辛伐他汀保护缺血-再灌注损伤心肌的线粒体蛋白质组学研究

目的建立大鼠心肌缺血-再灌注损伤模型,通过蛋白质组学的方法研究辛伐他汀对大鼠缺血-再灌注损伤心肌线粒体代谢的保护作用。方法将大鼠随机分为辛伐他汀干预组(n=14)和生理盐水对照组(n=14),建立缺血-再灌注损伤模型,通过伊文思蓝和TTC染色评估梗死面积,提取大鼠左心室心肌线粒体蛋白行双向凝胶电泳,应用质谱分析鉴定差异蛋白点。结果辛伐他汀组和对照组相比,梗死区与危险区(梗死区+缺血区)的比值有统计学差异(29.4%±8.4%vs57.7%±6.5%,P0.0001);梗死面积与左室面积的比值有统计学差异(15.9%±5.6%vs29.0%±8.9%,P=0.012)。双向凝胶电泳图谱分析有19个蛋白点的表达有差异,质谱鉴定了9种差异蛋白,相比对照组,辛伐他汀组4个蛋白表达上调:三功能酶亚基α(线粒体前体)、电子转移黄素蛋白脱氢酶、肌动蛋白α(心肌)、细胞色素c氧化酶亚基5A亚单位(线粒体前体);5个蛋白表达下调:L-乳酸脱氢酶B链、异柠檬酸脱氢酶[NAD]α亚基(线粒体前体)、α晶状体蛋白B链、内膜蛋白(线粒体)、肌动蛋白类似物(细胞质)。结论辛伐他汀组大鼠心肌在缺血-再灌注损伤后,心肌梗死面积显著减少,辛伐他汀改变线粒体呼吸链、能量代谢等途径上的蛋白,为阐明辛伐他汀保护缺血再灌注损伤提供了理论依据。     

海人酸癫痫大鼠海马组织的蛋白质组学

目的 研究海人酸颞叶癫痫(TLE)大鼠海马组织差异表达的蛋白质.方法 运用双向荧光差异凝胶电泳(2D-DIGE)和质谱技术对海人酸TLE大鼠海马组织的差异蛋白进行分析鉴定.结果 海人酸TLE大鼠海马组织中共检测出15个差异性表达的蛋白质点,其中9个表达上调,6个表达下调.结论 海人酸TLE大鼠海马组织中存在许多差异表达的蛋白质,可能与癫痫的发病机制有关.     

人肺腺癌细胞系A549线粒体差异蛋白质组学研究

目的 研究人肺腺癌细胞系A549与人正常支气管上皮细胞系16HBE线粒体蛋白质组的差异表达.方法 传代培养细胞系A549及16HBE,用线粒体提取试剂盒获取细胞线粒体蛋白质,进行双向凝胶电泳,运用液相色谱串联质谱分析技术筛选出A549和16HBE细胞系线粒体间表达水平显著差异的蛋白,所得结果通过Data Analysis软件标峰,用MASCOT进行结果搜索和数据分析.结果 双向电泳结果显示A549、16HBE细胞系线粒体存在差异的蛋白质点共41个,3倍以上差异的16个,A549细胞系中表达上调的15个,表达下调的26个,其中3倍以上差异表达上调的7个,表达下调的9个.运用液相色谱串联质谱技术鉴定出A549细胞系线粒体表达上调的蛋白质2个:AAA+ ATP酶家族结构域蛋白3B、tRNA鸟嘌呤糖基转移酶,表达下调的蛋白质7个:热休克蛋白75、复合物Ⅲ亚基1、复合物Ⅲ亚基2、鸟氨酸氨基转移酶、异柠檬酸脱氢酶亚基α、SLP-2、抗增殖蛋白.结论 应用亚细胞蛋白质组学方法,鉴定出肺腺癌细胞系线粒体差异表达蛋白,为阐明肺腺癌发生的分子机制、筛选早期诊断标志物提供了有益的线索.     

嗅成鞘细胞移植对AD大鼠脑内COX活性和线粒体超微结构的影响

目的 探讨嗅成鞘细胞(OECs)移植对阿尔茨海默病(AD)大鼠脑内COX活性和线粒体超微结构的影响.方法 SD大鼠双侧海马注射Aβ1～40,建立AD大鼠模型.实验动物分为四组:正常对照组、AD模型组、OECs移植组、人工脑脊液(MCSF)注射组,每组12只.体外原代培养OECs并将其移植至AD大鼠双侧海马.运用行为学测试、组织化学、原位杂交结合图像分析以及电镜等技术和工具,观察、比较各组大鼠学习记忆能力、海马CA1区线粒体细胞色素氧化酶(COX)活性、细胞色素氧化酶Ⅱ型亚基(COⅡ)mRNA表达,以及CA1区神经元线粒体超微结构等指标的变化.结果 与正常对照组比较,AD模型组大鼠空间学习记忆能力、海马CA1区线粒体COX活性及COⅡmRNA表达明显降低(P<0.05),线粒体数量减少,结构不清、肿胀、空泡样变、嵴断裂;OECs移植明显上调上述指标(P<0.05),并对线粒体超微结构有明显的保护作用.结论 OECs移植通过改善AD大鼠学习记忆能力、提高海马COX活性和COⅡmRNA表达以及保护线粒体等作用,对大鼠AD具有明显的治疗效果.     

间歇低氧对大鼠海马神经细胞自噬相关蛋白表达的影响

目的通过模拟阻塞性睡眠呼吸暂停低通气综合征的发病特征,建立大鼠间歇性低氧(IH)模型,观察IH后大鼠海马CA1区神经细胞线粒体自噬及相关蛋白的表达。方法 72只雄性Wistar大鼠随机分为对照组36只和间歇低氧(5%IH)组36只,对照组向低氧箱内持续注入压缩空气,5%IH组每天放入低氧箱内IH暴露7h,模型完成后分别于1、3、5、7、10和14d采用透射电镜观察大鼠海马CA1区神经细胞线粒体超微结构的改变;免疫组织化学法检测Beclin-1和微管相关蛋白1轻链3(LC3)的表达。结果与对照组比较,5%IH组3d开始出现线粒体超微结构的明显改变,可见线粒体自噬体形成;1、3、5、10和14dBeclin-1及LC3蛋白表达均明显升高(P<0.05),于10d达高峰(P<0.05),14d开始下降,差异有统计学意义(P<0.05)。结论 IH早期可诱导大鼠海马神经细胞线粒体发生自噬及自噬相关蛋白Beclin-1和LC3的表达。     

大鼠脑缺血再灌注后海马CA1区超微结构及Apaf-1表达的变化

目的 观察大鼠脑缺血再灌注后海马CA1区超微结构及凋亡相关基因凋亡蛋白激活因子(Apaf)-1表达的变化.方法 健康雄性SD大鼠随机分为假手术组和模型组,其中模型组缺血30 min后再灌注,根据再灌注时间不同又分为2、24、72 h3个亚组.采用Pulsinelli四血管阻断法建立大鼠全脑缺血再灌注模型,透射电镜下观察海马CA1区神经元超微结构变化,免疫组织化学法和Western印迹法检测大鼠海马组织凋亡相关基因Apaf-1蛋白表达的变化.结果 透射电镜结果显示:假手术组海马CA1区神经元胞核较大,呈圆形或椭圆形,核膜清晰完整,常染色质呈细颗粒状均匀分布,胞浆内可见丰富的细胞器.模型2h组海马CA1区神经元核膜凹陷,核染色质密度增高,线粒体轻微肿胀;模型24 h组海马CA1区神经元核膜邹缩严重,核仁物质增多、偏移,线粒体结构松散、空泡状,线粒体嵴断裂,粗面内质网脱颗粒;模型72 h组海马CA1区神经元核固缩,核染色质呈团块状边集于核膜下,线粒体不同程度脱空.免疫组化和Western印迹结果显示:假手术组Apaf-1蛋白仅有少量表达,模型组各时间点Apaf-1蛋白表达均增高(P＜0.05).结论 大鼠脑缺血再灌注可导致海马CA1区神经元的凋亡,这可能与凋亡相关基因Apaf-1的激活有关.     

慢性弓形虫感染大鼠海马蛋白质组的研究北大核心CSCD

目的观察慢性弓形虫感染大鼠海马组织的蛋白质组的表达与变化。方法将6只雄性SD大鼠随机分成健康对照组和弓形虫感染组,每组3只。感染组每鼠腹腔注射4×107个弓形虫RH株速殖子,对照组注射等量生理盐水,于感染后第5天,尾静脉采血,吉氏染色验证大鼠感染情况。感染10周后,分离大鼠海马组织,抽提蛋白,并采用双向凝胶电泳分离,考马斯亮蓝染色后用PDQuest1.0软件进行图像分析,从胶中选取分离蛋白质点,应用基质辅助激光解析电离飞行时间质谱(MALDI-TOF-MS)分析,获取肽质量指纹图谱(PMF),采用Mascot软件检索SwissProt数据库鉴定蛋白质。结果血涂片结果证实,感染组大鼠均感染成功。感染组和对照组大鼠海马组织经双向凝胶电泳分离后,分别检出蛋白斑点数(311±19)个和(327±13)个,对2张电泳图进行匹配后发现有16个蛋白斑点在2组大鼠海马组织中的含量有明显变化,其中5个蛋白斑点在感染组大鼠海马蛋白双向电泳图谱中消失,11个蛋白斑点在2组大鼠海马组织中含量发生了3倍以上的变化,其中感染组上调4个,下调7个。有差异表达的16个蛋白斑点经质谱鉴定和数据库检索,发现9个蛋白,分别为磷酸激酶1、类烯醇化酶、谷氨酰合成酶、肌酸激酶、B型肌酸激酶、ATP合酶、线粒体顺乌头酸酶、肌动蛋白和未命名蛋白,前3个蛋白在感染组上调,其余6个下调。结论共获得9个慢性弓形虫感染大鼠与健康大鼠海马组织差异表达蛋白。     

左归丸对老年性痴呆模型鼠脑神经元HSP70及超微结构的影响

目的 探讨左归丸对老年性痴呆(Alzheimer病,AD)动物模型HSPT0及超微结构的影响.方法 模型组以D-半乳糖腹腔注射合并A13注射海马制备AD动物模型,各治疗组分别在造模的同时灌胃左归丸和抗脑衰胶囊、哈伯因.采用生化法检测各组大鼠脑匀浆AchE,运用RT-PCR测定各组海马HSP70的表达并用透射电镜观察各组海马神经元超微结构的变化.结果 左归丸能明显抑制模型鼠脑组织中AchE活性,上调HSP70的表达,抑制细胞凋亡.超微结构观察发现模型组海马神经元显现凋亡早期的形态特点,各治疗组和对照组对凋亡皆有抑制作用.结论 左归丸对痴呆鼠海马神经元细胞凋亡有抑制作用,其机制可能与其抑制模型鼠脑组织中AchE活性、上调HSP70的表达和改善神经元细胞损害有关.     

APP17肽对DM大鼠海马神经元胰岛素和凋亡信号传导通路相关蛋白的影响

目的 观察糖尿病大鼠海马脑区胰岛素和凋亡信号传导通路中某些相关蛋白的表达及APP17肽对其表达的影响。方法 链脲佐菌素诱发大鼠糖尿病模型，并用APP17肽治疗。用免疫沉淀和Western-blot法分析海马中信号传导及部分凋亡相关蛋白；电镜观察大鼠脑组织超微结构。结果 DM大鼠IGF－IRα、Akt/PKB、CREB表明明显降低，APP17肽治疗后明显上调（P＜0．05），GSK－3β、PP－1及凋亡相关蛋白Bax、AIF表达增加，治疗后则明显降低（P＜0．05）；超微结构表明APP17肽治疗后兴奋性突触小泡明显减少。结论 糖尿病大鼠海马脑区胰岛素和凋亡信号传导通路中某些重要蛋白表达异常，APP17肽部分纠正这些蛋白的异常表达，这可能是其保护DM大鼠海马神经元的机制。     

人参皂苷Rg2抗拟缺血再灌注损伤大鼠海马神经细胞β_(1-40)淀粉样蛋白聚集研究

目的探讨人参皂苷Rg2对缺血再灌注损伤大鼠神经元细胞的干预机制。方法体外培养的大鼠海马神经元细胞,建立拟缺血再灌注损伤模型。分为模型组,对照组,低、中、高浓度组(人参皂苷Rg2 40、80、160μmol/L),MTT法测定神经元线粒体活性;免疫细胞化学法检测神经元细胞淀粉样蛋白前体(APP)和β淀粉样蛋白(Aβ1-40)表达。结果与对照组比较,模型组海马神经元线粒体活性降低,APP和Aβ1-40表达明显升高(P<0.05)。与模型组比较,低、中、高浓度组海马神经元线粒体活性明显增强,APP和Aβ1-40表达明显降低(P<0.05)。结论人参皂苷Rg2可能通过减少损伤海马神经元后升高的APP和Aβ1-40的表达;提高细胞活性,从而发挥其保护作用。     

Differences in expression of retinal proteins between diabetic and normal rats

AIM： To compare and identify the differences in expression of retinal proteins between normal and diabetic rats, and to analyze the molecular pathogenetic mechanisms of retinal diseases caused by diabetes.
METHODS： Changes in protein expression of retinal tissues from diabetic and normal rats were observed using 2-dimensional polyacrylamide gel electrophoresis （2-DE）. Some protein spots exhibiting statistically significant variations （P 〈 0.05） were selected randomly and identified by tandem mass spectrometry and analyzed by bioinformatics.
RESULTS： 2-DE showed that the expression was upregulated in 5 retinal proteins, down-regulated in 23retinal proteins, and disappeared in 8 retinal proteins.Eight spots were identified from the 36 spots by tandem mass spectrometry （MS/MS） and analyzed by bioinformatics. Guanylate kinase 1, triosephosphate isomerase 1, ATP synthase subunit d, albumin and dimethylarginine dimethylaminohydrolase 2 played an important role in signal transduction. Triosephosphate isomerase 1, crystallin alpha B, ATP synthase subunit d and peroxiredoxin 6 were involved in energy metabolism of retinal tissues. Guanylate kinase 1 played an important role in photoexcitation of retinal rod photoreceptor cells.Whether crystallin beta A1 plays a role in diabetic retinas is unknown so far.
CONCLUSION： There are differences in expression of retinal proteins between diabetic and normal rats.These proteins may be involved in the mechanisms and prognosis of retinal diseases caused by diabetes.     

Alteration of the phosphocreatine energy shuttle components in diabetic rat heart.

Considering the important role of the phosphocreatine energy shuttle in contractile function of the heart we decided to study the different components of this shuttle in STZ-induced diabetic rat heart with a known diabetic related cardiomyopathy. Diabetes produced a gradual decline in total CK activity, reaching a maximum of 35-40% decrease after 4 weeks of diabetes, in both atria and ventricles. All of the CK isoenzymes including the mitochondrial CK (CKm) were reduced but to a different extent in these two tissues. The percentage reduction in diabetic ventricles was BB greater than MB greater than CKm greater than MM and in atria was CKm greater than BB greater than MB greater than MM. A major difference between atrium and ventricle was the greater loss of CKm in diabetic atria than diabetic ventricle (75% in atria vs 32% in ventricle). The B subunit seemed to be the one that was affected the most followed by CKm isoenzyme and then the M subunit. The bound myofibrillar CK isoenzyme, expressed as units of activity/mg of myofibrillar protein, was not affected by 4 weeks of diabetes. The high energy phosphates were also reduced in diabetic heart with a greater reduction in phosphocreatine (43-45%) and a smaller change in ATP (27%). Mitochondrial oxidative phosphorylation with alpha-ketoglutarate was reduced (55%) in diabetic heart, whereas, there was no difference when succinate was used as substrate. These changes were reversible by 4 weeks of insulin treatment. The loss of CKm, phosphocreatine and the reduction in mitochondrial oxidative phosphorylation, could result in an inefficient phosphocreatine energy shuttle which could contribute to the cardiac functional defects associated with diabetes.     

Localization and regulation of GLUTx1 glucose transporter in the hippocampus of streptozotocin diabetic rats

We describe the localization of the recently identified glucose transporter GLUTx1 and the regulation of GLUTx1 in the hippocampus of diabetic and control rats. GLUTx1 mRNA and protein exhibit a unique distribution when compared with other glucose transporter isoforms expressed in the rat hippocampus. In particular, GLUTx1 mRNA was detected in hippocampal pyramidal neurons and granule neurons of the dentate gyrus as well as in nonprincipal neurons. With immunohistochemistry, GLUTx1 protein expression is limited to neuronal cell bodies and the most proximal dendrites, unlike GLUT3 expression that is observed throughout the neuropil. Immunoblot analysis of hippocampal membrane fractions revealed that GLUTx1 protein expression is primarily localized to the intracellular compartment and exhibits limited association with the plasma membrane. In streptozotocin diabetic rats compared with vehicle-treated controls, quantitative autoradiography showed increased GLUTx1 mRNA levels in pyramidal neurons and granule neurons; up-regulation of GLUTx1 mRNA also was found in nonprincipal cells, as shown by single-cell emulsion autoradiography. In contrast, diabetic and control rats expressed similar levels of hippocampal GLUTx1 protein. These results indicate that GLUTx1 mRNA and protein have a unique expression pattern in rat hippocampus and suggest that streptozotocin diabetes increases steady-state mRNA levels in the absence of concomitant increases in GLUTx1 protein expression.     

Down-regulation of alpha-2u globulin in renal mitochondria of STZ-induced diabetic rats observed by a proteomic method

AimTo identify the changes of mitochondrial protein expression in diabetic renal parenchyma and to characterize their molecular functions and biological processes in diabetes.MethodsMitochondrial proteins extracted from renal parenchyma mitochondria of streptozotocin-induced diabetic rats and normal rats were separated by two-dimensional polyacrylamide gel electrophoresis and identified by matrix-assisted laser desorption/ionization tandem time-of-?ight mass spectrometry.ResultsEleven proteins from 533 visualized protein spots displayed significant different expressions in mitochondria of diabetic kidneys compared with those in normal ones. Among these altered proteins, two proteins with the most obvious changes in protein expression were identified as alpha-2u globulin (mature protein, named A2) and its proteolytically modified form (named A2-fragment) respectively. These proteins were found in mitochondria of male rat renal parenchyma and were proved to be down-regulated in diabetic rats simultaneously.ConclusionOur results suggest that down-regulation of alpha-2u globulin may be associated with an abnormal β-oxidation of long-chain fatty acids during diabetes. The decreased expression of A2-fragment in renal mitochondria of diabetic nephropathy may reduce fatty acid β-oxidation, which leads to a diminished energy supply from mitochondria to kidney tissue and the deposition of a large number of fatty acids in the kidney, ultimately causing and aggravating kidney damage. In conclusion, these findings may be helpful for understanding the molecular mechanism of diabetic nephropathy.     

The effects of the Chinese medicine ZiBu PiYin recipe on the hippocampus in a rat model of diabetes-associated cognitive decline: a proteomic analysis

Aims/hypothesis

Increasing evidence suggests that diabetes is associated with an enhanced risk of cognitive decline. The precise mechanisms underlying diabetes-associated cognitive decline (DACD) remain unclear. Here we investigated the molecular changes associated with DACD using a comparative proteomics study of hippocampus in a rat model of type 2 diabetes. In addition, we tested the effects of the Chinese medicine ZiBu PiYin recipe (ZBPYR) on DACD.

Methods

The hippocampus was dissected from control, diabetic and diabetic rats treated with ZBPYR (DM/ZBPYR). Soluble proteins were separated using fluorescence-based difference gel electrophoresis. Protein spots were visualised with fluorescent dyes and spot density was compared between each pair of groups. Proteins of interest were identified using mass spectrometry. Proteins of specific interest were also tested by western blot and real-time PCR analysis.

Results

We found 13 spots that were altered between control and diabetes groups, and 12 spots that were changed between diabetes and DM/ZBPYR groups. The identities of nine proteins were determined by mass spectrometry. The identified proteins were largely involved in energy metabolism, cytoskeleton regulation and oxidative stress. The protein alterations observed in the diabetes group were ameliorated to varying degrees following ZBPYR treatment.

Conclusions/interpretation

The protein changes identified in hippocampus from a rat model of type 2 diabetes suggest that specific cellular alterations contribute to DACD. The Chinese medicine ZBPYR was found to affect multiple targets and partially repaired the original cellular balance. This study may provide important insights into the molecular events underlying DACD and allow the identification of novel therapeutic targets.     

Oxidative stress-induced up-regulation of the chloride channel and Na+/Ca2+ exchanger during cataractogenesis in diabetic rats

We have determined the abundance of the chloride channel, ClC-3, and Na(+)/Ca(2+) exchanger proteins in isolated rat lens cortex fiber cells by immunofluorescence method using polyclonal anti-ClC-3 antibodies and monoclonal antibodies against the canine cardiac Na(+)/Ca(2+) exchanger protein. These proteins were also quantified in the lens cortex of streptozotocin-injected rats by Western blots. Also, mRNA for ClC-3 was determined by Northern blot analysis. The isolated rat lens cortical fibers expressed basal levels of ClC-3 and Na(+)/Ca(2+) exchanger proteins. As compared to controls, the ClC-3 protein in the lens cortex of diabetic rats (blood glucose>400 mg%) increased by 2.5-fold in 7 days and 4.5-fold in 14 days. However, the ClC-3 protein decreased to near-normal values in 40 days. The changes in ClC-3 mRNA closely followed the protein levels. Similarly, as compared to controls, on Day 7, the Na(+)/Ca(2+) exchanger protein in the diabetic rat lens cortex increased by 3.5-fold and on Day14 by 5.5-fold. Subsequently, it decreased to control levels on Day 40. Treatment with the antioxidant, Trolox (2 mg/kg body weight), prevented the initial increase in ClC-3 and Na(+)/Ca(2+) exchanger proteins. The up-regulation of ClC-3 and Na(+)/Ca(2+) exchanger proteins during the early stages of diabetes and its prevention by antioxidants suggests that the proteins regulating ion transport may have a pathophysiological role in the development of diabetic cataracts.     

Mitochondrial dysfunction observed in situ in cardiomyocytes of rats in experimental diabetes.

OBJECTIVE: The aim was to investigate effects of experimental diabetes and insulin treatment on heart myocytes, particularly on the mitochondrial function studied in situ in isolated cardiomyocytes. METHODS: 20 male Sprague-Dawley rats (140-160 g) were made diabetic by intraperitoneal streptozotocin, 70 mg.kg-1. Ten then received daily subcutaneous injections of ultra lente insulin (starting dose of 3 units.d-1) for 7-15 d from the 20th day after streptozotocin. There was a control group of 11 rats. The rats were killed 21-35 d after the induction of diabetes, and heart myocytes were isolated by collagenase digestion. The 45[Ca]2+ uptake of mitochondria in situ in permeabilised myocytes, the transmembrane potential gradient of mitochondria, and the respiration of myocytes, as well as the cell yield and cell [45Ca]2+ uptake, were examined. RESULTS: Mitochondrial uptake of [45Ca]2+ was significantly decreased in the diabetic group compared to control at cytosolic calcium concentrations between 760 nM and 44.6 microM. The mitochondrial potential of diabetic myocytes, estimated from the distribution of [3H]triphenylmethylphosphonium+, was slightly but significantly decreased from the control value. Cell respiration, measured polarographically in the presence of pyruvate and malate or succinate as oxidisable substrates, and with or without 2,4-dinitrophenol, was decreased by diabetes. The rapidly exchangeable [45Ca]2+ content in the myocyte with intact sarcolemmal membrane ("cell Ca2+ uptake") and the yield of cells from heart tissue were also diminished in diabetic rats. These changes were returned to normal by insulin treatment of 7 d or longer. CONCLUSIONS: Insulin deficiency at early stages causes defects of mitochondrial function detectable in situ in cardiomyocytes. This suggests the possibility that such alterations are causative factors in the development of diabetic cardiomyopathy.     

Decreased thrombospondin-I (TSP-I) expression in the hippocampus of streptozotocin-induced diabetic rats

Diabetes mellitus (DM) may give rise to cognitive impairment, but the pathological mechanism involved was still unknown. We investigated the thrombospondin-I (TSP-I) expression level in hippocampus of streptozotocin-induced diabetic rats, which, as a matricellular, calcium-binding protein that participates in cellular responses to growth factors, cytokines and injury, has been indicated as important synaptogenic components recently. We employed 20 streptozotocin (STZ)-induced diabetic rats. The weight, blood sugar and urine sugar were measured before and after model induction in diabetes and normal groups. We did immunohistochemical localization of TSP-I and RT-PCR was applied to determine TSP-I mRNA level in the hippocampus of both groups. Moreover, transmission electron microscope (TEM) was used to study the ultrastuctural changes of the hippocampus. All data were analyzed by the independent samples t-test. We found that the expression of TSP-I markedly decreased in the hippocampal neuronal cells. Moreover, TEM results showed the ultrastructures of diabetic hippocampus, including area CA1 and DG, neurons were characterized by mitochondria swelling, increased heterochromatin accumulation and reduced synaptic contacts. The present study provides experimental evidences that decreased TSP-I expression may help to explain the reduced synaptogenesis and altered hippocampal ultrastucture, both of which may contribute to the pathogenesis of diabetic dementia.