Matrix metalloproteinase 14 modulates diabetes and Alzheimer’s disease cross-talk: a meta-analysis

Diabetes mellitus is associated with dementia, but whether diabetes is associated with Alzheimer’s disease remains controversial. Alzheimer’s disease is characterized by amyloid beta aggregation. We hypothesized that genes, involved in amyloid beta degradation, may be altered due to diabetes and thus participate in progression of Alzheimer’s disease. Expression profiling of amyloid beta-degrading enzymes in streptozotocin-induced diabetic mice and their correlation with expression of amyloid precursor protein in hippocampus of Alzheimer’s disease patients were accessed. We found that matrix metalloproteinase 14 decreased in brain but not in other tissues of streptozotocin-induced diabetic mice, and was negatively correlated with expression of amyloid precursor protein in hippocampus of Alzheimer’s disease patients. These findings suggested matrix metalloproteinase 14 may link insulin-deficient diabetes to Alzheimer’s disease.     

Changes in insulin-signaling transduction pathway underlie learning/memory deficits in an Alzheimer’s disease rat model

Brain metabolic dysregulation is a hallmark pathological change in Alzheimer’s disease (AD). Although detailed mechanisms are still not fully elucidated, recent studies suggest alterations of insulin-signaling transduction cascades underlie neuronal stresses in AD brains. In this study, we performed in vivo experiments to determine the impact of soluble Aβ oligomers on insulin-signaling transduction in rat hippocampi by utilizing lateral ventricular injection of amyloid beta (Aβ) oligomers on male Wistar rats (225?±?25?g, 3–4?months old) as an AD rat model. The Aβ-infused rats manifested remarkably increased escape latency and significantly decreased proportions of time and pathway crossing the hidden platform as compared to the rats in the pseudo-injection group and the non-injection group in Morris water maze test implicating the damaging effect of soluble Aβ oligomers on rat learning and memory functions. Accordingly, our subsequent results demonstrated that the infusion of soluble Aβ oligomers significantly decreased the expressions of insulin receptor, insulin receptor substrate-I, B cell lymphoma/leukemia-2 and serine/threonine protein kinase B in rat hippocampal neurons, whereas the expression level of total cAMP response element-binding protein was not changed. This study suggests that soluble Aβ oligomers instigated insulin-signaling disturbances which are potentially associated with learning and memory deficits in the AD rat model.     

Osthole improves synaptic plasticity in the hippocampus and cognitive function of Alzheimer’s disease rats via regulating glutamate

Osthole, an effective monomer in Chinese medicinal herbs, can cross the blood-brain barrier and protect against brain injury, with few toxic effects. In this study, a rat model of Alzheimer’s disease was established after intracerebroventricular injection of β-amyloid peptide (25-35). Subsequently, the rats were intraperitoneally treated with osthole (12.5 or 25.0 mg/kg) for 14 successive days. Results showed that osthole treatment significantly improved cognitive impairment and protected hippocampal neurons of Alzheimer’s disease rats. Also, osthole treatment alleviated suppressed long-term potentiation in the hippocampus of Alzheimer’s disease rats. In these osthole-treated Alzheimer’s disease rats, the level of glutamate decreased, but there was no significant change in γ-amino-butyric acid. These experimental findings suggest that osthole can improve learning and memory impairment, and increase synaptic plasticity in Alzheimer’s disease rats. These effects of osthole may be because of its regulation of central glutamate and γ-amino-butyric acid levels.     

突变型Aβ1～42致敏树突状细胞疫苗治疗阿尔茨海默病转基因鼠作用机制探讨

研究背景β-淀粉样蛋白在脑组织中沉积是阿尔茨海默病的典型病理特征之一,免疫疗法虽可有效清除β-淀粉样蛋白,但在治疗的同时也伴随出现一些不良反应.为了避免疫苗治疗过程中产生的严重不良反应如脑膜脑炎等.尝试采用突变型β-淀粉样蛋白(Aβ1～42)致敏树突状细胞制备阿尔茨海默病疫苗.并在充分评价其安伞性和有效性的基础上,进一步探讨其治疗阿尔茨海默病转基因鼠的作用机制.方法 提取C57/B6小鼠胫骨和股骨树突状细胞,分别以突变型Aβ1～42致敏树突状细胞(实验组)和经弗氏佐剂免疫的野生型Aβ1～42 多肽(佐剂阳性对照组)制备疫苗,然后接种于阿尔茨海默病转基因鼠.免疫组织化学染色观察小鼠脑组织中核激素肝x受体(LXR)、三磷酸腺苷结合盒转运子1(ABCA1)、CD45、晚期糖基化终产物受体(RAGE)和β-分泌酶(BACE)表达水平,体视学法半定量检测海马区cAl、CA2、CA3、DG、Rad和皮质区阳性神经元.结果 与阴性对照组相比.实验组和佐剂阳性对照组转基因鼠脑组织β-淀粉样蛋白表达水平显著降低(P=0.000),阴性对照组治疗前后无变化;经突变型Aβ1～42致敏的树突状细胞疫莆治疗后,转基因鼠脑组织中的LXR、ABCA1、CD45和BACE表达水平升高(P=0.000),RAGE表达水平降低(P=0.000).结论 经突变型Aβ1～42致敏树突状细胞制备的疫苗可通过多种因索的相互作用使阿尔茨海默病转基因鼠大脑β-淀粉样蛋白代谢达到新的免疫半衡,从而减少其在脑组织中的沉积.且无脑膜脑炎等严重不良反应,此与LXR/ABCA1通道作用有关.树突状细胞自身也在清除β-淀粉样蛋白的过程中扮演着预防小良反应发生的重要角色.     

ACEI和ARB类药物对AD大鼠认知功能的影响

目的探讨脑内的肾素-血管紧张素系统(RAS)在阿尔茨海默病(AD)发病中的作用,比较血管紧张素转换酶抑制剂(ACEI)和血管紧张素受体拮抗剂(ARB)两类药物对于认知功能的影响及作用机制的不同。方法本实验采用脑室内注射Aβ25-35制备的大鼠阿尔茨海默病(AD)模型,利用Y迷宫检测大鼠的学习记忆功能,比较培哚普利和厄贝沙坦对于认知功能的影响,采用免疫印迹方法检测大鼠海马1型和2型血管紧张素受体(AT1、AT2)的表达水平。结果同AD组相比,厄贝沙坦组Y迷宫中正确反应次数增多,说明可改善AD大鼠的学习记忆功能,其在阻断AT1受体的同时,上调了AT2受体的表达;培哚普利同时抑制了AT1和AT2受体的表达,行为学测试并未显示出对于认知功能的保护作用。结论 1型AT受体阻滞剂厄贝沙坦可以改善AD大鼠的学习记忆功能,这可能与其激活AT2受体有关。     

AGTR1、AGTR2在阿尔茨海默病模型大鼠海马中的变化

目的探讨AGTR1和AGTR2在阿尔茨海默病（alzheimer disease,AD）模型大鼠海马中的变化及缬沙坦的作用。方法用β-淀粉样蛋白（β-amyloid,Aβ）1-42海马注射建立AD大鼠模型,通过Y-形电迷宫进行学习记忆能力测定,HE染色、刚果红染色进行形态学观察,免疫组化（immunohistochemistry,I H）检测AGTR1、AGTR2的表达水平。结果模型组较对照组正确逃避电刺激所需要的次数多（P〈0.001）、海马CA1区神经元密度较对照组减少（P〈0.001）、AGTR1及AGTR2光密度值增加（P〈0.05）;缬沙坦组较模型组正确逃避电刺激所需要的次数少（P〈0.001）,海马CA1区神经元密度较模型组增加（P〈0.001）、AGTR1及AGTR2光密度值减少（P〈0.05）。结论缬沙坦可改善AD模型大鼠学习记忆能力,抑制AGTR1的表达而延缓AD进展;AGTR2可能延缓AD的进展。     

Von Willebrand factor promoter targets the expression of amyloid beta protein precursor to brain vascular endothelial cells of transgenic mice

Dysfunction of brain vascular endothelial cells may be associated with the pathogenesis of several diseases including cerebral amyloid angiopathy, hemorrhagic stroke and Alzheimer disease. New model systems are necessary to examine the contribution of brain endothelial cells in these disorders. The Von Willebrand factor gene promoter fragment that spans sequences -487 to +247 targets the expression of LacZ marker gene in transgenic mice specifically to brain vascular endothelial cells. Transgenic mice have been prepared that express human amyloid beta protein precursor protein (AbetaPP) isoforms 695 and 751 (wild-type and Dutch variant mutations) under the regulation of this VWF promoter sequence. These AbetaPP transgenes are specifically expressed in brain vascular endothelial cells. The VWF promoter is a valuable tool for targeting gene expression to brain vascular endothelial cells to provide a model to directly examine endothelial cell placement of genes and their contribution to cerebral vascular disease.     

Declining expression of neprilysin in Alzheimer disease vasculature: possible involvement in cerebral amyloid angiopathy

Molecular, genetic, and pharmacological studies have shown that neprilysin (also called NEP) catabolizes amyloid beta peptides (A beta) in healthy conditions. However, in Alzheimer disease (AD), A beta accumulates forming senile plaques in brain parenchyma and amyloid deposition around blood vessels. In this study, we tested at cellular level the relationship between neprilysin and A beta in human healthy and AD brain. Our results provided evidence for declining levels of neprilysin in AD brains as compared to healthy controls in parallel with increasing deposition of A beta. In hippocampus of AD individuals we observed a significant down-regulation of neprilysin expression in pyramidal neurons, consistent with the possibility that neprilysin controls the level of A beta accumulation and plaque formation in this area. In the cortex and leptomeninges, neprilysin was expressed in the smooth muscle cells of blood vessels. In sections from AD patients we observed a clear inverse relationship between neprilysin and A beta peptide levels in the vasculature, implicating neprilysin in cerebral amyloid angiopathy.     

Genistein suppresses the mitochondrial apoptotic pathway in hippocampal neurons in rats with Alzheimer’s disease

Genistein is effective against amyloid-β toxicity,but the underlying mechanisms are unclear.We hypothesized that genistein may protect neurons by inhibiting the mitochondrial apoptotic pathway,and thereby play a role in the prevention of Alzheimer's disease.A rat model of Alzheimer's disease was established by intraperitoneal injection of D-galactose and intracerebral injection of amyloid-β peptide(25–35).In the genistein treatment groups,a 7-day pretreatment with genistein(10,30,90 mg/kg) was given prior to establishing Alzheimer's disease model,for 49 consecutive days.Terminal deoxyribonucleotidyl transferase-mediated d UTP nick end labeling assay demonstrated a reduction in apoptosis in the hippocampus of rats treated with genistein.Western blot analysis showed that expression levels of capase-3,Bax and cytochrome c were decreased compared with the model group.Furthermore,immunohistochemical staining revealed reductions in cytochrome c and Bax immunoreactivity in these rats.Morris water maze revealed a substantial shortening of escape latency by genistein in Alzheimer's disease rats.These findings suggest that genistein decreases neuronal loss in the hippocampus,and improves learning and memory ability.The neuroprotective effects of genistein are associated with the inhibition of the mitochondrial apoptotic pathway,as shown by its ability to reduce levels of caspase-3,Bax and cytochrome c.     

雷公藤氯内酯醇对大鼠海马注射β淀粉样蛋白后诱导型一氧化氮合酶的影响

目的：研究雷公藤氯内酯醇（T4）对阿尔茨海默病（AD）大鼠脑内诱导型一氧化氮合酶（iNOS）表达及NO产生的影响。方法：通过大鼠海马注射Aβ1-40建立AD大鼠模型,以腹膜腔注射T4作为干预措施,免疫组化方法检测iNOS,硝酸还原酶法检测硝酸盐／亚硝酸盐水平。结果：AD组大鼠海马iNOS表达和NO产生较假手术组明显增加,Aβ＋T4组大鼠海马iNOS表达和NO产生较Ap组减少。结论：T4可以抑制Aβ1-40诱导的iNOS表达和NO产生。     

海马注射β-淀粉样蛋白建立阿尔茨海默病大鼠模型的实验研究

目的：海马注射β-淀粉样蛋白（Aβ）建立阿尔茨海默病（AD）大鼠模型，并进行初步评价。方法：应用凝聚态Aβ1-40进行大鼠右侧海马齿状回（DG）背侧细胞带微量注射，2周后从学州记忆、海马组织病理和异常磷酸化tau蛋白表达的变化3个方面评价大鼠模型。结果：Aβ1-40注射后大鼠Morris水迷宫学习记忆能力明显受损（P〈0．01）；注射区内DG背侧细胞带神经元丢失（P〈0．01）；注射侧海乌内Aβ沉积；海马神经元内异常磷酸化tau蛋白的表达显著增加（P〈0．01）。结论：凝聚态Aβ1-40海马注射具有明确的在体神经毒性作用，可导致大鼠认知功能下降以及海马内Aβ沉积、神经元丢失和神经元内异常磷酸化tau蛋白的表达，可成功建立AD大鼠模型。     

Presenilin-1 adopts pathogenic conformation in normal aging and in sporadic Alzheimer’s disease

Accumulation of amyloid-β (Aβ) and neurofibrillary tangles in the brain, inflammation and synaptic and neuronal loss are some of the major neuropathological hallmarks of Alzheimer’s disease (AD). While genetic mutations in amyloid precursor protein and presenilin-1 and -2 (PS1 and PS2) genes cause early-onset familial AD, the etiology of sporadic AD is not fully understood. Our current study shows that changes in conformation of endogenous wild-type PS1, similar to those found with mutant PS1, occur in sporadic AD brain and during normal aging. Using a mouse model of Alzheimer’s disease (Tg2576) that overexpresses the Swedish mutation of amyloid precursor protein but has normal levels of endogenous wild-type presenilin, we report that the percentage of PS1 in a pathogenic conformation increases with age. Importantly, we found that this PS1 conformational shift is associated with amyloid pathology and precedes amyloid-β deposition in the brain. Furthermore, we found that oxidative stress, a common stress characteristic of aging and AD, causes pathogenic PS1 conformational change in neurons in vitro, which is accompanied by increased Aβ42/40 ratio. The results of this study provide important information about the timeline of pathogenic changes in PS1 conformation during aging and suggest that structural changes in PS1/γ-secretase may represent a molecular mechanism by which oxidative stress triggers amyloid-β accumulation in aging and in sporadic AD brain.     

Hippocampal nitric oxide upregulation precedes memory loss and A beta 1-40 accumulation after chronic brain hypoperfusion in rats

Chronic brain hypoperfusion (CBH) using permanent occlusion of both common carotid arteries in an aging rat model, has been shown to mimic human mild cognitive impairment (MCI), an acknowledged high risk condition that often converts to Alzheimer's disease. An aging rat model was used to determine whether hippocampal nitric oxide (NO) is abnormally expressed following CBH for two or eight weeks. At each time point, spatial memory was measured with the Morris water maze and hippocampal A beta 1-40/1-42 concentrations were obtained using sandwich ELISA. Real-time amperometric measures of NO representing the constitutive isoforms of neuronal nitric oxide synthase (nNOS) and endothelial (e)NOS were also taken at each time point to ascertain whether NO levels changed as a result of CBH, and if so, whether such NO changes preceded or followed any memory or amyloid-beta pathology. We found that two weeks after CBH, NO hippocampal levels were upregulated nearly four-fold when compared to nonoccluded rats but no alteration in spatial memory of A beta products were observed at this time point. By contrast, NO concentration had declined to control levels by eight weeks but spatial memory was found significantly impaired and A beta 1-40 (but not A beta 1-42) had increased in the CBH group when compared to control rats. Since changes in shear stress are known to upregulate eNOS but generally not nNOS, these results suggest that shear stress induced by CBH hyperactivated vascular NO derived from eNOS in the first two weeks as a reaction by the capillary endothelium to maintain homeostasis of local cerebral blood flow. The return of vascular NO to basal levels after eight weeks of CBH may have triggered metabolic changes within hippocampal cells resulting in hippocampal dysfunction as reflected by spatial memory impairment and by accumulation of A beta 1-40 peptide. In conclusion, our study shows that CBH initiates spatial memory loss in aging rats thus mimicking human MCI and also increases A beta 1-40 in the hippocampus. The memory and amyloid changes are preceded by NO upregulation in the hippocampus. These preliminary findings may be important in understanding, at least in part, the molecular mechanisms that precede memory impairment during chronic brain ischemia and as such, the pre-clinical stage leading to Alzheimer's disease.     

Deregulation of brain insulin signaling in Alzheimer’s disease

Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer’s disease (AD). In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid β precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.     

Absence of Carboxypeptidase E/Neurotrophic Factor-Α1 in Knock-Out Mice Leads to Dysfunction of BDNF-TRKB Signaling in Hippocampus

The cerebral accumulation of amyloid beta (Aβ) is one of the key pathological hallmarks of Alzheimer’s disease (AD). Aβ is also found in bodily fluids such as the cerebrospinal fluid (CSF) and plasma. However, the significance of Aβ accumulation in the brain and different bodily pools, as well as its correlation with aging and cerebral amyloid pathology, is not completely understood. To better understand this question, we selected the rhesus monkey, which is phylogenetically and physiologically highly similar to the human, as a model to study. We quantified the levels of the two main Aβ isoforms (Aβ42 and Aβ40) in different sections of the brain (frontal cortex, temporal cortex, and hippocampus) and bodily fluids (CSF and plasma) of rhesus monkeys at different developmental phases (young, 5–9 years of age; mature, 10–19 years of age; and old, 21–24 years of age). We found that the levels of neuronal and insoluble Aβ42 increased significantly in the brain with aging, suggesting that this specific isoform might be directly involved in aging and AD-like pathophysiology. There was no significant change in the Aβ40 level in the brain with aging. In addition, the Aβ42 level, but not the Aβ40 level, in both the CSF and plasma increased with aging. We also identified a positive correlation between Aβ42 in the CSF and plasma and Aβ42 in the brain. Taken collectively, our results indicate that there is an association between Aβ accumulation and age. These results support the increased incidence of AD with aging.     

应用基因芯片技术检测Aβ1-40诱导痴呆大鼠脑皮质差异基因的表达

目的:比较Aβ处理前后大鼠额叶皮质的基因表达谱差异,探讨β-淀粉样蛋白(Aβ)神经毒性的分子机制。方法:应用含有4200条大鼠基因的cDNA表达谱芯片对Aβ1-40诱导后的大鼠额叶皮质进行基因表达谱分析。结果:芯片杂交结果分析显示,Aβ1-40诱导组和生理盐水对照组额叶皮质间的差异表达基因共46个,包括上调基因18个,下调基因28个。Go Miner软件对差别表达基因生物学功能的分类结果显示这些基因主要与细胞信号传导、细胞增殖与生长、免疫反应、细胞粘附、离子通道和能量代谢等功能有关。结论:Aβ通过多种途径和机制触发和诱导了神经元的变性,我们的结果为进一步阐明阿尔茨海默病的分子机理提供了一些新的线索。