Phosphorylation-Induced Structural Reorganization in Tau-Paired Helical Filaments

Information on the conformation of paired helical filaments (PHF) and the neurofilamentous (NF) network is essential for an understanding of the mechanisms involved in the formation of the primary lesions of Alzheimer's disease (AD): tangles and plaques. The structural and chemical relationships between the NF and the PHF have to be clarified in order to discover the etiological factors of this disease. We are investigating by stereo electron microscopic and biochemical techniques frontal lobe biopsies from patients with AD and squid giant axon preparations. The helical nature of the lesion in AD is related to pathological alterations of basic properties of the nervous system due to the helical symmetry that exists at all hierarchic structural levels in the normal brain. Because of this helical symmetry of NF protein assemblies and PHF, the employment of structure reconstruction techniques to determine the conformation, particularly the handedness of these structures, is most promising. Figs. 1-3 are frontal lobe biopsies.

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Alzheimer's Paired Helical Filaments Contain Insoluble Cytoskeletal Elements

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100120370 ◽

1985 ◽

Vol 43 ◽

pp. 748-751

Author(s):

P. Gambetti ◽

G. Perry ◽

L. Autillo-Gambetti

Keyword(s):

Paired Helical Filaments ◽

Microscope Level ◽

Antigenic Determinants ◽

Light Microscope Level ◽

Neuronal Cytoskeleton ◽

Ionic Detergent ◽

Associated Proteins ◽

Pathologic Lesions ◽

10 Nm Filaments ◽

Cytoskeletal Elements

Neurofibrillary tangles (NFT) are one of the major pathologic lesions of Alzheimer's disease. These neuronal inclusions are predominantly composed of paired helical filaments (PHF), which consist of two 10 nm filaments winding around each other with an approximately 80 nm periodicity. Besides PHF, NFT comprise also 15 nm filaments, 10 nm filaments which are probably neurofilaments, microtubules and granular material. At variance with the neuronal cytoskeleton, PHF are insoluble in ionic detergent.Studies at the light microscope level have shown that NFT have unique antigenic determinants as well as determinants in common with elements of the normal neuronal cytoskeleton such as neurofilaments and microtubule-associated proteins. The present study uses immunocytochemistry and cytochemistry at the electron microscope level to assess which NFT component contains these determinants and whether these antigenic determinants are soluble in an ionic detergent.

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Neurofilaments and Paired Helical Filaments

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100120357 ◽

1985 ◽

Vol 43 ◽

pp. 740-743

Author(s):

J. Metuzals

Keyword(s):

Animal Model ◽

Posttranslational Modifications ◽

Posttranslational Modification ◽

Giant Axon ◽

Paired Helical Filaments ◽

Squid Giant Axon ◽

In Vitro Experiments ◽

Thin Sections ◽

Structural Relationships

It has been demonstrated that the neurofibrillary tangles in biopsies of Alzheimer patients, composed of typical paired helical filaments (PHF), consist also of typical neurofilaments (NF) and 15nm wide filaments. Close structural relationships, and even continuity between NF and PHF, have been observed. In this paper, such relationships are investigated from the standpoint that the PHF are formed through posttranslational modifications of NF. To investigate the validity of the posttranslational modification hypothesis of PHF formation, we have identified in thin sections from frontal lobe biopsies of Alzheimer patients all existing conformations of NF and PHF and ordered these conformations in a hypothetical sequence. However, only experiments with animal model preparations will prove or disprove the validity of the interpretations of static structural observations made on patients. For this purpose, the results of in vitro experiments with the squid giant axon preparations are compared with those obtained from human patients. This approach is essential in discovering etiological factors of Alzheimer's disease and its early diagnosis.

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Liquid crystalline ordering of paired helical filaments in neurofibrillary tangles of Alzheimer's disease

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100143365 ◽

1986 ◽

Vol 44 ◽

pp. 348-349

Author(s):

D.F. Clapin ◽

V.J.A. Montpetit

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neurofibrillary Tangles ◽

Liquid Crystalline ◽

Amyloid Fibrils ◽

Geometric Analysis ◽

Paired Helical Filaments ◽

Microscopic Level ◽

Light Microscopic Level ◽

Regular Spacing

Alzheimer's disease is characterized by the accumulation of abnormal filamentous proteins. The most important of these are amyloid fibrils and paired helical filaments (PHF). PHF are located intraneuronally forming bundles called neurofibrillary tangles. The designation of these structures as "tangles" is appropriate at the light microscopic level. However, localized domains within individual tangles appear to demonstrate a regular spacing which may indicate a liquid crystalline phase. The purpose of this paper is to present a statistical geometric analysis of PHF packing.

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The microtubule associated protein (MAP) tau forms a new class of triple-stranded left-hand helical fibrous protein polymer

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100123106 ◽

1992 ◽

Vol 50 (1) ◽

pp. 540-541

Author(s):

G. C. Ruben ◽

K. Iqbal ◽

I. Grundke-Iqbal ◽

H. Wisniewski ◽

T. L. Ciardelli ◽

...

Keyword(s):

Axial Ratio ◽

Normal Structure ◽

Paired Helical Filaments ◽

Left Hand ◽

New Class ◽

Protein Polymer ◽

Fibrous Protein ◽

Protein Map ◽

Neurotransmitter Transport ◽

Alzheimer Neurofibrillary Tangles

In neurons, the microtubule associated protein, tau, is found in the axons. Tau stabilizes the microtubules required for neurotransmitter transport to the axonal terminal. Since tau has been found in both Alzheimer neurofibrillary tangles (NFT) and in paired helical filaments (PHF), the study of tau's normal structure had to preceed TEM studies of NFT and PHF. The structure of tau was first studied by ultracentrifugation. This work suggested that it was a rod shaped molecule with an axial ratio of 20:1. More recently, paraciystals of phosphorylated and nonphosphoiylated tau have been reported. Phosphorylated tau was 90-95 nm in length and 3-6 nm in diameter where as nonphosphorylated tau was 69-75 nm in length. A shorter length of 30 nm was reported for undamaged tau indicating that it is an extremely flexible molecule. Tau was also studied in relation to microtubules, and its length was found to be 56.1±14.1 nm.

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Paired helical filaments (PHF) in rats: An experimental animal model for Alzheimer's disease

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100128493 ◽

1987 ◽

Vol 45 ◽

pp. 842-843

Author(s):

V.J.A. Montpetit ◽

S. Dancea ◽

S.W. French ◽

D.F. Clapin

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Animal Model ◽

Paired Helical Filaments ◽

Ethanol Intoxication ◽

Drg Neurons ◽

Critical Difference ◽

Suitable Animal Model ◽

The Central Nervous System ◽

Chronic Ethanol Intoxication

A continuing problem in Alzheimer research is the lack of a suitable animal model for the disease. The absence of neurofibrillary tangles of paired helical filaments is the most critical difference in the processes by which the central nervous system ages in most species other than man. However, restricting consideration to single phenomena, one may identify animal models for specific aspects of Alzheimer's disease. Abnormal fibers resembling PHF have been observed in dorsal root ganglia (DRG) neurons of rats in a study of chronic ethanol intoxication and spontaneously in aged rats. We present in this report evidence that PHF-like filaments occur in ethanol-treated rats of young age. In control animals lesions similar in some respects to our observations of cytoskeletal pathology in pyridoxine induced neurotoxicity were observed.Male Wistar BR rats (Charles River Labs) weighing 350 to 400 g, were implanted with a single gastrostomy cannula and infused with a liquid diet containing 30% of total calories as fat plus ethanol or isocaloric dextrose.

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Surface confinement induces the formation of solid-like insulating ionic liquid nanostructures

10.26434/chemrxiv.5573287.v1 ◽

2017 ◽

Author(s):

Massimiliano Galluzzi ◽

Simone Bovio ◽

Paolo Milani ◽

Alessandro Podestà

Keyword(s):

Ionic Liquid ◽

Electrical Properties ◽

Electric Fields ◽

Relative Dielectric Constant ◽

Ionic Mobility ◽

Electric Properties ◽

Bulk Liquid ◽

Structural Reorganization ◽

Surface Confinement ◽

Insulator Layers

We report on the modification of the electric properties of the imidazolium-based [BMIM][NTf2] ionic liquid upon surface confinement in the sub-monolayer regime. Solid-like insulating nanostructures of [BMIM][NTf2] spontaneously form on a variety of insulating substrates, at odd with the liquid and conductive nature of the same substances in the bulk phase. A systematic spatially resolved investigation by atomic force microscopy of the morphological, mechanical and electrical properties of [BMIM][NTf2] nanostructures showed that this liquid substance rearranges into lamellar nanostructures with a high degree of vertical order and enhanced resistance to mechanical compressive stresses and very intense electric fields, denoting a solid-like character. The morphological and structural reorganization has a profound impact on the electric properties of supported [BMIM][NTf2] islands, which behave like insulator layers with a relative dielectric constant between 3 and 5, comparable to those of conventional ionic solids, and significantly smaller than those measured in the bulk ionic liquid. These results suggest that in the solid-like ordered domains confined either at surfaces or inside the pores of the nanoporous electrodes of photo-electrochemical devices, the ionic mobility and the overall electrical properties can be significantly perturbed with respect to the bulk liquid phase, which would likely influence the<br>performance of the devices.<br>

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