Nitric Oxide Decreases the Enzymatic Activity of Insulin Degrading Enzyme in APP/PS1 Mice

Nitric oxide has been implicated in the regulation of enzyme activity, particularly the activity of metalloproteinases. Since the inducible form of the nitric oxide synthase (NOS2), is upregulated in Alzheimer’s disease, we investigated the activity of two amyloid β degrading enzymes, IDE and neprilysin. In vitro we demonstrated that the activity of IDE was inhibited by *NO donor Sin-1, whereas activity of neprilysin remained unaffected. In vivo the activity of insulin-degrading enzyme was lowered in APP/PS1 mice, but not in APP/PS1/NOS2(−/−) mice. These data suggest that NOS2 upregulation impairs amyloid β degradation through negative regulation of IDE activity and thus loss of NOS2 activity will positively influence amyloid β clearance.     

Microglial Activation is Required for Aβ Clearance After Intracranial Injection of Lipopolysaccharide in APP Transgenic Mice

Inflammation has been argued to play a fundamental role in the pathogenesis of Alzheimer's disease. Mice transgenic for mutant human amyloid precursor protein (APP) develop progressive amyloid deposition, gliosis, and cognitive impairment. Paradoxically, intracranial administration of lipopolysaccharide (LPS) to promote neuroinflammation results in a reduction in amyloid-beta peptide (Abeta) burden concurrent with the inflammatory response. To determine whether microglia mediate Abeta clearance after LPS, we used dexamethasone to inhibit the microglial response. Amyloid precursor protein mice were injected intrahippocampally with either LPS or saline and were allowed to survive for 7 days with or without dexamethasone cotreatment. Brain tissue was then analyzed by immunohistochemistry. Hippocampal Abeta burden was reduced 7 days after LPS injection, and this was prevented by cotreatment with dexamethasone. Markers of microglial activation [CD45, complement receptor 3 (CR3), and macrosialin (CD68)] were increased by LPS, and these increases were attenuated by dexamethasone. Dexamethasone failed to block LPS-induced increases in all microglial markers, and Fcgamma receptors II/III and scavenger receptor A were increased by LPS but were unaffected by dexamethasone cotreatment. These results indicate a complex response by microglia to acute LPS treatment, with only some responses sensitive to steroidal anti-inflammatory drug treatment. Nonetheless, microglial activation was necessary to remove Abeta in this model of neuroinflammation.     

Amelioration of Cognitive Dysfunction in APP/PS1 Double Transgenic Mice by Long-Term Treatment of 4-O-Methylhonokiol

Alzheimer’s disease (AD) is the most common neurodegenerative disease without known ways to cure. A key neuropathologic manifestation of the disease is extracellular deposition of beta-amyloid peptide (Aβ). Specific mechanisms underlying the development of the disease have not yet been fully understood. In this study, we investigated effects of 4-O-methylhonokiol on memory dysfunction in APP/PS1 double transgenic mice. 4-O-methylhonokiol (1 mg/kg for 3 month) significantly reduced deficit in learning and memory of the transgenic mice, as determined by the Morris water maze test and step-through passive avoidance test. Our biochemical analysis suggested that 4-O-methylhonokiol ameliorated Aβ accumulation in the cortex and hippocampus via reduction in beta-site APP-cleaving enzyme 1 expression. In addition, 4-O-methylhonokiol attenuated lipid peroxidation and elevated glutathione peroxidase activity in the double transgenic mice brains. Thus, suppressive effects of 4-O-methylhonokiol on Aβ generation and oxidative stress in the brains of transgenic mice may be responsible for the enhancement in cognitive function. These results suggest that the natural compound has potential to intervene memory deficit and progressive neurodegeneration in AD patients.     

左乙拉西坦通过抑制NLRP3炎症小体的活化和氧化应激改善APP/PS1小鼠的认知障碍

目的 以氧化应激和神经炎症为切入点,考察左乙拉西坦治疗阿尔茨海默病的药效和潜在机制。方法 淀粉样蛋白前体蛋白/I型早老素双转基因（amyloid precursor protein-swe/presenilin-1-1dE9,APP/PS1）模型小鼠按照体质量每2 d通过尾静脉注射不同剂量左乙拉西坦（5,10,20 mg·kg^-1）,连续给药30 d。自主活动试验考察实验动物自主活动能力;Morris水迷宫试验考察实验动物认知能力;免疫组化试验考察实验动物海马脑区小胶质细胞活化程度;半胱天冬酶-1（caspase-1）活力检测试剂盒考察实验动物海马脑区caspase-1活力;蛋白免疫印迹试验考察实验动物海马脑区白介素-1β（interleukin-1β,IL-1β）、核苷酸结合寡聚化结构域样受体家族pyrin结构域蛋白3（NOD-,LRR-and pyrin domain-containing protein 3,NLRP3）、凋亡相关斑点样蛋白（apoptosis-associated speck-like protein containing a CARD,ASC）、caspase-1蛋白表达水平;比色法试剂盒检测实验动物海马脑区超氧化物歧化酶（superoxide dismutase,SOD）活力、谷胱甘肽（glutathione,GSH）水平、过氧化氢（H₂O₂）含量和丙二醛（malondialdehyde,MDA）水平。结果 与空白组小鼠相比,APP/PS1模型组小鼠的逃避潜伏期显著延长,且海马脑区小胶质细胞活化程度明显加剧,IL-1β水平明显增加,NLRP3和caspase-1蛋白水平明显增加,SOD活力显著下降,GSH水平显著减少,MDA水平显著增加。与模型组相比,左乙拉西坦10 mg·kg^-1和20 mg·kg^-1可以显著缩短APP/PS1小鼠逃避潜伏期,显著减轻海马脑区小胶质细胞活化程度,显著降低IL-1β水平,显著减少NLRP3和caspase-1蛋白水平,显著增加SOD活力和GSH水平、显著减少MDA水平。结论 左乙拉西坦可以显著改善APP/PS1小鼠的认知功能,其作用机制可能与抑制炎症小体的活化和氧化应激密切相关。     

米索前列醇对APP/PS1转基因小鼠的神经保护作用

目的观察米索前列醇对APP/PS1转基因小鼠海马和皮层损伤的保护作用并探讨其机制。方法实验动物设4组:转基因模型组和药物处理组APP/PS1转基因小鼠各10只,老年对照组为野生型C57小鼠10只,药物处理组给予米索前列醇,另两组给予羧甲基纤维素钠,均在小鼠24周龄时以200μg·kg-1的量开始灌胃给予,连续给药20周,每周连续5 d,每天1次;在指标测试阶段,另取10只8周龄野生型C57小鼠作为青年对照组。采用Morris水迷宫测试空间学习记忆能力,HE染色观察海马和皮层神经元形态变化,生化法检测海马和皮层SOD活性、MDA含量变化,免疫组织化学法检测海马和皮层Aβ表达情况。结果与老年对照组小鼠相比,转基因模型组小鼠寻台潜伏期明显延长,海马和皮层神经元出现明显核固缩,SOD活性明显下降,MDA含量明显增加,Aβ表达明显增多;给予米索前列醇后,APP/PS1转基因小鼠寻台潜伏期明显缩短,海马和皮层神经元核固缩明显减轻,SOD活性明显升高,MDA含量明显降低,Aβ表达明显减少。结论米索前列醇对APP/PS1转基因小鼠海马和皮层的神经损伤有显著保护作用,其机制可能与米索前列醇减轻APP/PS1转基因小鼠脑组织氧化应激有关。     

氟西汀对阿尔茨海默病模型小鼠的神经元保护作用

目的:研究氟西汀对老年APP/PS1双重转基因阿尔茨海默病模型小鼠学习记忆能力的影响及对神经元的保护作用.方法:实验分为动物实验和细胞实验.动物实验中取APP/PS1双重转基因小鼠随机分为氟西汀组(n=8)和生理盐水组(n=8),另取C57同窝生同月龄正常小鼠10只为对照组.氟西汀组小鼠给予氟西汀(10 mg/kg)腹腔注射,生理盐水组及对照组注射等量生理盐水1次/d,持续8周.Morris水迷宫实验进行行为学检测.Tunel染色检测海马区神经元凋亡.细胞实验中将人神经母细胞瘤细胞(SH-SY5Y)培养48 h后分为正常组、Aβ组、氟西汀组和氟西汀+Aβ组,后3组分别在含10μmol/L β-淀粉样蛋白、100 nmol/L氟西汀和100 nmol/L氟西汀+10μmol/L β-淀粉样蛋白的DMEM中继续培养48 h.行原位细胞凋亡染色检测各组细胞凋亡.结果:水迷宫定位航行实验中,氟西汀组小鼠较生理盐水组相比平均潜伏期明显缩短(P＜0.01);空间探索实验中跨越平台次数增加(P＜0.01);海马区凋亡神经元数量减少(P＜0.01).细胞实验中,氟西汀组和氟西汀+Aβ组与Aβ组相比,凋亡细胞数量明显减少(P＜0.01).结论:氟西汀对神经元细胞有保护作用,能减少神经元的凋亡,长期服用氟西汀能显著改善APP/PS1阿尔茨海默病模型小鼠学习记忆力能力.     

Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity,Attenuates Cognitive Deficits in APP/PS1 Mice

Journal of Neuroimmune Pharmacology - Neuroinflammation plays an early and prominent role in the pathology of Alzheimer’s disease (AD). Tumor necrosis factor-α-induced protein 8-like 2...     

类叶升麻苷对APP/PS1双转基因小鼠抗炎及抗氧化作用的研究

目的：探讨类叶升麻苷（Acteoside，AS）对APP/PS1双转基因小鼠炎症因子及氧化应激因子变化的影响。方法：健康APP/PS1转基因小鼠90只，对照B6C3雄鼠16只，雌雄各半，连续90 d灌胃给药，给药76 d进行Morris水迷宫实验，87 d进行跳台实验，解剖后检测血清、海马和皮层中炎症及氧化应激相关因子。结果：模型组小鼠血清中IL6、TNF-α含量显著高于正常组，模型组小鼠海马中IL1-β、IL6、IFN-γ、ROS含量显著高于正常组，模型组小鼠皮层中IL1-β、ROS含量显著高于正常组，IL6、TNF-α、IFN-γ含量与正常组无明显差异。AS可显著降低皮层中IL1-β、IL6、IFN-γ、ROS含量。结论：AS可通过降低痴呆小鼠致炎因子含量以抑制炎症反应，从而对机体产生免疫调节作用，保护神经细胞并改善脑部损伤，进而发挥其神经保护及改善学习记忆的作用。同时，AS可显著降低ROS含量，说明AS可通过抑制氧化应激损伤达到改善小鼠学习记忆功能的作用。     

右美托咪定对减轻 APP/PS1小鼠海马区炎性因子分泌及细胞凋亡的作用

目的 探讨右美托咪定(dexmedetomidine,DEX)对APP/PS1转基因小鼠海马区抗炎抗凋亡的作用,并探讨其可能的机制.方法 2018年3月至2019年3月,将APP/PS1小鼠采用随机数字表法分为模型组(TG)、DEX低、高剂量组(TG+10、20μg/kg DEX,每天腹腔注射1次,连续4周)和4-苯基丁酸(PBA)阳性对照组(TG+400 mg/kg PBA,每天腹腔注射1次,连续4周),另取野生型C57BL/6小鼠作为对照组(WT);水迷宫检测各组小鼠的学习与记忆能力;Nissl染色各组小鼠海马区神经细胞的数量;TUNEL检测各组小鼠海马区凋亡细胞数;ELISA检测各组小鼠海马区白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)及肿瘤坏死因子α(TNF-α)蛋白的表达;WB法检测海马区B淋巴细胞瘤-2相关X蛋白(Bax)、B淋巴细胞瘤-2(Bcl-2)和半胱氨酸天冬氨酸蛋白酶(caspase-3)的表达;WB法检测小鼠海马区内质网应激相关蛋白葡萄糖调节蛋白78(GRP78)和内质网应激蛋白(CHOP)的表达.结果 与TG组比较,PBA和DEX明显提高APP/PS1小鼠的学习与记忆能力;增强海马区神经元的数量并减少神经细胞的凋亡;显著降低IL-1β、IL-6及TNF-α蛋白的浓度;抑制Bax/Bcl-2和裂解的caspase-3的表达;降低GRP78和CHOP的蛋白表达.结论 DEX对APP/PS1小鼠海马区炎症因子分泌以及细胞凋亡有一定的减轻作用,可能是通过抑制海马区内质网应激来发挥治疗作用.     

Kinetic Analysis of Aggregated Amyloid-β Peptide Clearance in Adult Bone-marrow-derived Macrophages from APP and CCL2 Transgenic Mice

Accumulating evidence suggests that bone-marrow (BM)-derived mononuclear phagocytes have an important role in the clearance of soluble and aggregated amyloid-β peptides (Aβ) in Alzheimer’s disease (AD) brains. However, the exact kinetics of Aβ clearance in mononuclear phagocytes derived from transgenic animal models of AD expressing β-amyloid precursor protein (APP) mutants have been poorly characterized. We have examined whether CCL2 and APP expression affects the clearance of Aβ in conjunction with our control, acetylated low-density lipoprotein (AcLDL), using primary cultured BM-derived macrophages derived from adult APP, CCL2, APP/CCL2, and control littermates. Pulse-chase analysis demonstrated three distinct destinations for Aβ40 and AcLDL: intracellular retention, degradation, and secretion. As predicted, 50% of Aβ remained intracellularly contained even 5 days after pulse, while 40% of degraded and 14% of nondegraded Aβ were secreted. APP/CCL2 macrophages show reduced intracellular Aβ retention, along with enhanced secretion of both degraded and nondegraded Aβ. Aβ accumulation in aggresome is also partially reduced in APP/CCL2 macrophages as compared to other APP, CCL2, or control groups, suggesting impaired sorting of aggregated Aβ in aggresomes. The degradation of intracranially injected ¹²⁵I-Aβ40 aggregates was also enhanced in adult APP/CCL2 mice as compared to APP littermates in vivo. These data suggest that APP and CCL2 synergistically enhance BM-derived macrophage-mediated clearance of Aβ. In contrast, the clearance of AcLDL by BM-derived macrophages was not significantly enhanced by the presence of either APP or CCL2.     

APP/PS1 transgenic mice treated with aluminum: an update of Alzheimer's disease model

There is still no animal model available that can mimic all the cognitive, behavioral, biochemical, and histopathological abnormalities observed in patients with Alzheimer's disease (AD). We undertook to consider the interaction between genetic factors, including amyloid precursor protein (APP) and presenilin-1 (PS1), and environmental factors, such as Aluminum (Al) in determining susceptibility outcomes when studying the pathogenesis of AD. In this article, we provide an AD model in APP/PS1 transgenic mice triggered by Al. The animal model was established via intracerebral ventricular microinjection of aluminum chloride once a day for 5 days in APP/PS1 transgenic mice. Twenty wild type (WT) mice and 20 APP/PS1 transgenic (TG) mice were separately divided into 2 groups (control and Al group), and a stainless steel injector with stopper was used for microinjection into the left-lateral cerebral ventricle of each mouse. The Morris water maze task was used to evaluate behavioral function of learning and memory ability on the 20th day after the last injection. This AD model's brain was analyzed by: (1) amyloid beta immunohistochemical staining; (2) Tunnel staining; (3) apoptotic rates; (4) caspase-3 gene expression. Here, decrease of cognitive ability and neural cells loss were shown in APP/PS1 transgenic mice exposed to Al, which were more extensive than those in APP/PS1 TG alone and WT mice exposed to Al alone. These findings indicate that there is a close relationship between over-expression of APP and PS1 genes and Al overload. It is also suggested that APP/PS1 TG mice exposed to Al have potential value for improving AD models.     

荭草苷对APP/PS1转基因痴呆小鼠认知功能和海马自噬的影响

目的探究荭草苷对APP/PS1转基因小鼠认知功能的影响及其可能的作用机制。方法实验动物分为3组:7月龄的转基因模型组(Tg)、荭草苷处理转基因组(Tg+Ori)、同月龄的野生型C57BL/6J小鼠作为非转基因对照组(NT),每组8只。Tg+Ori组连续30 d每天腹腔注射荭草苷(10 mg·kg~(-1)),NT和Tg组注射同等剂量的生理盐水。水迷宫实验检测学习记忆能力,免疫组化检测β淀粉样蛋白(Aβ),免疫印迹检测自噬相关蛋白。结果与NT组相比,Tg组小鼠学习记忆能力受损,海马出现大量Aβ斑块, LC3-Ⅱ、p62、Cathepsin D蛋白表达升高;与Tg组相比,Tg+Ori组小鼠学习记忆能力增强,海马Aβ斑块减少,LC3-Ⅱ、p6、Cathepsin D蛋白水平降低;组间Beclin-1蛋白水平无明显差异。结论荭草苷能够改善转基因小鼠认知功能,减少海马Aβ沉积,促进自噬溶酶体降解。     

复方丹参片对APP/PS1转基因小鼠焦虑样行为的调节作用

目的探讨复方丹参片对阿尔采末病(AD)APP/PS1转基因小鼠焦虑样行为的作用及机制。方法4月龄野生型小鼠(正常组)和APP/PS1转基因小鼠分别灌胃给予溶剂(模型组)或复方丹参片低剂量(180 mg·kg~(-1))、中剂量(360 mg·kg~(-1))、高剂量(720 mg·kg~(-1))和阳性药物舍曲林(15 mg·kg~(-1))60 d后,采用Morris水迷宫实验、新奇抑制摄食实验和高架十字迷宫实验评价复方丹参片对小鼠记忆障碍和焦虑样行为学表现的影响,采用高效液相色谱法(HPLC)和ELISA分别检测小鼠前额皮质、海马和杏仁核γ-氨基丁酸(GABA)和脑源性神经营养因子(BDNF)的含量。结果复方丹参片中、高剂量明显缩短小鼠找到平台的潜伏期,明显增加小鼠原有平台象限的探索时间(P<0.05,P<0.01)。高架十字迷宫试验结果显示,复方丹参片高剂量显著增加APP/PS1转基因小鼠在开臂的时间百分比和进入开臂的次数(P<0.01);新奇抑制摄食实验结果显示,复方丹参片中、高剂量显著缩短APP/PS1转基因小鼠摄食潜伏期(P<0.05,P<0.01)。HPLC和ELISA结果显示,复方丹参片中、高剂量可显著增加APP/PS1转基因小鼠不同脑区如前额皮质、海马和杏仁核GABA和BDNF含量(P<0.05,P<0.01)。结论复方丹参片改善AD转基因小鼠的学习记忆损伤和焦虑样行为,可能与增加脑组织GABA和BDNF水平有关。     

The Phosphodiesterase-4 Inhibitor Roflumilast,a Potential Treatment for the Comorbidity of Memory Loss and Depression in Alzheimer’s Disease: A Preclinical Study in APP/PS1 Transgenic Mice

BackgroundDepression is highly related to Alzheimer’s disease (AD), yet no effective treatment is available. Phosphodiesterase-4 (PDE4) has been considered a promising target for treatment of AD and depression. Roflumilast, the first PDE4 inhibitor approved for clinical use, improves cognition at doses that do not cause side effects such as emesis.MethodsHere we examined the effects of roflumilast on behavioral dysfunction and the related mechanisms in APPswe/PS1dE9 transgenic mice, a widely used model of AD. Mice at 10 months of age were examined for memory in the novel object recognition and Morris water-maze tests and depression-like behavior in the tail-suspension test and forced swimming test before killing for neurochemical assays.ResultsIn the novel object recognition and Morris water-maze, APPswe/PS1dE9 mice showed significant cognitive declines, which were reversed by roflumilast at 5 and 10 mg/kg orally once per day. In the tail-suspension test and forced swimming test, the AD mice showed prolonged immobility time, which was also reversed by roflumilast. In addition, the staining of hematoxylin–eosin and Nissl showed that roflumilast relieved the neuronal cell injuries, while terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling analysis indicated that roflumilast ameliorated cell apoptosis in AD mice. Further, roflumilast reversed the decreased ratio of B-cell lymphoma-2/Bcl-2-associated X protein and the increased expression of PDE4B and PDE4D in the cerebral cortex and hippocampus of AD mice. Finally, roflumilast reversed the decreased levels of cyclic AMP (cAMP) and expression of phosphorylated cAMP response element-binding protein and brain derived neurotrophic factor in AD mice.ConclusionsTogether, these results suggest that roflumilast not only improves learning and memory but also attenuates depression-like behavior in AD mice, likely via PDE4B/PDE4D-mediated cAMP/cAMP response element-binding protein/brain derived neurotrophic factor signaling. Roflumilast can be a therapeutic agent for AD, in particular the comorbidity of memory loss and depression.     

Geniposide Attenuates the Phosphorylation of Tau Protein in Cellular and Insulin‐deficient APP/PS1 Transgenic Mouse Model of Alzheimer's Disease

Our previous studies have shown that geniposide plays an essential role in glucose‐stimulated insulin secretion from pancreatic β cells and also regulates the metabolism of Aβ and its deposition in neurons. In this study, we reported that insulin deficiency induced significant increase of tau phosphorylation. Administration of geniposide for 4 weeks significantly decreased the phosphorylated level of tau and the acceleration of GSK‐3β phosphorylation in the brain of APP/PS1 transgenic mice induced by insulin deficiency. We also observed that geniposide decreased the phosphorylation of tau protein directly and increased the phosphorylation of Akt in primary cultured cortical neurons. Furthermore, geniposide enhanced the role of insulin on the phosphorylation of Akt, GSK‐3β, and tau in primary cultured cortical neurons. And these effects of geniposide in cortical neurons could be prevented by preincubation with LY294002, an inhibitor of PI3K. Taken together, our findings provide a mechanistic and perhaps a foundational link between diabetes and Alzheimer's disease and are consistent with the notion that geniposide might play an essential role on the phosphorylation of tau protein via enhancing insulin signaling and may convey a therapeutic benefit in Alzheimer's disease.     

Subchronic memantine administration on spatial learning, exploratory activity, and nest-building in an APP/PS1 mouse model of Alzheimer's disease

Glutamate neurotoxicity has been proposed to be involved in Alzheimer pathogenesis, with clinical data supporting succesful treatment with the NMDA receptor antagonist memantine. In the present study, the effects of subchronic memantine administration were assessed on spatial and non-spatial learning as well as exploratory activity and nest-building in APP/PS1 mutant mice. Memantine (10 mg/kg, i.p.) was better than placebo during the reversal phase of left-right discrimination, though equivalent to saline for Morris water maze and passive avoidance learning. The drug had no effect on non-learned behaviors in elevated plus-maze exploration and nest-building. These results support a specific action of the NMDA receptor antagonist on behavioral flexibility in mutant mice with amyloid pathology.     

Effects of Calcium Gluconate,a Water Soluble Calcium Salt on the Collagen-Induced DBA/1J Mice Rheumatoid Arthritis

This study examined the effects of calcium (Ca) gluconate on collagen-induced DBA mouse rheumatoid arthritis (CIA). A single daily dose of 200, 100 or 50 mg/kg Ca gluconate was administered orally to male DBA/1J mice for 40 days after initial collagen immunization. To ascertain the effects administering the collagen booster, CIA-related features (including body weight, poly-arthritis, knee and paw thickness, and paw weight increase) were measured from histopathological changes in the spleen, left popliteal lymph node, third digit and the knee joint regions. CIA-related bone and cartilage damage improved significantly in the Ca gluconate- administered CIA mice. Additionally, myeloperoxidase (MPO) levels in the paw were reduced in Ca gluconate-treated CIA mice compared to CIA control groups. The level of malondialdehyde (MDA), an indicator of oxidative stress, decreased in a dosedependent manner in the Ca gluconate group. Finally, the production of IL-6 and TNF-α, involved in rheumatoid arthritis pathogenesis, were suppressed by treatment with Ca gluconate. Taken together, these results suggest that Ca gluconate is a promising candidate anti-rheumatoid arthritis agent, exerting anti-inflammatory, anti-oxidative and immunomodulatory effects in CIA mice.     

基于六味地黄丸新配方的LW-AFC对认知缺陷、突触可塑性损伤和神经免疫调节病变APP/PS1和SAMP8小鼠的作用（英文）

OBJECTIVE To investigate the effect of LW-AFC,a new formula of the main active components extracted from Liuwei Dihuang decoction,on treatment of Alzheimer′s disease in mouse models.METHODS The APP/PS1 transgenic mice and senescence-accelerated mouse prone 8(SAMP8)were administered orally by LW-AFC continuously for 3 months.The behavioral tests were conducted by the novel object recognition(recognition memory task),the Morris water maze(spatial memory test),the shuttle box and step-down tests(active and passive avoidance,associative learning task).The synaptic plasticity was evaluated by long-term potentiation(LTP)experiment in anesthetized mice.The cytokine profiles in serum were assayed by multiplex Luminex assay methods.The hormone levels associated with hypothalamo-pituitary-adrenal(HPA)and hypothalamo-pituitary-gonad(HPG)were measured by radioimmunoassay.The levels of Aβ1-40 and Aβ1-42 were assayed by AlphaLISA technique.RESULTS The administration of LW-AFC significantly improved the behavioral performances in novel object recognition tasks,spatial memory tasks,and associative learning tasks both in APP/PS1 transgenic mice and SAMP8 mice,and the inductions of LTP were also significantly facilitated.Meanwhile,the concentrations of Aβ1-40 and Aβ1-42 in cerebral cortex,hippocampus and serum were decreased in LW-AFC treated groups.The serum concentration of some proinflammatory cytokines,such as IL-1β,IL-2,IL-6,IL-17,IL-23,INF-γ,TNF-α,TNF-β,MCP-1 and MIP-1β were significantly decreased,while the anti-inflammatory cytokines,such as IL-4,IL-10,IL-5 and G-CSF were significantly increased.In addition,LW-AFC could also improved the abnormalities of the corticotropin releasing hormone(CRH)and gonadotropin-releasing hormone(GnRH)levels in hypothalamus,the adrenocorticotropic hormone(ACTH),luteinizing hormone(LH)and follicle stimulating hormone(FSH)levels in pituitary,the corticosterone and testosterone level in serum,respectively.CONCLUSION LW-AFC improves cognitive deficits and synaptic plasticity impairments in AD mouse models,and this may be due to,at least in part,the modulation of neuroimmunomodulation network by LW-AFC,suggesting that LW-AFC might be a promising therapy for AD.     

Combined phenotypes of APP/PS1 transgenic mouse and senescence accelerated mouse P8(SAMP8) demonstrate more severe cognitive impairment and progressive neuropathology

Amyloid beta(Aβ) is the primary constituent of plaque seen in Alzheimer’s disease.APP/PS1 mice,which possess the human APP/PS1 mutation,have been shown to demonstrate both Aβ plaque pathology and memory deficits in behavioral task.While SAMP8 mice are the strain of animal exhibiting age-related pathological changes in the brain and deficit in learning and memory.We crossed APP/PS1 mice with SAMP8 strain mice and generated AD model(P8-APP/PS1) mice expressing human APP/PS1 gene in SAMP8 background.To characterize the P8-APP/PS1 model,behavioral evaluations in a full of sensorimotor,anxiety,and cognitive tasks were conducted in the new strain mice with same ages of C57 wild,C57 APP/PS1 and SAMP8 wild mice serving as control groups.At the ages of 3,6 and 9 months,P8-APP/PS1 mice exhibited greater open field activity than C57 APP/PS1.The elevated plus maze experiment showed that P8-APP/PS1 mouse spent more time in open arm compared with C57 APP/PS1.The learning memory ability was measured by applying shuttle box and Morris water maze.At 9 months old,the learning and memory deficit was found in P8-APP/PS1 mice,but there was not in control groups.To further evaluate the pathological changes,beta amyloid immunohistochemistry was performed and dense APP deposit was observed at the earlier life time as 6 months in P8-APP/PS1,but not in control groups.Moreover,APP deposit in P8-APP/PS1 was aggravated and most severe compared to other groups at 9 months old.Induced APP/PS1 into SAMP8 strain exacerbated cognitive impairment and accelerated APP deposition at an early age in SAMP8 life.Thus,P8-APP/PS1 model could be considered as a more relevant AD model for the AD research.