Literature: A-K ; L-Z ; subject area
Compiled by: Julian Thorpe
Electron Microscopy
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Please Note: Due to time constraints, the text part of this page has not been updated for some time. However, references are added reasonably frequently. |
PHF ultrastructure ; PHF formation ; glial cells ; beta-amyloid ; apoE ; neurotransmitters
references
Our Research on Pin1 Protein and AD
 | We have developed a novel transmission electron microscope (TEM) methodology whereby Pin1 is used as a probe for its target proteins within tissues (Thorpe et al., 1999) . |
| Recently, we have utilised this latter methodology in work including a preliminary examination (restricted to one brain sample) of the levels and distribution of both endogenous Pin1 and exogenous Pin1 binding in (normal and) AD human brain tissue (Thorpe et al., 2001) . This work showed enhanced levels of Pin1 binding to its (unbound, phosphorylated) target proteins (in mitotic cells and AD brain). In the AD-affected neurones, endogenous levels of Pin1 in the cytoplasm were increased and the highest levels of (exogenous) Pin1 binding were to the tau-rich NFTs, reflecting a redirection to the cytoplasm and a shortfall of available Pin1 in these cells. |
| See more detail (including data) on the results from the above work. |
| More detail on the methodology of using chaperone proteins as 'TEM Probes ' of their target proteins. |
| N.B. Also see the author's EM and FACS Lab Website for full details on immunogold labelling labelling TEM . |
| Katsuragi et al. (1991) examined NFTs by tilt-stage electron microscopy and concluded that a fibril of NFT consisted of twisted protofilaments made up of globular subunits (rather than the paired helical arrangement). |
| Wille et al., (1992) looked at tau constructs derived from human brain tau expressed in E. coli . All the constructs were rod-like with a tendency to dimerize in an anti-parallel fashion. Constructs could form PHF-like structures in vitro and there was no requirement for phosphorylation. |
| Ruben et al. (1993) used a high resolution transmission EM method involving shadowed replicas of freeze-dried material to elucidate the fine structure of PHFs. They observed the filaments to be right-handed helices with a twist period of about 80nm and a maximum width of around 15nm. They also found a new filament within the tangles which was in the form of a triple-stranded left helix of 2.1nm diameter; the structure was identical to bovine tau. |
| Pollanen et al. (1994) used atomic force microscopy to re-evaluate the ultrastructure of PHF s. They concluded that the 'PHFs' should instead be considered to be a twisted ribbon structure. |
| Aluminium/glutamate effects on PHF formation: Using rat cerebral explants, Jones et al. (1998) examined the effects of aluminium and glutamate upon PHF formation. Found that aluminium could cause significant accumulations of curved filaments but only one of the samples looked at had possibly PHF-like filaments. The authors suggested that postulations of a link between aluminium and AD might be premature. |
| Wille et al., (1992) looked at tau constructs derived from human brain tau expressed in E. coli . All the constructs were rod-like with a tendency to dimerize in an anti-parallel fashion. Constructs could form PHF-like structures in vitro and there was no requirement for phosphorylation. |
| Ahlijanian et al. (2000) used transgenic mice (overexpressing human p25, which activates cdK5) to show hyperphosphorylation of tau and neurofilaments by cdk5. Ultrastructurally, this latter was accompanied by cytoskeletal disruption reminiscent of AD. |
| PHFs in astrocytes: Nakano et al.(1992) studied an atypical case of AD. The brain contained abundant amyloid plaques, ghost (extracellular) NFTs many hypertrophic astrocytes. The latter were frequently found to be tau - (and ubiquitin-) positive. Double-staining showed tau to be present in glial fibrillary acidic peptide (GFAP)-positive astrocytic perikarya and processes. Electron microscopy (of the hippocampal CA1) showed that astrocytes contained abnormal filaments identical to the PHFs of neurons; these filaments were tau- (and ubiquitin-) positive. In later work (Yamazaki et al.,1995 ), this group showed the presence of PHFs and straight tubules in astrocytes of 3 advanced cases of long duration AD. These features were indistinguishable from those seen in neurons. They were associated mainly with ghost tangles and also with small vessels. They suggested that the duration of the disease condition has a significant effect upon the formation of these features in astrocytes. |
| Astrocytic tubules: Arima et al. (1998) reported the presence of astrocytic tubules (As-Tbs) in astrocytic processes in brains with presenile-onset AD. These were located almost exclusively in the highly-devastated neuropil and were associated with glial filaments. The tubules were either twisted or non-twisted and some were observed to be adjacent to extracellular NFT s. Because they were tau-immunoreactive to an antibody which does not recognise extracellular NFTs they concluded that the As-Tbs were astrocytic in origin. As they were indistinguishable from dystrophic neurites under the light microscope they suggested that they may be more common than previously thought. |
| From their results of light and EM histochemical staining using antibodies directed against four segments of the amyloid precursor protein (APP), McGeer et al. (1992) found that APP is usually located in intraneuronal granules. In AD, they postulated the following sequence of events: 1 APP accumulates in damaged neuronal fibres; 2 The amino terminal portion binds to abnormal neurofilaments; 3 APP fragments are phagocytosed by microglia (resident cerebral tissue macrophages) and processed; 4 The beta-amyloid portion is extruded and accumulates extracellularly. |
| Wegiel et al. (2000) have looked (ultrastructurally) at the relationship between microglial and astrocytic cells and beta-amyloid plaue formation and degradation. They describe three stages of classical plaque development. |
| Serpell (2000) and Roher et al. (2000) have looked at the structure and assembly of the beta-amyloid protein. Both stress the importance of the shift from a predominantly alpha-helical to a beta-sheet structure. |
| Serpell et al. (2000) have utilised cryo-TEM and diffraction studies of magnetically aligned preparations of a central beta-amyloid domain to deduce a proposed high-resolution structure based on a beta-hairpin motif. |
| Serpell and Smith (2000) examined synthetic amyloid fibrils composed of A beta residues 11-25 and 1-42 by cryo-TEM. Beta-strands were seen to be in direct register and to run perpendicular to the fibre axis. |
| Roses et al. (1996) localised apoE to the neuronal cytoplasm and suggested that apoE3 (and apoE2) prevented PHF formation by interacting with the microtubule binding domain of tau . In this way it also protects the site for microtubule stabilising interactions with beta-tubulin. |
| Cholinesterase activity: Carson et al. (1991) looked at the distribution of acetyl- (AChE) and butyryl- cholinesterase (BChE) by EM immunocytochemistry. In normal neurons AChE was found in the nuclear envelope, RER and Golgi, while there were low levels of BChE. In AD tissue (the medial temporal cortex) most AChE was associated with the NFT s (which also contained BChE). Both AChE and BChE were localised predominantly with the amyloid in neuritic plaques. |
(These journals include: Neurology, Neurobiology of Disease, Journal of Neurochemistry, Alzheimer's Disease Review)
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