维生素C保护Aβ1-40Cu(Ⅱ)复合物引起的神经元氧化损伤

老年斑中存在大量β 淀粉样蛋白（β-amyloid, Aβ）是老年痴呆症（Alzheimer′s disease, AD）的重要病理特征.大量数据表明,Aβ上具有与过渡态金属离子共价结合的位点,二者能结合成为寡聚复合物. Aβ_1-40Cu（Ⅱ）复合物通过Cu²⁺的还原催化O₂产生H₂O₂但反应机制不清.本文尝试以天然抗氧化剂维生素C（VC）来对抗Aβ_1-40及Aβ_1-40Cu（Ⅱ）复合物产生的H₂O₂对原代培养的神经细胞的毒性.结果表明,VC能够起到显著的保护作用,其有效浓度为1mmol/L.本文用胞外乳酸脱氢酶泄漏量和H₂O₂生成量的数据证实了细胞存活率（MTT实验）的实验结果.这些结果表明,Aβ_1-40Cu（Ⅱ）复合物能够释放更多的H₂O₂,引发细胞膜破裂并最终引起细胞死亡.加入VC后,神经元受到的损伤较轻,提示VC在保护细胞免受氧化损伤方面发挥了重要作用.     

Zn~(2+)对Aβ_(1-40)诱导PC12细胞损伤的保护作用

阿尔茨海默病(Alzheimer’s disease,AD)是一种进行性中枢神经系统退行性疾病,也是最常见的老年痴呆症.锌是人体必不可少的微量元素,在大脑海马中含量丰富,若海马中锌含量不足,会出现记忆力减退等症状并最终导致AD.通过MTT法探索不同浓度锌离子作用于Aβ1-40损伤PC12细胞模型的最适浓度,并将实验分为对照组、Aβ损伤组、Aβ损伤前补锌组、Aβ损伤后补锌组、Aβ损伤前同时补锌和锌离子螯合剂TPEN组,通过Hoechst33342荧光染色和Caspase-3活性检测实验分析细胞凋亡情况;通过检测LDH含量分析细胞损伤程度并运用Western blotting方法检测相关蛋白表达量,结果表明锌离子具有保护PC12细胞免受Aβ1-40损伤的作用,并且这种保护作用发生在Aβ损伤作用之前,在Aβ损伤后补充锌作用不明显.这一结论为进一步研究锌离子在AD发生发展中的作用提供了实验依据.     

多烯磷脂酰胆碱对β- 淀粉样蛋白（Aβ1-40）致阿尔茨海默病 模型大鼠的治疗作用

目的:研究多烯磷脂酰胆碱(Polyene Phosphatidyl choline,PPC)对β-淀粉样蛋白(Aβ1-40)致阿尔茨海默病(Alzheimer’s Dis-ease,AD)模型大鼠的治疗作用。方法:32只SD大鼠随机分为正常组、假手术组、模型组和处理组,海马内注射淀粉样蛋白(Aβ1-40),制作大鼠阿尔茨海默病模型,处理组给予多烯磷脂酰胆碱。通过Morris水迷宫实验验检测各组大鼠认知行为学改变,海马组织学及免疫组化染色,观察多烯磷脂酰胆碱对阿尔茨海默病模型大鼠的影响,并进行统计学分析。结果:①Morris水迷宫实验,模型组与正常组、假手术组比较,学习和记忆潜伏期显著增加;处理组与模型组比较,学习和记忆潜伏期显著减少;组间比较差异有统计学意义(P<0.05),提示多烯磷脂酰胆碱使AD模型大鼠的认知行为学功能改善。②Nissl染色,模型组与正常对照组、假手术组组织学染色结果有显著性差异(P<0.05),PPC处理组与模型组比较有显著性差异(P<0.05),PPC处理组与正常组及假手术组比较也呈现出显著性差异(P<0.05);提示多烯磷脂酰胆碱可以减少神经元的凋亡。③β-淀粉样蛋白免疫组化染色,模型组与正常对照组、假手术组比较,Aβ沉积明显增加;PPC处理组与模型组比较,Aβ沉积范围明显缩小,PPC处理组与正常对照组、假手术组也呈现出显著性差。结论:多烯磷脂酰胆碱对淀粉样蛋白(Aβ1-40)致阿尔茨海默病模型大鼠有治疗作用。     

异槲皮苷对Aβ25-35导致的PC12细胞损伤的保护作用及机制研究

探讨异槲皮苷对β-淀粉样蛋白(Aβ25-35)导致的PC12细胞氧化损伤的保护作用.首先通过分子对接技术分析异槲皮苷与AMPK的结合情况.采用Aβ25-35(20 μmol/L)损伤PC12细胞建立细胞氧化损伤模型,采用甲基噻唑蓝(MTT)法检测细胞活力,通过试剂盒检测乳酸脱氢酶(LDH)漏出量、活性氧(ROS)含量、...     

硒代蛋氨酸对Aβ1-42诱导N2a细胞损伤的保护作用

探索硒代蛋氨酸（Se-Met）的早期干预对Aβ1-42诱导的Neuro-2A（N2a）细胞损伤的保护作用。将N2a细胞分为对照组、Aβ1-42诱导损伤组、Se．Met组和Se—Met预处理的ADl-42组,CCK．8法检测显示不同浓度Se-Met对N2a细胞活力的影响不同,且Se．Met能减弱Aβ1-42诱导N2a细胞活力的降低（P〈0．01）：DCFH．DA标记检测可见Se-Met预处理明显抑制Aβ1-42引起的N2a细胞内总活性氧（reactive oxygen species,ROS）水平增高,Aβ1-42作用24h组效果更显著（P〈0．05）;Westernblot检测发现,Se-Met可显著回升Aβ1-42引起的N2a细胞synaptophysin和PSD95水平的降低（P〈0．05;P〈0．05）;同时,Se-Met可显著降低Aβ1-42引起的N2a细胞内LC3-II／LC3-I水平的升高（P〈0．05）。因此,Se-Met在一定作用时间和浓度下可以提高N2a细胞的活力,对Aβ1-42引起的N2a细胞ROS水平增高、自噬均有抑制作用,同时缓解Aβ1-42引起的突触损伤;Se-Met对Aβ1-42诱导N2a细胞损伤具有较好的保护作用。     

多烯磷脂酰胆碱对β-淀粉样蛋白（Aβ 1—40）致阿尔茨海默病模型大鼠的治疗作用

目的：研究多烯磷脂酰胆碱（Polyene Phosphatiayl choline,PPC）对β-淀粉样蛋白（Apl-40）致阿尔茨海默病（Alzheimer＇s Dis．ease,AD）模型大鼠的治疗作用。方法：32只SD大鼠随机分为正常组、假手术组、模型组和处理组,海马内注射淀粉样蛋白（Aβ1—40）,制作大鼠阿尔茨海默病模型,处理组给予多烯磷脂酰胆碱。通过Moms水迷宫实验验检测各组大鼠认知行为学改变,海马组织学及免疫组化染色,观察多烯磷脂酰胆碱对阿尔茨海默病模型大鼠的影响,并进行统计学分析。结果：①Moms水迷宫实验,模型组与正常组、假手术组比较,学习和记忆潜伏期显著增加;处理组与模型组比较,学习和记忆潜伏期显著减少;组间比较差异有统计学意义（P〈0．05）,提示多烯磷脂酰胆碱使AD模型大鼠的认知行为学功能改善。（2）Nissl染色,模型组与正常对照组、假手术组组织学染色结果有显著性差异（P〈0．05）,PPC处理组与模型组比较有显著性差异（P〈0．05）,PPC处理组与正常组及假手术组比较也呈现出显著性差异（P〈0．05）;提示多烯磷脂酰胆碱可以减少神经元的凋亡。③β-淀粉样蛋白免疫组化染色,模型组与正常对照组、假手术组比较,Aβ沉积明显增加;PPC处理组与模型组比较,Aβ沉积范围明显缩小,PPC处理组与正常对照组、假手术组也呈现出显著性差。结论：多烯磷脂酰胆碱对淀粉样蛋白（Aβ1—40）致阿尔茨海默病模型大鼠有治疗作用。     

以Aβ4-11为免疫原制备Aβ1-42多克隆抗体

β淀粉样蛋白1-42(βamyloid 1-42,Aβ1-42)是阿尔茨海默病(Alzheimer’s disease,AD)的主要致病蛋白,其抗体一直处于研发当中。现以Aβ4-11耦联KLH免疫2月龄雌兔,ELISA检测雌兔免疫血清中所产生的抗Aβ4-11 IgG滴度,Protein G-琼脂糖亲和层析纯化IgG,Bradford方法进行IgG蛋白含量测定,SDS-PAGE进行IgG纯度测定,最后运用所制备的多克隆抗体采用免疫组化的方法分别对正常小鼠和9月龄APP转基因小鼠进行老年斑的检测,以鉴定此抗体对Aβ1-42的特异性及亲和力。结果显示Aβ4-11具有良好的体液免疫原性,而且以其为免疫原制备的抗体对Aβ1-42表现出良好的特异性及亲和力。结果表明,以Aβ4-11亚单位片段为免疫原制备的Aβ1-42多克隆抗体,可以作为AD的一种有效研究工具,同时也为AD的诊断和治疗提供了一种新的可能。     

乌鸡白凤丸有效成分抑制C31引起的电压门控型Ca2+通道电流增强的作用

目的研究C31对大鼠肾上腺髓质嗜铬细胞瘤细胞(PC12)电压门控性钙通道(VGCC)电流的影响,以及乌鸡白凤丸有效成分(BFP)对此效应的干预作用.方法将PC12细胞分成空白对照组、C31组、C31+BFP组、BFP组、β-雌二醇组和C31+β-雌二醇组,分别孵育12 h.在全细胞膜片钳记录模式下,记录各组细胞VGCC电流的电流峰值,求得细胞的电流密度(电流值/膜电客),作为Ca2+内流的指标.结果对照组平均VGCC电流密度为(16.01±9.75)p/ApF,C31组为(26.47±14.55)pA/pF,两组相比,差别具有显著性(P＜0.05);C31+BFP组的平均电流密度为(17.68±10.52)pA/pF,C31+β-雌二醇组的电流密度为(13.41±4.21)pA/pF,与C31组(26.47±14.55pA/pF)比较,差别具有显著性(P＜0.05).结论C31能够促进VGCC开放,Ca2+内流增多,引起细胞损伤;BFP和β-雌二醇能有效抑制C31所引起的VGCC电流增强效应,在一定程度上避免了细胞内Ca2+超载;BFP的这些作用可能是通过类雌激素样作用实现的.     

可溶的和纤维化的Aβ1-40对膜脂的通透性的影响

利用光散射,浊度,荧光以及电镜等技术研究了可溶性的A茁1-40聚集形成纤维的动力学过程;用三种水溶性的分子质量不同的荧光探剂ANTS/DPX,Calcein,DextranFD-4包裹在脂质体内,检测可溶的和纤维化的A茁1-40对其内含物漏出的影响。结果表明:可溶性的A茁1-40在pH7.4,37℃温育4天以后开始聚集,7天后形成稳定的纤维;聚集的A茁1-40能够诱导包裹在脂质体内的ANTS/DPX,Calcein的漏出,但不能诱发Dextran(FD-4)的漏出,并初步估算出聚集的A茁1-40在膜上能产生孔径为13-18魡的小孔,而可溶的A茁1-40无此作用。这提示我们,聚集成纤维的A茁1-40能改变膜脂的物理化学性质,并造成内含物的漏出,这些作用可能是造成神经细胞毒性的重要原因。     

Cu（Ⅱ） Potentiation of Alzheimer Aβ1-40 Cytotoxicity and Transition on its Secondary Structure

Mounting evidence has shown that dyshomeostasis of the redox-active biometals such as Cuand Fe can lead to oxidative stress,which plays a key role in the neuropathology of Alzheimer's disease(AD).Here we demonstrate that with the formation of Cu(Ⅱ)·Aβ1-40 complexes,copper markedly potentiatesthe neurotoxicity exhibited by β-amyloid peptide (Aβ).A greater amount of hydrogen peroxide was releasedwhen Cu(Ⅱ)·Aβ1-40 complexes was added to the xanthine oxidase/xanthine system detected by potassiumiodide spectrophotometry.Copper bound to Aβ1-40 was observed by electron paramagnetic resonance(EPR) spectroscopy.Circular dichroism (CD) studies indicated that copper chelation could cause a structuraltransition of Aβ.The addition of copper to Aβ introduced an increase on β-sheet as well as α-helix,whichmay be responsible for the aggregation of Aβ.We hypothesized that Aβ aggregation induced by copper maybe responsible for local injury in AD.The interaction between Cu~(2 ) and Aβ also provides a possible mechanismfor the enrichment of metal ions in amyloid plaques in the AD brain.     

Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain

Previously, we found that amyloid beta-protein (Abeta)1-42 exhibits neurotoxicity, while Abeta1-40 serves as an antioxidant molecule by quenching metal ions and inhibiting metal-mediated oxygen radical generation. Here, we show another neuroprotective action of nonamyloidogenic Abeta1-40 against Abeta1-42-induced neurotoxicity in culture and in vivo. Neuronal death was induced by Abeta1-42 at concentrations higher than 2 microm, which was prevented by concurrent treatment with Abeta1-40 in a dose-dependent manner. However, metal chelators did not prevent Abeta1-42-induced neuronal death. Circular dichroism spectroscopy showed that Abeta1-40 inhibited the beta-sheet transformation of Abeta1-42. Thioflavin-T assay and electron microscopy analysis revealed that Abeta1-40 inhibited the fibril formation of Abeta1-42. In contrast, Abeta1-16, Abeta25-35, and Abeta40-1 did not inhibit the fibril formation of Abeta1-42 nor prevent Abeta1-42-induced neuronal death. Abeta1-42 injection into the rat entorhinal cortex (EC) caused the hyperphosphorylation of tau on both sides of EC and hippocampus and increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the ipsilateral EC, which were prevented by the concurrent injection of Abeta1-40. These results indicate that Abeta1-40 protects neurons from Abeta1-42-induced neuronal damage in vitro and in vivo, not by sequestrating metals, but by inhibiting the beta-sheet transformation and fibril formation of Abeta1-42. Our data suggest a mechanism by which elevated Abeta1-42/Abeta1-40 ratio accelerates the development of Alzheimer's disease (AD) in familial AD.     

Abeta(31-35) peptide induce apoptosis in PC 12 cells: contrast with Abeta(25-35) peptide and examination of underlying mechanisms

The toxic behaviour of the two shorter sequences of the native Abeta amyloid peptide required for cytotoxicity i.e., Abeta(31-35) and Abeta(25-35) peptides, was studied. We have shown that Abeta(31-35) peptide induces neurotoxicity in undifferentiated PC 12 cell via an apoptotic cell death pathway, including caspase activation and DNA fragmentation. Abeta(25-35) peptide, like the shorter amyloid peptide has the ability to induce neurotoxicity, as evaluated by the MTS reduction assay and by adherent cell count, but the Abeta(25-35) peptide-induced neurotoxicity is not associated with any biochemical features of apoptosis. The differences observed between the neurotoxic properties of Abeta(31-35) and Abeta(25-35) peptides might result on their different ability to be internalised within the neuronal cells. Furthermore, this study reveals that the redox state of methionine residue, C-terminal in Abeta(31-35) and Abeta(25-35) peptides affect in a different way the toxic behaviour of these two short amyloid fragments. Taken together our results suggest that Abeta(31-35) peptide induces cell death by apoptosis, unlike the Abeta(25-35) peptide and that role played by methionine-35 in Abeta induced neurotoxicity might be related to the Abeta aggregation state.     

Protective Effects of Vitamin E against Oxidative Damage Induced by Aβ1-40Cu（Ⅱ） Complexes

β-amyloid peptide (Aβ) is considered to be responsible for the formation of senile plaques,which is the hallmark of Alzheimer's disease (AD).Oxidative stress,manifested by protein oxidation andlipid peroxidation,among other alterations,is a characteristic of AD brain.A growing body of evidence hasbeen presented in support of Aβ_(1-40) forming an oligomeric complex that binds copper at a CuZn superoxidedismutase-like binding site. Aβ_(1-40)Cu(Ⅱ) complexes generate neurotoxic hydrogen peroxide (H_2O_2) from O_2via Cue reduction,though the precise reaction mechanism is unclear.The toxicity of Aβ_(1-40) or the Aβ_(1-40)Cu(Ⅱ)complexes to cultured primary cortical neurons was partially attenuated when ( )-α-tocopherol (vitamin E)as free radical antioxidant was added at a concentration of 100 μM.The data derived from lactate dehydro-genase (LDH) release and the formation of H_2O_2 confirmed the results from the MTT assay.These findingsindicate that copper binding to Aβ_(1-40) can give rise to greater production of H_2O_2, which leads to a break-down in the integrity of the plasma membrane and subsequent neuronal death.Groups treated with vitaminE exhibited much slighter damage,suggesting that vitamin E plays a key role in protecting neuronal cellsfrom dysfunction or death.     

Secondary structure conversions of Alzheimer's Abeta(1-40) peptide induced by membrane-mimicking detergents

The amyloid beta peptide (Abeta) with 39-42 residues is the major component of amyloid plaques found in brains of Alzheimer's disease patients, and soluble oligomeric peptide aggregates mediate toxic effects on neurons. The Abeta aggregation involves a conformational change of the peptide structure to beta-sheet. In the present study, we report on the effect of detergents on the structure transitions of Abeta, to mimic the effects that biomembranes may have. In vitro, monomeric Abeta(1-40) in a dilute aqueous solution is weakly structured. By gradually adding small amounts of sodium dodecyl sulfate (SDS) or lithium dodecyl sulfate to a dilute aqueous solution, Abeta(1-40) is converted to beta-sheet, as observed by CD at 3 degrees C and 20 degrees C. The transition is mainly a two-state process, as revealed by approximately isodichroic points in the titrations. Abeta(1-40) loses almost all NMR signals at dodecyl sulfate concentrations giving rise to the optimal beta-sheet content (approximate detergent/peptide ratio = 20). Under these conditions, thioflavin T fluorescence measurements indicate a maximum of aggregated amyloid-like structures. The loss of NMR signals suggests that these are also involved in intermediate chemical exchange. Transverse relaxation optimized spectroscopy NMR spectra indicate that the C-terminal residues are more dynamic than the others. By further addition of SDS or lithium dodecyl sulfate reaching concentrations close to the critical micellar concentration, CD, NMR and FTIR spectra show that the peptide rearranges to form a micelle-bound structure with alpha-helical segments, similar to the secondary structures formed when a high concentration of detergent is added directly to the peptide solution.     

Abeta(25-35) and Abeta(1-40) act on different calcium channels in CA1 hippocampal neurons

The acute effects of beta-amyloid (25-35) and (1-40) on high voltage activated calcium channels were compared in CA1 pyramidal cells of adult mouse hippocampal slices using the whole-cell patch-clamp recording. Bath application of oligomeric beta-amyloid (25-35) reversibly increased the barium current (I(Ba)) to 1.61 (normalized amplitude), while oligomeric beta-amyloid (1-40) reversibly enhanced the I(Ba) to 1.74. Reverse-sequence beta-amyloid [(35-25) and (40-1)] had no effect. The effect of beta-amyloid (25-35) was blocked by nifedipine, a selective antagonist of L-type calcium channels. In contrast, the effect of beta-amyloid (1-40) was not blocked by nifedipine and I(Ba) was enhanced to 4.96. It is concluded that these oligomeric peptides may act through different types of calcium channels and/or receptors. The toxicity of Abeta(25-35) implicates a potentiation of L-type calcium channels while the one of Abeta(1-40) is related to an increase of non-L-type calcium channels, which may involve an increase in transmitter release.     

Formation of toxic Abeta(1-40) fibrils on GM1 ganglioside-containing membranes mimicking lipid rafts: polymorphisms in Abeta(1-40) fibrils

The abnormal aggregation and deposition of amyloid β protein (Aβ) on neuronal cells are critical to the onset of Alzheimer's disease. The entity (oligomers or fibrils) of toxic Aβ species responsible for the pathogenesis of the disease has been controversial. We have reported that the Aβ aggregates on ganglioside-rich domains of neuronal PC12 cells as well as in raft-like model membranes. Here, we identified toxic Aβ(1-40) aggregates formed with GM1-ganglioside-containing membranes. Aβ(1-40) was incubated with raft-like liposomes composed of GM1/cholesterol/sphingomyelin at 1:2:2 and 37 °C. After a lag period, toxic amyloid fibrils with a width of 12 nm were formed and subsequently laterally assembled with slight changes in their secondary structure as confirmed by viability assay, thioflavin-T fluorescence, circular dichroism, and transmission electron microscopy. In striking contrast, Aβ fibrils formed without membranes were thinner (6.7 nm) and much less toxic because of weaker binding to cell membranes and a smaller surface hydrophobicity. This study suggests that toxic Aβ(1-40) species formed on membranes are not soluble oligomers but amyloid fibrils and that Aβ(1-40) fibrils exhibit polymorphisms.     

Characterizations of distinct amyloidogenic conformations of the Abeta (1-40) and (1-42) peptides

Major constituents of the amyloid plaques found in the brain of Alzheimer's patients are the 39-43 residue beta-amyloid (Abeta) peptides. Extensive in vitro as well as in vivo biochemical studies have shown that the 40- and 42-residue Abeta peptides play major roles in the neurodegenerative pathology of Alzheimer's disease. Although the two Abeta peptides share common aggregation properties, the 42-residue peptide is more amyloidogenic and more strongly associated with amyloid pathology. Thus, characterizations of the two Abeta peptides are of critical importance in understanding the molecular mechanism of Abeta amyloid formation. In this report, we present combined CD and NMR studies of the monomeric states of the two peptides under both non-amyloidogenic (<5 degrees C) and amyloid-forming conditions (>5 degrees C) at physiological pH. Our CD studies of the Abeta peptides showed that initially unfolded Abeta peptides at low temperature (<5 degrees C) gradually underwent conformational changes to more beta-sheet-like monomeric intermediate states at stronger amyloidogenic conditions (higher temperatures). Detailed residue-specific information on the structural transition was obtained by using NMR spectroscopy. Residues in the N-terminal (3-12) and 20-22 regions underwent conformational changes to more extended structures at the stronger amyloidogenic conditions. Almost identical structural transitions of those residues were observed in the two Abeta peptides, suggesting a similar amyloidogenic intermediate for the two peptides. The 42-residue Abeta (1-42) peptide was, however, more significantly structured at the C-terminal region (39-42), which may lead to the different aggregation propensity of the two peptides.     

Alanine scanning mutagenesis of Abeta(1-40) amyloid fibril stability

We describe here an alanine scanning mutational analysis of the Abeta(1-40) amyloid fibril monitored by fibril elongation thermodynamics derived from critical concentration values for fibril growth. Alanine replacement of most residues in the amyloid core region, residues 15-36, leads to destabilization of the elongation step, compared to wild-type, by about 1kcal/mol, consistent with a major role for hydrophobic packing in Abeta(1-40) fibril assembly. Where comparisons are possible, the destabilizing effects of Ala replacements are generally in very good agreement with the effects of Ala replacements of the same amino acid residues in an element of parallel beta-sheet in the small, globular protein Gbeta1. We utilize these Ala-WT DeltaDeltaG values to filter previously described Pro-WT DeltaDeltaG values, creating Pro-Ala DeltaDeltaG values that specifically assess the sensitivity of a sequence position, in the structural context of the Abeta fibril, to replacement by proline. The results provide a conservative view of the energetics of Abeta(1-40) fibril structure, indicating that positions 18-21, 25-26, and 32-33 within amyloid structure are particularly sensitive to the main-chain disrupting effects of Pro replacements. In contrast, residues 14-17, 22, 24, 27-31, and 34-39 are relatively insensitive to Pro replacements; most N-terminal residues were not tested. The results are discussed in terms of amyloid fibril structure and folding energetics, in particular focusing on how the data compare to those from other structural studies of Abeta(1-40) amyloid fibrils grown in phosphate-buffered saline at 37 degrees C under unstirred ("quiescent") conditions.     

Beta-amyloid-derived pentapeptide RIIGLa inhibits Abeta(1-42) aggregation and toxicity

Pr-IIGL(a), a derivative of the tetrapeptide beta-amyloid 31-34 (Abeta(31-34)), exerts controversial effects: it is toxic in a neuroblastoma culture, but it protects glial cells from the cytotoxic action of Abeta(1-42). For an understanding of this phenomenon, a new pentapeptide, RIIGL(a) was synthetized, and both compounds were studied by different physicochemical and biological methods. Transmission electron microscopic (TEM) studies revealed that Pr-IIGL(a) forms fibrillar aggregates, whereas RIIGL(a) does not form fibrils. Congo red binding studies furnished the same results. Aggregated Pr-IIGL(a) acts as a cytotoxic agent in neuroblastoma cultures, but RIIGL(a) does not display inherent toxicity. RIIGL(a) co-incubated with Abeta(1-42) inhibits the formation of mature amyloid fibres (TEM studies) and reduces the cytotoxic effect of fibrillar Abeta(1-42). These results indicate that RIIGL(a) is an effective inhibitor of both the aggregation and the toxic effects of Abeta(1-42) and can serve as a lead compound for the design of novel neuroprotective peptidomimetics.