摘要:

The X-ray crystal structure of the transthyretin variant Ile 84 Ser has been determined to 1.7Åresolution. The functional form of normal transthyretin is a tetramer, having a cylindrical cavity which binds thyroxine and an exterior binding site for the complex of retinol with retinol-binding protein. The naturally occurring amyloidogenic variant Ile 84 Ser has reduced affinity for retinol-binding protein. The results of this study show that the overall structural homology between the C-alpha atoms of the variant and normal protein is very high with differences mainly in the loop regions, in the vicinity of the substitution, and the ligand binding areas. The known functional differences for the variant (ligand-binding) are correlated with the structural changes observed in the region of the ligand-binding site. The substitution at position 84 results in changes in the shape of the putative site for complexation with retinol binding protein. The substitution site occurs at the interface between two tetramers which are nearest neighbors in the crystal in the direction parallel to the a axis of the unit cell. The variant tetraners move closer together resulting in a hydrogen bond across the interface which does not form in the normal protein. This dominant packing interface may be significant in amyloidogenesis.

ISSN:1350-6129    

DOI:10.3109/13506129609014349

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Platelets carry over 95% of the circulating Alzheimer'sβ-amyloid precursor protein (AβPP), and release soluble and hydrophobic proteolytic fragments of AβPP upon activation. These cells may be the source of cerebrovascular amyloid peptides, a part of Alzheimer's disease (AD) pathology. Our previous studies showed that platelets from patients with advanced AD exhibit both signal transduction (hyperacidification) and AβPP processing defects. Here, we show further that a similar hyperacidification also exists in patients with Pick's disease (a dementia with AD-like symptoms but a different amyloid pathology) or Down syndrome (trisomy and hence overproduction of AβPP), while the AβPP processing defect and consequent AβPP retention on the membrane is absent and is thus likely to be AD-specific. The hyperacidiftcation defect correlates with all three dementias and with the presence of apolipoprotein E4 which has been implicated as a risk factorial-AD.

ISSN:1350-6129    

DOI:10.3109/13506129609014350

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Amyloid is a generic term which refers to extracellular protein deposits with specific staining, morphological, and structural properties, that are seen in a variety of clinical disorders, the most common of which is Alzheimer's disease. In rapid induction models of murine inflammation-associated (AA) amyloid, amyloid deposits cannot be detected in the spleen by conventional histochemical techniques earlier than 36–48 h after administration of the amyloidogenic stimulus. The fluorescent dye Thioflavin T exhibits specific excitation emission wavelength shifts when bound by amyloid. In the present studies, an existing Thioflavin T fluorescence assay was modified and evaluated for its ability to detect amyloid fonnation during accelerated murine splenic AA amyloidogenesis. Concentrations of fibrils as low as 50 m;g/ml were measurable. Furthermore, the assay reliably identified amyloid in splenic homogenates 18 h following the amyloidogenic stimulus, a time point 18–24 h prior to the initial histological detection of amyloid in tissue sections. These data demonstrate the marked sensitivity of the Thioflavin T assay and show the rapidity with which the onset of amyloid formation occurs in vivo following an induction stimulus. The rapidity of the model provides a unique system to test compounds that may protect against amyloid formation.

ISSN:1350-6129    

DOI:10.3109/13506129609014351

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

The presence ofprothrontbin, thrombin receptors and thrombin inhibitors in the brain, together with recent evidence that thrombin can affect neuronal outgrowth and survival, suggests that thrombin signaling may be involved in neuronal plasticity and injury. In Alzheimer 's disease, thrombin is associated with plaques comprised largely of amyloidβ-peptide (Aβ). Because recent studies have shown that 4βcan destabilize neuronal calcium homeostasis, and because thrombin receptors are linked to inositol phospholipid hydrolysis and elevation of [Ca2+]i, we tested the hypothesis that Aβmodifies [Ca2+]iresponses to thrombin. Studies using thrombin receptor antibodies and antisense oligodeoxynucleotide technology to suppress expression of thrombin receptors demonstrated that human SH-SY5Y neuroblastoma cells expressed thrombin receptors linked to Ca2+release from intracellular stores. Relatively short term pretreatment (1 to 3 h) of the SH-SY5Y cells with Aβ25–35 or 4β1–40 resulted in a significant two-to three fold enhancement of thrombin-induced elevation of [Ca2+]i. In contrast, chronic pretreatment with Aβs (8 to 16 h) resulted in an attenuation or complete abrogation of' [Ca2+]iresponses to thrombin. Imaging of thiobarbituric acid fluorescence demonstrated that Aβinduced lipid peroxidation, and the effects of both short and long term exposure to 4βon [Ca2+]iresponses, were largely abrogated in cultures pretreated with antioxidants. Collectively, these data suggest that Aβinduces lipid peroxidation which impairs thrombin receptor-mediated Ca2+signaling. Taken together with an increasing amount of data suggesting that thrombin plays roles in neuronal plasticity and neurodegenerative processes, our data suggest that Aβmay induce aberrant thrombin signal transduction which could contribute to the pathogenesis of AD.

ISSN:1350-6129    

DOI:10.3109/13506129609014352

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

A 61 year old male was diagnosed as having hypertensive nephropathy at age 50. Chronic renal failure at age 55 resulted in his beginning hemodialysis at age 57. A diagnosis of myeloma was also established at age 57 on the basis of Bence Jones proteinuria, increased bone marrow plasma cells and anemia. Amyloid deposits developed in nodules on the eyelids, in the carpal joints, cervical spine, shoulder synovial membrane, bone marrow and rectum. By immunostaining, the amyloid deposits reacted with anti-Ak and less abundantly with anti-4β2M.

ISSN:1350-6129    

DOI:10.3109/13506129609014353

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

ISSN:1350-6129    

DOI:10.3109/13506129609014354

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

ISSN:1350-6129    

DOI:10.3109/13506129609014355

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

ISSN:1350-6129    

DOI:10.3109/13506129609014356

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

ISSN:1350-6129    

DOI:10.3109/13506129609014357

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor

摘要:

Fatal familial insomnia - Inherited prion diseases, sleep and the thalamusEdited by C. Guilleminadt, E. Lugaresi, P. Montana and P. Gambetti Raven Press, New York 1994 234 Pages, $90.00 ISBN: 0-7817-0114-7Liver transplantation: Practice and managementEdited by James Neuberger and Michael R. Lucey BMJ Publishing Group, London 1994 400 Pages, Illustrated.£37.00 ISBN: 0-7279-0787-5Pathology of the peripheral nerveEdward P. Richardson, Jr. and Umberto DeGirolaini 32 in the series Major Problerns in Pathology W.B. Saunders Co., Philadelphia 1995 159 Pages, $55.00 ISBN: 0-72 16-3298-XImmunocytochemistry. A Practical ApproachEdited by Julian E. Beesley Oxford University Press, New York 1993 248 Pages, ISBN: 0-19-963270-7 $59.00NMR of macromolecules. A practical approachEdited by Gordon C. K. Roberts Oxford University Press, New York, 1993 399 pages ISBN: 0-19-963225-1 (h/bk) $68.00 0-19-963224-3 (pibk) $47.00

ISSN:1350-6129    

DOI:10.3109/13506129609014358

出版商:Taylor&Francis    

年代:1996

数据来源: Taylor