Altered astrocyte calcium homeostasis and proliferation in theTs65Dn mouse,a model of Down syndrome

Genes from the Down syndrome (DS) critical region of human chromosome 21, which contribute to the pathology of DS, are also found on mouse chromosome 16. Several animal models of DS with triplication of genes from the DS critical region have been generated, including mouse trisomy 16 (Ts16) and a partial trisomic mouse, Ts65Dn. Using computer-assisted imaging of fura-2 fluorescence, we found an elevation of intracellular cytoplasmic calcium in cortical astrocytes from neonatal Ts65Dn mouse brain, similar to that observed previously in embryonic Ts16 astrocytes. Furthermore, astrocytes from both Ts65Dn and Ts16 cortex fail to respond to the anti-proliferative actions of glutamate. These results suggest that defective regulation of cell proliferation and cellular calcium can result from triplication of DS critical region genes.     

Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome

The Ts65Dn mouse, an adult model of Down syndrome displays behavioral deficits consistent with a dysfunctional hippocampus, similar to that seen with DS. In looking for mechanisms underlying these performance deficits, we have assessed adult neurogenesis in the dentate gyrus of Ts65Dn. Under untreated conditions, Ts65Dn mice (2-5 months old) showed markedly fewer BrdU-labeled cells than euploid animals. Chronic antidepressant treatment for over 3 weeks with the serotonin selective reuptake inhibitor, fluoxetine, increased neurogenesis in the Ts65Dn to comparable levels seen in the euploid by augmenting both proliferation and survival of BrdU-labeled cells in the subgranular layer and granule cell layer of the hippocampus, respectively.     

Restoring microglial and astroglial homeostasis using DNA immunization in a Down Syndrome mouse model

Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40.In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ_1-11 fragment, in ameliorating Aβ-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aβ_1-11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities.Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aβ from a young age by slowing the progression of dementia.     

Vasoactive intestinal peptide in the brain of a mouse model for Down syndrome

The most common genetic cause of mental retardation is Down syndrome, trisomy of chromosome 21, which is accompanied by small stature, developmental delays, and mental retardation. In the Ts65Dn segmental trisomy mouse model of Down syndrome, the section of mouse chromosome 16 most homologous to human chromosome 21 is trisomic. This model exhibits aspects of Down syndrome including growth restriction, delay in achieving developmental milestones, and cognitive dysfunction. Recent data link vasoactive intestinal peptide malfunction with developmental delays and cognitive deficits. Blockage of vasoactive intestinal peptide during rodent development results in growth and developmental delays, neuronal dystrophy, and, in adults, cognitive dysfunction. Also, vasoactive intestinal peptide is elevated in the blood of newborn children with autism and Down syndrome. In the current experiments, vasoactive intestinal peptide binding sites were significantly increased in several brain areas of the segmental trisomy mouse, including the olfactory bulb, hippocampus, cortex, caudate/putamen, and cerebellum, compared with wild-type littermates. In situ hybridization for VIP mRNA revealed significantly more dense vasoactive intestinal peptide mRNA in the hippocampus, cortex, raphe nuclei, and vestibular nuclei in the segmental trisomy mouse compared with wild-type littermates. In the segmental trisomy mouse cortex and hippocampus, over three times as many vasoactive intestinal peptide-immunopositive cells were visible than in wild-type mouse cortex. These abnormalities in vasoactive intestinal peptide parameters in the segmental trisomy model of Down syndrome suggest that vasoactive intestinal peptide may have a role in the neuropathology of Down-like cognitive dysfunction.     

Poor correlation between delayed neuronal death induced by transient forebrain ischemia,and immunoreactivity for parvalbumin and calbindin D-28k in developing gerbil hippocampus

In the normal developing hippocampus of the gerbil, parvalbumin-immunoreactive neurons first appear in the stratum pyramidale of CA3 at postnatal day 15 (P15), and in CA2 and hilus of the dentate gyrus from P21 onwards. Immunoreactive terminals also follow the same sequence from CA3 to CA1 to reach adult patterns by the end of the 1st month. Calbindin D-28k immunoreactivity is seen in the external part of the upper blade of the dentate gyrus at P5, and progresses to the granule cell and molecular layers of the whole gyrus by P15, except for a thin band of immature cells located at the base of the granule cell layer which are calbindin negative. Calbindin immunoreactivity in mossy fibers progresses from the external to the hilar region of CA3 during the same period. A few immunoreactive cells are also found in the stratum radiatum/lacunare of the CA3, but no calbindin-immunoreactive cells are observed in the CA1 and CA2 subfields. The adult pattern of calbindin immunoreactivity is reached at P21. Vulnerability following transient forebrain ischemia for 20 min was examined in the hippocampal formation of gerbils during postnatal development. No cellular damage was seen in animals aged 7 days. Dying cells were observed at the base of the granule cell layer of the dentate gyrus in animals aged 15, 21 and 30 days. Pyramidal cells in the CA3 subfield were also sensitive to ischemia in gerbils aged 15 days, and less frequently in animals aged 21 days. The adult pattern of cellular damage, characterized by selective vulnerability of the CA1 subfield, was seen from day 30 onwards. These findings show that the pattern of selective vulnerability following transient forebrain ischemia is different in young and adult gerbils, and suggest that little, if any, correlation exists between resistance to delayed cellular damage and parvalbumin and calbindin D-28k content in the hippocampus of young gerbils.Supported in part by grant FIS 93-131 and a grant from the Fundacio Pi i Synyer (to A.T.)     

The Ts65Dn mouse model of Down syndrome shows reduced expression of the Bcl-XL antiapoptotic protein in the hippocampus not accompanied by changes in molecular or cellular markers of cell death

The Ts65Dn (TS) mouse, the most widely used model of Down syndrome (DS), has a partial trisomy of a segment of chromosome 16 that is homologous to the distal part of human chromosome 21. This mouse shares many phenotypic characteristics with people with DS including neuromorphological, neurochemical, and cognitive disturbances. Both TS and DS brains show earlier aging and neurodegeneration. Since fibroblast cultures from TS mice and human DS hippocampal regions show increased apoptotic cell death it has been suggested that alterations in cerebral apoptosis might be implicated in the cognitive deficits found in TS mice and in people with DS. In the present study we have evaluated brain expression levels of several proapoptotic and antiapoptotic proteins from the mitochondrial (Bcl-2, Bcl-X_L, Bax and Bad) and the extrinsic (Fas-R and Fas-L) apoptotic pathways as well as the final executioner caspase-3, in the cortex and hippocampus of TS mice. No significant alterations in the expression levels of the proapoptotic Bad and Bax or the antiapoptotic Bcl-2 proteins in the cortex or hippocampus were found in TS mice. However, TS mice showed downregulation of Bcl-X_L in the hippocampus. In the extrinsic pathway we found unchanged levels of Fas-L in both structures and also in the expression levels of Fas-R in the hippocampus. Although Bcl-X_L downregulation suggests that the hippocampus of TS mice is less protected against programmed cell death, we did not find any evidence for increased apoptosis in TS mice since neither TUNEL-positive cells nor active caspase-3 expression were found in cortex or hippocampus of TS or CO mice.     

Reduced phospholipase C-beta activity and isoform expression in the cerebellum of TS65Dn mouse: a model of Down syndrome.

Agonist- and guanine-nucleotide-stimulated phospholipase C-beta (PLC) activity was characterized in crude plasma membrane preparations from cerebral cortex, hippocampus and cerebellum of Ts65Dn mice, a model for Down syndrome, and their control littermates. The levels of expression of PLC-beta((1-4)) isoforms and G-protein alpha(q/11) subunits were also quantified by Western blot analysis to establish their contribution to the patterns of PLC functioning. PLC activity regulated by G-proteins and muscarinic and 5-HT(2) receptors presented a regional distribution in both control and Ts65Dn mice. In both groups of mice, the intensity of PLC responses to maximal activation by calcium followed the sequence cerebellum > cortex > hippocampus. Both basal and maximal PLC activities, however, were significantly lower in cerebellar membranes of Ts65Dn than in control mice. This difference was mostly revealed in crude plasma membranes prepared from cerebellum at the level of G-protein-dependent-PLC activity because the concentration-response curve to GTPgammaS showed a reduction of the maximal effect in Ts65Dn mice, with no change in sensitivity (EC(50)). Western blot analysis showed a heterogeneous distribution of PLC-beta((1-4)) isoforms in both groups of mice. The levels of PLC-beta4 isoform, however, were significantly lower in the cerebellum of Ts65Dn than in control mice. We conclude that the cerebellum of Ts65Dn mice has severe deficiencies in PLC activity stimulated by guanine nucleotides, which are specifically related to a lower level of expression of the PLC-beta4 isoform, a fact that may account for the neurological phenotype observed in this murine model of Down syndrome.     

Glutathione levels and nerve cell loss in hippocampal cultures from trisomy 16 mouse – a model of Down syndrome

The tripeptide glutathione (reduced state, GSH) is an important intracellular free radical scavenger protecting cells against oxidative stress. The trisomy 16 mouse is a model of the human trisomy 21 (Down syndrome). Here we demonstrate that cultured hippocampal neurons from trisomy 16 mouse exhibit decreased GSH levels and augmented cell death when compared to diploid cells. Additional lowering of GSH levels led to enhanced cell death in trisomy 16 cells. Based on these results we suggest that a GSH level which is decreased under a specific threshold by increased consumption, reduced synthesis or lack in precursor contributes to cell loss and neurodegeneration in Down syndrome.     

Three-dimensional synaptic ultrastructure in the dentate gyrus and hippocampal area CA3 in the Ts65Dn mouse model of Down syndrome

Down syndrome (DS) results from trisomy of human chromosome 21. Ts65Dn mice are an established model for DS and show several phenotypes similar to those in people with DS. However, there is little data on the structural plasticity of synapses in the trisynaptic pathway in the hippocampus. Here we investigate 3D ultrastructure of synapses in the hippocampus of age-matched control (2N) and Ts65Dn male mice. Serial ultrathin sections and 3D reconstructions characterize synapses in the middle molecular layer (MML) of dentate gyrus and in thorny excrescences (TEs) in proximal portions of apical dendrites of CA3 pyramidal neurons. 3D analysis of synapses shows phenotypes that distinguish Ts65Dn from 2N mice. For the MML, synapse density was reduced by 15% in Ts65Dn vs. 2N mice (P < 0.05). Comparative 3D analyses demonstrate a significant decrease in the number of thorns per TE in CA3 in Ts65Dn vs. 2N mice (by ≈45%, P = 0.01). Individual thorn volume was 3 times smaller in Ts65Dn vs. 2N mice (P = 0.02). A significant decrease in the number of thorn projections per TE in Ts65Dn vs. 2N mice was accompanied by a decrease of filopodium-like protrusions on the surface of TEs (P = 0.02). However, the volume of postsynaptic densities in CA3 Ts65Dn and 2N mice was unchanged (P = 0.78). Our findings suggest that the high degree of plasticity of CA3 thorns may be connected with their filopodial origin. Alterations of 3D synaptic structure in Ts65Dn mice may further contribute to the diminished plasticity in DS.     

Alteration of NO-producing system in the basal forebrain and hypothalamus of Ts65Dn mice: an immunohistochemical and histochemical study of a murine model for Down syndrome

Ts65Dn mice have been developed as a model for Down syndrome (DS). Because of its involvement in complex behaviors, including sexual and aggressive behaviors, we investigated the nitric oxide (NO) system in specific brain regions of these mutant mice (TS) after isolation-induced aggression. Male TS mice displayed significantly higher aggression than wild type (WT) mice and the comparison of the NO system, both with immunohistochemical and histochemical methods, resulted in robust differences between TS and WT mice in the hypothalamic paraventricular nucleus, in the nucleus of the diagonal band and in the medial septum, but not in the striatum of TS mice. In conclusion, we document alterations in the neuronal NO system of the TS mouse model of DS, suggesting a correlation of the behavioral aggressiveness with deficient NO production.     

Spatial learning and memory impairment and increased locomotion in a transgenic amyloid precursor protein mouse model of Alzheimer's disease

This study provides an examination of spatial learning and a behavioral assessment of irritability and locomotion in TgCRND8 mice, an amyloid precursor protein transgenic model of Alzheimer's disease. Performance was assessed using the Barnes maze, the touch escape test, and an open-field test. While past research focused primarily on 2-5-month-old TgCRND8 mice, the present study used an older age cohort (9-month-old female mice), in addition to a 4-month-old cohort of both transgenic (Tg) and wildtype female mice. Both younger and older Tg mice displayed poor spatial learning in the Barnes maze task compared to their wildtype littermates, as demonstrated by significantly longer latencies and more errors both during acquisition and at a 2-week retest. No differences in irritability were found between Tg and control mice in the younger cohort; however, older Tg mice displayed significantly higher irritability compared with wildtype littermates, as measured by the touch escape test. Additionally, Tg mice of both age cohorts showed increased locomotion and slowed habituation during a 60-min open-field test over 3 days of testing. These results demonstrate that TgCRND8 mice show significant deficits in spatial and nonspatial behavioral tasks at advanced stages of amyloid pathology.     

Alterations in ApoE and ApoJ in relation to degeneration and regeneration in a mouse model of entorhinal cortex lesion

Apolipoproteins are primarily involved in the transport of lipid and cholesterol within the central nervous system (CNS) and are thought to play a role in synaptic remodeling, repair, and regeneration after brain injury. In the present study, alterations in apolipoproteins E (apoE) and J (apoJ) were examined in the molecular layers of the dentate gyrus after unilateral chemical lesioning of the entorhinal cortex (ECL), at days 0, 1, 3, 7, 28, and 90 days following injury. Alterations in immunostaining for these proteins were assessed in relation to accumulation of silver-labeled degeneration products and alterations in synaptophysin and GAP-43 immunoreactivity. Quantitative analysis of synaptophysin and GAP-43 immunostaining highlighted synaptic loss and fiber degeneration initially (3-7 days post-ECL), with subsequent terminal sprouting and reactive synaptogenesis occurring at longer survival periods (28-90 days post-ECL). Increased apoE and apoJ immunoreactivity was evident first within the neuropil (*P < 0.05 and **P < 0.01) followed by intense glial staining by day 7 post-ECL. By day 28 apoE and apoJ immunostaining had returned almost to baseline levels. However, at day 90 post-ECL, neuropil apoE and apoJ immunoreactivity was dramatically increased compared to contralateral levels (**P < 0.01 and ***P < 0.0001, respectively). Silver-labeled degeneration products were found to be in abundance at day 3 postlesion; however, by day 7 this was reduced leaving only a thin band of material within the MML and at day 90 post-ECL, dentate silver staining was similar to that of controls. The results indicate that apoE and apoJ are upregulated after injury and parallel clearance of cholesterol and lipid debris from the site of injury. This coordinated alteration in apolipoproteins may redistribute lipid material to sprouting fibers to promote neurite extension and may play an important role in long-term plasticity changes following injury.     

Gastrodin alleviates memory deficits and reduces neuropathology in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive, neurodegenerative disease, characterized by excessive accumulation of amyloid‐beta (Aβ) and activation of microglia cells and astrocytes. In this research, we evaluated whether gastrodin, an active component isolated from the rhizome of Gastrodia elata, has neuroprotective effects in a mouse model of AD, Tg2576 mice. Treatment of gastrodin (60 mg/kg for 15 days) significantly improved memory impairments in the Morris water maze test and probe test. Moreover, immunohistochemical and ELISA results indicated that gastrodin significantly attenuated Aβ deposition and glial activation in brains of these transgenic mice. These findings suggested that gastrodin exerted neuroprotective activity via anti‐inflammatory and anti‐amyloidogenic effects and that gastrodin may be a potential option for AD therapy.     

Effect of Panax notoginseng saponins on the expression of beta-amyloid protein in the cortex of the parietal lobe and hippocampus, and spatial learning and memory in a mouse model of senile dementia

BACKGROUND： The pharmacological actions of Panax notoginseng saponins （PNS） lie in removing free radicals, anti-inflammation and anti-oxygenation. It can also improve memory and behavior in rat models of Alzheimer＇s disease. OBJECTIVE： Using the Morris water maze, immunohistochemistry, real-time PCR and RT-PCR, this study aimed to measure improvement in spatial learning, memory, expression of amyloid precursor protein （App） and β -amyloid （A β ）, to investigate the mechanism of action of PNS in the treatment of AD in the senescence accelerated mouse-prone 8 （SAMP8） and compare the effects with huperzine A. DESIGN, TIME AND SETTING： A completely randomized grouping design, controlled animal experiment was performed in the Center for Research ＆ Development of New Drugs, Guangxi Traditional Chinese Medical University from July 2005 to April 2007. MATERIALS： Sixty male SAMP8 mice, aged 3 months, purchased from Tianjin Chinese Traditional Medical University of China, were divided into four groups： PNS high-dosage group, PNS low-dosage group, huperzine A group and control group. PNS was provided by Weihe Pharmaceutical Co., Ltd. （batch No.： Z53021485, Yuxi, Yunan Province, China）. Huperzine A was provided by Zhenyuan Pharmaceutical Co., Ltd. （batch No.： 20040801, Zhejiang, China）. METHODS： The high-dosage group and low-dosage group were treated with 93.50 and 23.38 mg/kg PNS respectively per day and the huperzine A group was treated with 0.038 6 mg/kg huperzine A per day, all by intragastric administration, for 8 consecutive weeks. The same volume of double distilled water was given to the control group. MAIN OUTCOME MEASURES： After drug administration, learning and memory abilities were assessed by place navigation and spatial probe tests. The recording indices consisted of escape latency （time-to-platform）, and the percentage of swimming time spent in each quadrant. The number of A β 1-40, A β 1-42 and App immunopositive neurons in the brains of SAMP8 mice w     

APP/PS1双转基因小鼠早期记忆功能障碍与胆碱能系统的关系研究

目的观察转APP/PS1基因阿尔茨海默病小鼠(APP/PS1小鼠)早期空间学习记忆功能及乙酰胆碱能系统的变化以及两者之间的相关性,探讨阿尔茨海默病早期学习记忆障碍的发病机制。方法应用Morris水迷宫法评定3月龄APP/PS1小鼠及相应野生型(WT)小鼠的空间学习记忆功能;采用免疫组织化学及组织化学染色方法检测脑组织中β-淀粉样蛋白(Aβ)斑块沉积情况;采用ELISA法检测脑组织中乙酰胆碱(ACh)含量以及胆碱乙酰转移酶(ChAT)和乙酰胆碱酯酶(AChE)活性,并探讨小鼠脑组织中ACh含量与其空间记忆能力、ChAT活性的相关性。结果水迷宫评定结果显示两组小鼠到达平台的潜伏期无统计学差异(P>0.05);APP/PS1小鼠在目标象限的游泳时间百分比〔(29.02±4.27)%〕和距离百分比〔(28.85±3.77)%〕较WT小鼠均下降(P<0.05)。APP/PS1小鼠脑组织中尚无Aβ斑块的沉积。APP/PS1小鼠脑组织中ACh含量〔(45.23±1.40)ng/g prot〕和ChAT活性〔(279.53±12.13)U/g组织湿重〕均较WT小鼠〔分别为(54.08±4.84)ng/gprot、(315.84±11.32)U/g组织湿重〕显著降低(P<0.05),两组小鼠脑组织中AChE活性无统计学差异(P>0.05)。小鼠脑组织中ACh含量与其空间记忆功能(目标象限航行时间百分比、目标象限航行路程百分比)呈正相关(r=0.861、r=0.874,P<0.05),ACh含量与ChAT活性呈正相关(r=0.926,P<0.05)。结论 APP/PS1小鼠空间记忆功能障碍、ACh含量减少和ChAT活性降低可发生于Aβ斑块沉积之前。脑组织中ACh含量减少和ChAT活性降低可能与APP/PS1小鼠记忆功能损害密切相关。     

Effects of Acanthopanax senticosus on learning and memory in a mouse model of Alzheimer''''s disease and protection against free radical injury to brain tissue

BACKGROUND:Acanthopanax senticosus,a plant of the Araliaceae family,is used in traditional Chinese medicine.It can be used to replenish Qi,strengthen the spleen,tonify the kidney,and relieve mental strain.OBJECTIVE:To observe effects ofAcanthopanax senticosus on learning and memory in a mouse model of Alzheimer's disease and abnormal biochemical changes in the brain tissue.DESIGN:A completely randomized grouping,controlled animal experiment.SETTING:Department of Preventive Medicine,School of Basic Medical Sciences,Yanbian University.MATERIALS:A total of 50 Kunming mice,aged 1-1.5 months,equal numbers of males and females,were provided by the Laboratory Animal Center,Yanbian University Medical College.The study was performed in accordance with ethical guidelines for the use and care of animals.Acanthopanax was provided by Yanbian Chengda Pharmaceutical Co.,Ltd.Acanthopanax senticosus(0.5 kg)was soaked in water for 1 hour and transferred to 1.5 kg distilled water for extraction.It was boiled for 1 hour and extracted after 1 hour of boiling.The procedure was repeated 3 times.The extract was condensed to 500 mL and then adjusted to 500 and 1 000 g/L with water.Piracetam tablets were produced by Shandong Luoxin Pharmaceutical Corporation, China.Malonaldehyde(MDA),superoxide dismutase(SOD),and acetylcholinesterase(ACHE)kits were purchased from Nanjing Jiancheng Bioengineering Co.,Ltd.,China. METHODS:This study was performed at the Department of Preventive Medicine,School of Basic Medical Sciences,Yanbian University from January to June 2007.All mice were randomly divided into 5 groups with 10 mice in each:control group,model group,low-,and high-dose Acanthopanax senticosus-treated groups, and piracetam-treated group.All groups were administered 0.1 mL/10 g.In the control and model groups, mice were intragastrically administered saline each morning for 5 days prior to experimentation.Five days later,they were intraperitoneally perfused with saline and aluminum trichloride(100 mg/kg),respectively, every other afternoon.In the low- and high-dose Acanthopanax senticosus-treated groups,as well as the piracetam-treated groups,mice were intragastrically administered 500 and 1 000 g/L Acanthopanax senticosus and 23 g/L piracetam suspension,respectively,every morning.Five days later,they were intraperitoneally perfused with aluminum trichloride(100 mg/kg)every other afternoon,20 successive times.MAIN OUTCOME MEASURES:On days 20,23,26,and 29 after treatment,time-to-platform,number of errors,and accuracy were measured by water maze.After anesthesia,mice were euthanized and whole brain tissues were immediately resected and homogenized.MDA levels,and SOD and AChE activities,were measured using the corresponding kits. RESULTS:Fifty mice were included in the final analysis.In the model group,accuracy increased,and time-to-platform was prolonged,compared to control group(P＜0.05-0.01).In the model group,MDA levels significantly increased(P＜0.05),while SOD activity significantly decreased(P＜0.01 ),compared to control group.MDA levels were significantly lower and SOD activity was significantly higher in the low-and high-dose Acanthopanax senticosus-treated groups,compared to the model group(P＜0.05-0.01).In the model group,AChE activity significantly increased,compared to the control group(P＜0.05).AChE activity was significantly lower in the high-dose Acanthopanax senticosus-treated and the piracetam-treated groups than in the model group(P＜0.05).CONCLUSION:Acanthopanax senticosus can improve learning and memory in a mouse model of Alzheimer's disease,and concomitantly increase SOD activity,inhibit AChE activity,and decrease MDA levels.     

人工培植雪莲黄酮干预阿尔茨海默病模型小鼠学习记忆能力：与雌二醇阳性对照组的比较

实验建立阿尔茨海默病小鼠模型,用人工培植的雪莲黄酮提取物灌胃,同时以苯甲酸雌二醇设阳性对照。用8臂迷宫实验对各组小鼠进行暗环境被动回避反应测试和信号方位辨别学习能力的测试。结果显示,雪莲黄酮提取物干预的阿尔茨海默病模型小鼠的学习记忆能力和信号辨别能力明显升高,雪莲黄酮干预组和雌二醇阳性对照组海马神经元细胞数量均增高,说明人工培植的雪莲黄酮能提高阿尔茨海默病模型小鼠的学习记忆能力,其作用与雌二醇阳性对照组一致。     

Influence of flavone extract from cultivated saussurea on learning and memory in a mouse model of Alzheimer's disease A comparison with estradiol benzoate

The present study established a mouse model of Alzheimer’s disease,and investigated the effects of treatment with flavone extract from artificially cultivated saussurea.A positive control group was treated with estradiol benzoate,and learning and memory ability were examined in the 8-arm radial maze.The learning and recognition ability of mice with Alzheimer’s disease treated with flavone extract was significantly improved and the number of hippocampal neurons was significantly increased in the flavone-treated and positive control groups compared with the model group.The results indicate that flavone extract from artificially cultivated saussurea can improve learning and memory deficits in mice with Alzheimer’s disease,exerting effects similar to those of estradiol benzoate.     

Sendai virus vector-mediated brain-derived neurotrophic factor expression ameliorates memory deficits and synaptic degeneration in a transgenic mouse model of Alzheimer's disease

Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain.