Creation of "amyloid" fibrils from Bence Jones proteins in vitro

"Amyloid" fibrils have been created from some human Bence Jones proteins by proteolytic digestion under physiologic conditions. These fibrils with an antiparallel, beta-pleated sheet conformation consist of only a portion of the variable region of the immunoglobulin light polypeptide chain and share the physical properties of amyloid fibrils. The relation between amyloidosis and immunoglobulins is thus more firmly established and a pathogenetic mechanism for amyloid fibril formation is suggested.     

Role of intermolecular forces in defining material properties of protein nanofibrils

Protein molecules have the ability to form a rich variety of natural and artificial structures and materials. We show that amyloid fibrils, ordered supramolecular nanostructures that are self-assembled from a wide range of polypeptide molecules, have rigidities varying over four orders of magnitude, and constitute a class of high-performance biomaterials. We elucidate the molecular origin of fibril material properties and show that the major contribution to their rigidity stems from a generic interbackbone hydrogen-bonding network that is modulated by variable side-chain interactions.     

Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis

Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.     

A portrait of Alzheimer secretases--new features and familiar faces

The amyloid beta-peptide (Abeta) is a principal component of the cerebral plaques found in the brains of patients with Alzeheimer's disease (AD). This insoluble 40- to 42-amino acid peptide is formed by the cleavage of the Abeta precursor protein (APP). The three proteases that cleave APP, alpha-, beta-, and gamma-secretases, have been implicated in the etiology of AD. beta-Secretase is a membrane-anchored protein with clear homology to soluble aspartyl proteases, and alpha-secretase displays characteristics of certain membrane-tethered metalloproteases. gamma-Secretase is apparently an oligomeric complex that includes the presenilins, which may be the catalytic component of this protease. Identification of the alpha-, beta-, and gamma-secretases provides potential targets for designing new drugs to treat AD.     

Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease

The deposition of amyloid-beta (Abeta) peptides into amyloid plaques precedes the cognitive dysfunction of Alzheimer's disease (AD) by years. Biomarkers indicative of brain amyloid burden could be useful for identifying individuals at high risk for developing AD. As in AD in humans, baseline plasma Abeta levels in a transgenic mouse model of AD did not correlate with brain amyloid burden. However, after peripheral administration of a monoclonal antibody to Abeta (m266), we observed a rapid increase in plasma Abeta and the magnitude of this increase was highly correlated with amyloid burden in the hippocampus and cortex. This method may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with AD.     

Prevention of transthyretin amyloid disease by changing protein misfolding energetics

Genetic evidence suggests that inhibition of amyloid fibril formation by small molecules should be effective against amyloid diseases. Known amyloid inhibitors appear to function by shifting the aggregation equilibrium away from the amyloid state. Here, we describe a series of transthyretin amyloidosis inhibitors that functioned by increasing the kinetic barrier associated with misfolding, preventing amyloidogenesis by stabilizing the native state. The trans-suppressor mutation, threonine 119 --> methionine 119, which is known to ameliorate familial amyloid disease, also functioned through kinetic stabilization, implying that this small-molecule strategy should be effective in treating amyloid diseases.     

Atomic view of a toxic amyloid small oligomer

Amyloid diseases, including Alzheimer's, Parkinson's, and the prion conditions, are each associated with a particular protein in fibrillar form. These amyloid fibrils were long suspected to be the disease agents, but evidence suggests that smaller, often transient and polymorphic oligomers are the toxic entities. Here, we identify a segment of the amyloid-forming protein αB crystallin, which forms an oligomeric complex exhibiting properties of other amyloid oligomers: β-sheet-rich structure, cytotoxicity, and recognition by an oligomer-specific antibody. The x-ray-derived atomic structure of the oligomer reveals a cylindrical barrel, formed from six antiparallel protein strands, that we term a cylindrin. The cylindrin structure is compatible with a sequence segment from the β-amyloid protein of Alzheimer's disease. Cylindrins offer models for the hitherto elusive structures of amyloid oligomers.     

Purification and reconstitution of the periodic fibril and unit structure of human amyloid

Extraction with alkaline sodium glycinate of the periodic fibril and unit structure of human amyloid and subsequent acidification of the extract provided a method for the purification as well as for the reconstitution of the periodic rod and of the unit structure. Guanidine completely solubilized and irreversibly dissociated both the rod and the unit structure of the human amyloid fibril.     

Games played by rogue proteins in prion disorders and Alzheimer's disease

The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the Abeta peptide, whereas PrPC begets the malignant prion protein PrPSc. Both Abeta and PrPSc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa.     

The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics

It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.     

Diverse gene expression for isotypes of murine serum amyloid A protein during acute phase reaction

Serum amyloid A protein (SAA) is a precursor for a major component of amyloid fibrils, which, upon deposition, cause secondary amyloidosis in diseases such as rheumatoid arthritis. In mice, SAA is encoded by at least three genes, which show diverse expression during inflammation. Furthermore, in amyloidosis-resistant SJL mice, the gene expression for one SAA isotype, SAA2, is defective, although SAA2 gene expression is normal in amyloidosis-susceptible BALB/c mice. Because only SAA2-derived products deposit in mouse amyloid tissues, the resistance of SJL mice to amyloidosis seems to be due to defective SAA2 gene expression. Thus, the study emphasizes the importance of SAA gene structure in determining susceptibility to amyloidosis.     

绵羊住肉孢子虫的超微结构

利用电镜下包囊的超微结构从绵羊鉴别出3种住肉孢子虫,它们是巨型住肉孢子虫、绵羊犬住肉孢子虫、羯犬住肉孢子虫。巨型住肉孢子虫的包囊壁由次生壁和原囊壁组成,原囊壁形成的突起呈花椰菜样,突起内含有管状纤丝和致密颗粒。绵羊犬住肉孢子虫的原囊壁向表面形成栅栏样的突起,突起内无纤丝和致密颗粒。羯犬住肉孢子的原囊壁向表面皱褶形成条带状突起,突起内无纤丝,含少量致密颗粒。在绵羊体内还发现一待定种,其原囊壁向表面形成指形突起,突起内不含纤丝和致密颗粒。     

Fe-Co-P非晶态与晶态纳米线的磁性研究

[目的]研究双过渡金属-类金属的三元合金纳米线各成分的改变对磁学性质的影响。[方法]在氧化铝模板中用电化学沉积法制备2种体系的Fe-Co-P三元合金纳米线。[结果]用扫描电子显微镜和透射电子显微镜观测氧化铝模板和纳米线的形貌。选区电子衍射和X射线衍射结果表明,(Fe1-xCox)0.88P0.12纳米线为非晶结构,而(Fe1-xCox)0.92P0.08纳米线近似为晶态结构。用振动样品磁强计和穆斯堡尔谱仪研究了非晶态体系和晶态体系在室温下的宏观和微观磁性。随Co含量x的变化,每个体系磁参量的变化趋势基本相似,而当x相同时两体系的磁学性质又有所不同。[结论]纳米线中非晶体系的形状各向异性比晶态更明显,更适宜用于垂直磁记录中。     

葛仙米表层结构的扫描电子显微镜观察

近年来由于全球气候变化和土壤生态环境改变等原因导致葛仙米产量大大降低。现已有葛仙米室内规模批量培育生产,但室内培养的葛仙米在生长过程中容易发生破裂,且其群体韧性要比野生葛仙米群体弱、其所含蛋白质与维生素含量均比野生葛仙米低。因此,笔者运用扫描电子显微镜（SEM）观察野生葛仙米和室内规模葛仙米表层结构,了解两者的区别,同时为葛仙米表层结构观察找寻新方法。     

Amyloid fibrils of the HET-s(218-289) prion form a beta solenoid with a triangular hydrophobic core

Prion and nonprion forms of proteins are believed to differ solely in their three-dimensional structure, which is therefore of paramount importance for the prion function. However, no atomic-resolution structure of the fibrillar state that is likely infectious has been reported to date. We present a structural model based on solid-state nuclear magnetic resonance restraints for amyloid fibrils from the prion-forming domain (residues 218 to 289) of the HET-s protein from the filamentous fungus Podospora anserina. On the basis of 134 intra- and intermolecular experimental distance restraints, we find that HET-s(218-289) forms a left-handed beta solenoid, with each molecule forming two helical windings, a compact hydrophobic core, at least 23 hydrogen bonds, three salt bridges, and two asparagine ladders. The structure is likely to have broad implications for understanding the infectious amyloid state.     

Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils

beta-Amyloid plaques and neurofibrillary tangles (NFTs) are the defining neuropathological hallmarks of Alzheimer's disease, but their pathophysiological relation is unclear. Injection of beta-amyloid Abeta42 fibrils into the brains of P301L mutant tau transgenic mice caused fivefold increases in the numbers of NFTs in cell bodies within the amygdala from where neurons project to the injection sites. Gallyas silver impregnation identified NFTs that contained tau phosphorylated at serine 212/threonine 214 and serine 422. NFTs were composed of twisted filaments and occurred in 6-month-old mice as early as 18 days after Abeta42 injections. Our data support the hypothesis that Abeta42 fibrils can accelerate NFT formation in vivo.     

葛仙米表层结构的扫描电子显微镜观察(英文)

[Objective]The experiment aimed to explore a new way for observing surface structure of Nostoc sphaeroides Kutzing. [Method] The scanning electron microscope was used to observe the epidermal ultrastructure of wild and cultured Nostoc sphaeroides Kutzing. [Result] The epidermis of wild and cultured Nostoc sphaeroides Kutzing showed mixture structure of fibril colloid which was reticular arranged. The difference between wild and cultured Nostoc sphaeroides Kutzing was that the outer epidermis of cultured Nostoc sphaeroides Kutzing had trichome distribution but the wild Nostoc sphaeroides Kutzing did not has such distribution. The obsevation results of under smaller than 10 μm by scanning electron microscope was touched thick and showed many folds and distortions.[Conclusion] The scanning electron microscope was an effective way to study development of Nostoc sphaeroides Kutzing colony and it was worth popularizing.     

葛仙米表层结构的扫描电子显微镜观察

[目的]探寻观察葛仙米表层结构的新方法。[方法]利用扫描电镜技术,对野生葛仙米与室内培育葛仙米表皮超微结构进行观察。[结果]野生与室内培育葛仙米表皮都呈网状交错排列的纤丝胶质混合结构特征,不同的是室内规模培育葛仙米群体表皮外层有藻丝分布,而野生葛仙米表皮外层未见藻丝分布。10μm以下的葛仙米群体表皮质感厚实,呈现出很多皱纹,扭曲。[结论]扫描电子显微镜技术是研究葛仙米群体发育的有效工具,值得推广。     

Initiation and synergistic fibrillization of tau and alpha-synuclein

Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.     

寒冷刺激鸡膝关节软骨显微结构变化观察

以冰浴鸡为试材,研究在寒冷刺激条件下对其膝关节软骨显微结构变化的影响。将20只健康蛋鸡随机分为对照组与试验组,对照组正常饲喂,试验组在正常饲喂的情况下每天对其膝关节进行2 h冰浴,持续30 d。取其膝关节软骨进行扫描电镜观察。结果表明:试验组关节软骨结构与对照组具有明显的差异。对照组软骨基质中胶原纤维排列呈拱形结构和薄壳结构,软骨细胞则顺胶原纤维方向排列于其间,结构致密;试验组软骨出现明显的退行性改变,软骨表面波浪状结构低平,拱形结构消失,软骨表面断裂,有胶原纤维及软骨细胞裸露,结构变得明显疏松。