouse model.Meanwhile,JHP improved learning and memory function in AD mice,reduced neuronal damage,and enriched the Nissl bodies in the hippocampus.Moreover,IL-1βand TNF-αin the cortex were significantly downregulated after JHP administration,whereas IL-10showed increased expression.Conclusions:It was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF-κB signaling pathway.

The relationship among amyloid-βdeposition,sphingomyelin level,and the expression and function of P-glycoprotein in Alzheimer’s disease pathological process

In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.

Overexpression of fibroblast growth factor 13 ameliorates amyloid-β-induced neuronal damage

Previous studies have shown that fibroblast growth factor 13 is downregulated in the brain of both Alzheimer’s disease mouse models and patients,and that it plays a vital role in the learning and memory.However,the underlying mechanisms of fibroblast growth factor 13 in Alzheimer’s disease remain unclear.In this study,we established rat models of Alzheimer’s disease by stereotaxic injection of amyloid-β(Aβ_(1-42))-induced into bilateral hippocampus.We also injected lentivirus containing fibroblast growth factor 13 into bilateral hippocampus to overexpress fibroblast growth factor 13.The expression of fibroblast growth factor 13 was downregulated in the brain of the Alzheimer’s disease model rats.After overexpression of fibroblast growth factor 13,learning and memory abilities of the Alzheimer’s disease model rats were remarkably improved.Fibroblast growth factor 13 overexpression increased brain expression levels of oxidative stress-related markers glutathione,superoxide dismutase,phosphatidylinositol-3-kinase,AKT and glycogen synthase kinase 3β,and anti-apoptotic factor BCL.Furthermore,fibroblast growth factor 13 overexpression decreased the number of apoptotic cells,expression of pro-apoptotic factor BAX,cleaved-caspase 3 and amyloid-βexpression,and levels of tau phosphorylation,malondialdehyde,reactive oxygen species and acetylcholinesterase in the brain of Alzheimer’s disease model rats.The changes were reversed by the phosphatidylinositol-3-kinase inhibitor LY294002.These findings suggest that overexpression of fibroblast growth factor 13 improved neuronal damage in a rat model of Alzheimer’s disease through activation of the phosphatidylinositol-3-kinase/AKT/glycogen synthase kinase 3βsignaling pathway.

Cannabidiol-Mediated Sequestration of Alzheimer’s Amyloid-β Peptides in ADDL Oligomers

Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.

壳寡糖对Amyloid-β_(1-42)致痴呆大鼠的学习记忆及血清抗氧化功能的影响

目的:探讨壳寡糖(chitosan oligosaccharide,COS)对Aβ_(1-42)致痴呆大鼠学习记忆及血清抗氧化功能的影响及其作用机制。方法:采用海马区微注射Aβ_(1-42)建立阿尔茨海默病大鼠痴呆模型,并使用COS干预,通过Morris水迷宫实验观察COS对阿尔茨海默病大鼠学习记忆能力的影响,同时通过测定血清中谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)和超氧化物歧化酶(superoxide dismutase,SOD)等抗氧化酶的活力以及蛋白质羰基和丙二醛(malondialdehyde,MDA)含量变化观察COS的抗氧化能力。结果:经行为学测试,与假手术对照组相比,模型组大鼠的学习记忆能力明显下降;COS干预后,其学习记忆功能力有所改善。同时,模型组大鼠血清中的SOD和GSH-Px活力相比较假手术组显著降低,MDA和蛋白质羰基含量显著增加;经COS干预后,与模型组相比,大鼠血清中SOD和GSH-Px活力显著上升,MDA和蛋白质羰基含量均显著减少。结论:COS对海马区微注射Aβ_(1-42)致痴呆大鼠有一定的改善和保护作用,具体的作用机制可能与COS的抗氧化作用有关。

胰岛素抵抗与阿尔茨海默病的关联性研究进展

随着中国老龄化人口的比例不断增加,阿尔茨海默病的发病率也随之升高。阿尔茨海默病作为最常见的神经退行性疾病,会表现出不可逆转的认知功能障碍。多项研究表明,胰岛素抵抗与阿尔茨海默病的β淀粉样蛋白异常积累、tau蛋白的异常以及神经炎症等发病机制具有关联性。本文系统总结了胰岛素抵抗与阿尔茨海默病的关联性及其可能机制。

淀粉样脑血管病相关心脏损伤的研究进展

淀粉样脑血管病是在世界范围内普遍存在的一种疾病,在老年人阿尔茨海默病患者中更为常见,最终结果就是导致大脑多发微出血灶。其特征是淀粉样蛋白-β在大脑皮质和软脑膜血管壁沉积,可能通过激活星形胶质细胞、小胶质细胞和促炎症物质来诱导大脑慢性炎症状态,损伤血脑屏障的完整性。淀粉样脑血管病是老年人认知改变和脑内出血的主要原因,患者也经常伴有心脏损伤。淀粉样脑血管病造成的心脏损伤是一个新的研究领域,需要深入分析从而提供治疗及预防靶点。

不同神经阻滞麻醉方案对胃癌根治患者术后疼痛、认知功能及血清Aβ-42、IL-6、tau-181蛋白影响

目的 探讨不同神经阻滞麻醉方案[椎旁神经阻滞术(TPVB)和星状神经节阻滞术(SGB)]对胃癌根治患者术后疼痛、认知功能及血清β淀粉样蛋白-42(Aβ-42)、白细胞介素-6(IL-6)、tau-181蛋白影响。方法 选取河北北方学院附属第一医院2020年1月至2023年1月收治的择期行腹腔镜胃癌根治术的患者120例为研究对象,按照随机数字表法分为TPVB组和SGB组,各60例。两组术中全麻方式相同,TPVB组在麻醉诱导前进行椎旁神经阻滞术,SGB组在麻醉诱导前进行星状神经节阻滞术。分别采用视觉模拟评分法(VAS)及蒙特利尔认知评估量表(MoCA)评估患者疼痛情况及认知功能;监测两组术后不同时间点疼痛变化情况,比较两组术前、术后1、3 d的认知功能及血清Aβ-42、IL-6、tau-181蛋白水平变化。结果 两组术后1、6、12、24 h的VAS评分差异均无统计学意义(t=1.183、1.325、0.397、0.611,P>0.05);术后1、3 d两组MoCA量表评分比较为TPVB组评分低于SGB组,差异均有统计学意义(t=2.281、3.218,P<0.05);术后1、3 d两组血清指标比较均为TPVB组Aβ-42、IL-6及tau-181蛋白水平高于SGB组,差异均有统计学意义(t=2.065、2.122、2.558、2.167、2.515、2.596,P<0.05)。结论 TPVB及SGB两种神经阻滞麻醉方案对胃癌根治患者术后镇痛均有良好的效果,但SGB比TPVB在减轻患者炎症反应及认知功能的改善方面更具优势。

3,6ʹ-二芥子酰基蔗糖神经保护作用研究

目的:研究远志中寡糖酯类成分3,6ʹ-二芥子酰基蔗糖(DISS)对神经的保护作用。方法:将不同浓度的DISS与APP-SH-SY5Y细胞共同孵育24 h,四甲基偶氮唑盐(MTT)法检测各组细胞的存活率,免疫荧光法检测细胞内活性氧(ROS)水平,生化法检测超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)活性,ELISA法检测细胞内和培养液中β-淀粉样蛋白(Aβ)含量,蛋白质免疫印迹法(Western blot)检测细胞内淀粉样前体蛋白(APP)、微管相关蛋白轻链3-Ⅰ(LC3-Ⅰ)和LC3-Ⅱ的表达。结果:DISS可以提高APP-SH-SY5Y细胞的存活率(P<0.05),减少细胞内ROS的生成(P<0.01),提高SOD和GSH-Px活力(P<0.05),降低细胞内和培养液中的Aβ含量(P<0.01,P<0.05),明显升高细胞内LC3Ⅱ蛋白表达水平,升高LC3Ⅱ/LC3Ⅰ水平(P<0.05),对APP表达无明显影响。结论:DISS可能通过降低细胞内氧化应激,减少细胞Aβ表达及调节自噬发挥神经保护作用。

去氢骆驼蓬碱改善阿尔茨海默病作用及其机制研究进展

去氢骆驼蓬碱(HM)是一种在自然界中丰富存在的β-咔啉类生物碱,具有多种生物学作用。近年体内外研究发现,HM对阿尔茨海默病(AD)具有明显改善作用。其机制可能与HM降低β-淀粉样蛋白(Aβ)异常沉积和Tau蛋白过度磷酸化、调节胆碱能系统、抗氧化应激和神经炎症等作用有关。该文综述HM改善AD的作用及其机制研究进展,以期为HM的临床应用和AD防治药物的开发提供参考。

太子参改善斑马鱼和APP/PS 1小鼠学习记忆

太子参是一种可用于保健食品的传统中药,具有抗疲劳和调节免疫等作用,但神经保护和改善记忆作用报道较少。为探究太子参改善记忆和认知障碍的有效成分及作用机制,利用Aβ1-42脑室显微注射斑马鱼模型初步探究太子参醇提物对记忆的改善作用;CCK8试剂盒测定太子参水提物、醇提物、多糖、皂苷、环肽对Aβ25-35诱导皮层神经元存活率的影响;荧光定量PCR测定太子参环肽B(heterophyllin B,HB)对神经元中凋亡相关基因的表达,免疫细胞化学染色探究HB对神经元的保护作用;利用APP/PS 1转基因小鼠探究HB对痴呆样行为和记忆的改善作用。太子参醇提物给药后,斑马鱼新臂和奖励臂探寻的潜伏期显著降低,在新臂和奖励臂游动时间和总路程增加。HB显著增加神经元存活率及β3-tubulin、MAP2阳性突起的表达,并改善APP/PS 1转基因小鼠记忆障碍。综上,太子参的神经保护作用可能通过HB减少突起萎缩,从而改善认知功能障碍和记忆缺陷。

电针“智三针”对5xFAD小鼠Notch信号通路及突触可塑性的影响

背景:阿尔茨海默病是以认知功能障碍为主要临床表现的退行性神经系统疾病,针刺是治疗阿尔茨海默病的传统特色疗法,但作用机制尚不明晰。目的:观察电针“智三针”对5xFAD小鼠Notch信号通路、β-淀粉样蛋白及突触可塑性的影响。方法:将16只SPF级、雄性、6月龄5xFAD小鼠随机分为电针“智三针”组和模型组,每组8只,另取8只同条件C57BL/6小鼠作为野生对照组。电针“智三针”组进行电针“智三针”干预,每周5次,连续4周;模型组、野生对照组不进行干预。干预结束后,采用Morris水迷宫初步评价学习记忆能力;硫磺素S染色检测β-淀粉样蛋白斑块沉积情况;Western blot和qPCR检测跨膜受体蛋白Notch 1、Notch 1胞内段(Notch 1 intracellular domain,NICD)、Split多毛增强子1(hairy and enhancer of split 1,Hes 1)、Split多毛增强子5(hairy and enhancer of split 5,Hes 5)、突触生长蛋白(synaptophysin,SYN)、突触后密度蛋白95(postsynaptic density protein-95,PSD-95)及β-淀粉样蛋白的表达水平。结果与结论:①与模型组相比,野生对照组、电针“智三针”组小鼠逃避潜伏期缩短,穿越平台次数及目标象限停留时间增加(P<0.05);②与野生对照组相比,模型组小鼠海马区β-淀粉样蛋白斑块沉积显著增加,而电针“智三针”抑制了β-淀粉样蛋白斑块沉积(P<0.05);③与野生对照组相比,模型组小鼠海马组织中SYN、PSD-95、Notch 1、NICD、Hes 1及Hes 5 mRNA表达降低,β-淀粉样蛋白mRNA表达增加(P<0.05);与模型组相比,电针“智三针”组SYN、PSD-95、Notch 1、NICD、Hes 1及Hes 5 mRNA表达升高,β-淀粉样蛋白mRNA表达降低(P<0.05);④与野生对照组相比,模型组小鼠海马组织中SYN、PSD-95、Notch 1、NICD、Hes 1及Hes 5蛋白表达降低,β-淀粉样蛋白表达增加(P<0.05),与模型组相比,电针“智三针”组SYN、PSD-95、Notch 1、NICD、Hes 1及Hes 5蛋白表达增加,β-淀粉样蛋白表达降低(P<0.05);⑤结果表明,电针“智三针”能够改善5xFAD小鼠的学习记忆功能,其机制可能与抑制海马区β-淀粉样蛋白沉积及激活Notch信号通路从而增强神经突触可塑性有关。

嗅三针对帕金森病痴呆小鼠海马CA1区载脂蛋白E和病理底物表达的影响

目的:观察嗅三针干预对帕金森病痴呆(Parkinson’s disease dementia,PDD)小鼠海马CA1区载脂蛋白E(apolipoprotein E,Apo E)、胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)以及相关核心病理底物表达的影响,探讨嗅三针改善PDD认知功能的部分作用机制。方法:将雄性C57BL/6小鼠随机分为空白组(Control)、假手术组(Sham)、模型组(Model)和电针组(AE),每组10只;采用单侧内侧前脑束(medial forebrain tract,MFB)注射6-羟多巴胺(6-hydroxydopamine,6-OHDA)建立PD模型并筛选PDD小鼠。建模筛选成功后,电针组选取嗅三针进行电针治疗,各组小鼠干预14天后采用Morris水迷宫实验和穿梭箱实验评估各组小鼠学习记忆能力;HE染色观察海马CA1区细胞病理改变;免疫印迹法检测海马CA1区α-syn、Aβ、Apo E蛋白的表达;免疫荧光双标观察海马CA1区Apo E与GFAP的共定位率。结果:与模型组比较,电针组小鼠水迷宫逃避潜伏期缩短(P<0.01),穿越平台次数增加(P<0.05),穿梭箱主动回避次数增加(P<0.05),电击刺激平均时间减少(P<0.01)。模型组小鼠海马CA1区神经细胞排列稀疏、变性坏死,细胞核体积变小、浓染、结构不清,呈核固缩表现;而电针组小鼠海马CA1区神经元病变有明显改善,大部分细胞排列规则,细胞核圆而大,染色浅,形态清晰。电针组小鼠海马CA1区α-syn、Aβ、Apo E蛋白以及Apo E与GFAP共定位率均较模型组减少(P<0.01,P<0.01,P<0.01,P<0.05)。结论:嗅三针可提高PDD小鼠认知能力并改善神经元形态结构与功能,机制可能与其抑制星形胶质细胞Apo E表达从而减少海马CA1区α-syn、Aβ沉积有关。

The roles of RACK1 in the pathogenesis of Alzheimer's disease

The receptor for activated C kinase 1(RACK1)is a protein that plays a crucial role in various signaling pathways and is involved in the pathogenesis of Alzheimer's disease(AD),a prevalent neurodegenerative disease.RACK1 is highly expressed in neuronal cells of the central nervous system and regulates the pathogenesis of AD.Specifically,RACK1 is involved in regulation of the amyloid-β precursor protein processing through α-or β-secretase by binding to different protein kinase C isoforms.Additionally,RACK1 promotes synaptogenesis and synaptic plasticity by inhibiting N-methyl-D-aspartate receptors and activating gamma-aminobutyric acid A receptors,thereby preventing neuronal excitotoxicity.RACK1 also assembles inflammasomes that are involved in various neuroinflammatory pathways,such as nuclear factor-kappa B,tumor necrosis factor-alpha,and NOD-like receptor family pyrin domain-containing 3 pathways.The potential to design therapeutics that block amyloid-β accumulation and inflammation or precisely regulate synaptic plasticity represents an attractive therapeutic strategy,in which RACK1 is a potential target.In this review,we summarize the contribution of RACK1 to the pathogenesis of AD and its potential as a therapeutic target.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease

Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.

BACE-1修饰的人骨髓间充质干细胞对创伤性颅脑损伤大鼠脑组织的保护作用

目的探究β-位点淀粉样前体蛋白剪切酶-1(BACE-1)修饰的人骨髓间充质干细胞(BMSCs)对创伤性颅脑损伤(TBI)大鼠脑组织的保护作用。方法将敲低BACE-1基因的腺病毒及空载体腺病毒感染BMSCs,并检测绿色荧光和BACE-1表达。将100只大鼠随机分为假手术(Sham)组、TBI组、空载体腺病毒感染BMSCs(Ad-BMSCs)组和敲低BACE-1基因的腺病毒感染BMSCs(Ad-si-BACE-1-BMSCs)组,每组各25只。采用Marmarou′s自由落体方法建立大鼠TBI模型,Sham组仅切开、缝合头皮,不致伤。建模2 h后,Ad-si-BACE-1-BMSCs组和Ad-BMSCs组分别经尾静脉注射敲低BACE-1基因的腺病毒及空载体腺病毒感染的BMSCs,Sham组和TBI组均给予等体积生理盐水。BMSCs移植7 d后,Morris水迷宫实验检测大鼠认知能力;苏木精-伊红染色和尼氏染色评估大鼠海马组织损伤;TUNEL染色检测海马神经元凋亡;硫黄素-S染色、免疫组化染色检测海马组织β-淀粉样蛋白(Aβ)含量;硫代巴比妥酸法和全自动生化分析仪检测海马组织丙二醛(MDA)、超氧化物歧化酶(SOD)水平;免疫荧光染色检测海马组织离子钙结合接头分子1(Iba-1)^(+)肿瘤坏死因子-α(TNF-α)+、Iba-1^(+)白细胞介素(IL)-6^(+)、Iba-1^(+)IL-1β^(+)、胶质纤维酸性蛋白(GFAP)+TNF-α^(+)、GFAP+IL-6^(+)、GFAP+IL-1β^(+)水平;蛋白免疫印迹(Western blot)检测海马组织BACE-1、Aβ、TNF-α、IL-6、IL-1β水平。结果与Sham组比较,TBI组大鼠逃避潜伏期增加、到达先前平台的次数和在平台停留的时间减少,海马神经元排列紊乱,尼氏小体减少,TUNEL阳性率增加,海马组织Aβ、BACE-1、TNF-α、IL-6、IL-1β蛋白、MDA含量、Iba-1^(+)TNF-α^(+)、Iba-1^(+)IL-6^(+)、Iba-1^(+)IL-1β^(+)、GFAP+TNF-α^(+)、GFAP+IL-6^(+)、GFAP+IL-1β^(+)细胞数增加,SOD含量减少(P均<0.05);与TBI组比较,Ad-BMSCs组和Ad-si-BACE-1-BMSCs组大鼠逃避潜伏期减少、到达先前平台的次数和在平台停留的时间增加,神经元排列较规则,尼氏小体增加,TUNEL阳性率减少,海马组织Aβ、BACE-1、TNF-α、IL-6、IL-1β蛋白、MDA含量、Iba-1^(+)TNF-α^(+)、Iba-1^(+)IL-6^(+)、Iba-1^(+)IL-1β^(+)、GFAP+TNF-α^(+)、GFAP+IL-6^(+)、GFAP+IL-1β^(+)细胞数减少,SOD含量增加(P均<0.05);且Ad-si-BACE-1-BMSCs对大鼠上述指标的影响优于Ad-BMSCs(P<0.05)。结论BACE-1修饰的人BMSCs能够抑制TBI大鼠氧化应激和炎症反应,对TBI大鼠脑组织具有保护作用。

Gamma-glutamyl transferase 5 overexpression in cerebrovascular endothelial cells improves brain pathology,cognition,and behavior in APP/PS1 mice

In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.

Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer's disease progression?

Astrocytes＇ roles in late-onset Alzheimer＇s disease （LOAD） promotion are important, since they survive soluble or fibrillar amyloid-β peptides （Aβs） neurotoxic effects, undergo alterations of intracellular and intercellular Ca2＋ signaling and gliotransmitters release via the Aβ/a7-nAChR （αT-nicotinic acetylcholine receptor） signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR （calcium-sensing receptor） signaling. Recently, it was suggested that the NMDAR （N-methyl-D-aspartate receptor） inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist （calcilytic）.

Epigenetic Regulation of Amyloid-beta Metabolism in Alzheimer’s Disease

Senile plaques(SPs)are one of the pathological features of Alzheimer’s disease(AD)and they are formed by the overproduction and aggregation of amyloid-beta(Aβ)peptides derived from the abnormal cleavage of amyloid precursor protein(APP).Thus,understanding the regulatory mechanisms during Aβ metabolism is of great importance to elucidate AD pathogenesis.Recent studies have shown that epigenetic modulation-including DNA methylation,non-coding RNA alterations,and histone modifications-is of great significance in regulating Aβ metabolism.In this article,we review the aberrant epigenetic regulation of Aβ metabolism.