EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2010
Cheryl A. Hawkes
Abstract ,-Amyloid (A,) peptides are thought to play a major role in the pathogenesis of Alzheimer's disease. Compounds that disrupt the kinetic pathways of A, aggregation may be useful in elucidating the role of oligomeric, protofibrillar and fibrillar A, in the etiology of the disease. We have previously reported that scyllo -inositol inhibits A,42 fibril formation but the mechanism(s) by which this occurs has not been investigated in detail. Using a series of scyllo -inositol derivatives in which one or two hydroxyl groups were replaced with hydrogen, chlorine or methoxy substituents, we examined the role of hydrogen bonding and hydrophobicity in the structure,function relationship of scyllo -inositol,A, binding. We report here that all scyllo -inositol derivatives demonstrated reduced effectiveness in preventing A,42 fibrillization compared with scyllo -inositol, suggesting that scyllo -inositol interacts with A,42 via key hydrogen bonds that are formed by all hydroxyl groups. Increasing the hydrophobicity of scyllo -inositol by the addition of two methoxy groups (1,4-di- O -methyl- scyllo -inositol) produced a derivative that stabilized A,42 protofibrils in vitro. Prophylactic administration of 1,4-di- O -methyl- scyllo -inositol to TgCRND8 mice attenuated spatial memory impairments and significantly decreased cerebral amyloid pathology. These results suggest that A, aggregation can be targeted at multiple points along the kinetic pathway for the improvement of Alzheimer's disease-like pathology. [source]

Modulation of amyloid-, aggregation and toxicity by inosose stereoisomers

FEBS JOURNAL, Issue 8 2008
Mark Nitz
Amyloid-, (A,) aggregation and amyloid formation are key pathological features of Alzheimer's disease, and are considered to be two of the major contributing factors to neurodegeneration and dementia. Identification of small molecule inhibitors that are orally available, have low toxicity and high central nervous system bioavailability is one approach to the potential development of a disease-modifying treatment for Alzheimer's disease. We have previously identified inositol stereoisomers as exhibiting stereospecific inhibition of A, aggregation and toxicity in vitro and in vivo. We report here the effects of inosose versus inositol stereoisomers on A, fibrillogenesis as determined using CD and fluorescence spectroscopy and negative-stain electron microscopy. The inososes differ from inositols by the oxidation of one of the hydroxyl groups to a ketone. These molecules help in the further elucidation of the structure,activity relationships of inositol,A, interactions and identify both allo -inositol and epi -2-inosose as in vitro inhibitors of A, aggregation. [source]

Accumulation of amyloid-, protein in exocrine glands of transgenic mice overexpressing a carboxyl terminal portion of amyloid protein precursor

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 4 2000
Ken-Ichiro Fukuchi
Amyloid-, protein (A,) and its precursor (,PP) play important roles in the pathogenesis of Alzheimer disease and inclusion-body myositis. In humans, A, deposits are found in brain, skeletal muscle, and skin. Therefore, we have investigated possible A, deposits in multiple tissues of two transgenic mouse lines overexpressing the signal plus A,-bearing 99-amino acid carboxyl terminal sequences of ,PP under the control of a cytomegalovirus enhancer/,-actin promoter. One of the lines developed A,-immunoreactive intracellular deposits consistently in the pancreas and lacrimal gland, and occasionally in gastric, DeSteno's, and lingual glands. Although the A, deposits increased during ageing and degenerative changes of the tissues were observed, little or no extracellular A, deposits were observed up to the age of 25 months. These lines of transgenic mice are useful for studying the molecular mechanisms of development and clearance of intracellular A, deposits. [source]

The diagnostic value of tau protein, ,-amyloid (1,42) and their ratio for the discrimination of alcohol-related cognitive disorders from Alzheimer's disease in the early stages

INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 8 2005
Elisabeth Kapaki
Abstract Background Chronic and heavy alcohol abuse or dependence may result in impaired cognition and dementia. The increased risk of Alzheimer's disease (AD) in older individuals interferes with the differential diagnosis, especially when dealing with elderly patients with a long history of alcohol abuse. The aim of the present study was to evaluate the diagnostic value of the putative cerebrospinal fluid (CSF) biomarkers tau, ,-amyloid 1,42 (A,42) and their ratio in differentiating alcohol related cognitive disorder (ARCD) from AD. Methods Double-sandwich ELISA (Innotest htau antigen and ,-Amyloid (1,42), Innogenetics) were used to quantify the above markers in a total of 20 patients with ARCD, 33 AD patients with mild to moderate dementia and 50 mentally intact subjects. Results Tau protein successfully differentiated AD from normal ageing with 96% specificity and 93.9% sensitivity and from ARCD with 95% specificity, and 87.9% sensitivity. A,42 alone had a specificity of 88% and a sensitivity of 69.7% in differentiating AD from normal ageing, while the corresponding values for differentiating AD from ARCD were 80% and 84.8% respectively. The tau/A,42 ratio was better than tau alone for differentiating AD from normal ageing (specificity 94%, sensitivity 97%) and better than any of the candidate markers alone, for differentiating AD from ARCD (specificity 100%, sensitivity 97%). Conclusions The combined use of CSF tau and A,42 may be a useful tool in the differential diagnosis of ARCD from AD, especially in the early stages, where diagnostic uncertainty is greater. Copyright © 2005 John Wiley & Sons, Ltd. [source]

pH dependent self assembly of ,-amyloid(10-35) and ,-amyloid(10-35)-PEG3000

JOURNAL OF APPLIED CRYSTALLOGRAPHY, Issue 3-1 2000
P. Thiyagarajan
Small angle neutron and x-ray scattering (SANS/SAXS) studies were conducted on the structure of the aggregates formed from both the truncated model peptide ,-Amyloid(10-35) (A,10-35) and a block copolymer ,-Amyloid(10-35)-PEG3000 (A,10-35 -PEG) in D2O at pHs from 3.0 to 7.0. These studies indicate that A,10-35 aggregates into rod-like particles (fibril) and their radii are strongly dependent on the pH of the solution. The fibril-fibril association in A,10-35 solutions is less at pH < 5.6, but becomes larger at higher pH. A,10-35 -PEG also assembles into rod-like particles whose radius is larger by about 30 Å than that for A,10-35 fibril at pH 4.2, while it is about 23 Å larger at higher pH. Contrast matching SAXS/SANS experiments that eliminate the coherent scattering from PEG reveal that PEG moiety is located at the periphery of the fibril. Also the mass per unit length of the peptide portion is similar for both A,10-35 and A,10-35 fibrils at pH 5.6. The mass per unit length of the rods from SANS provides key information on the packing of A,10-35 peptides in the fibril. [source]

A, aggregation and possible implications in Alzheimer's disease pathogenesis

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 3 2009
Prashant R. Bharadwaj
,,Introduction ,,Amyloid Structure ,,Mechanism of Amyloid aggregation ,,A,: a natively unfolded protein? ,,Ambiguities in synthetic Ab studies ,,Formation of Amyloid plaques ,,Role of Ab in AD Pathogenesis ,,Conclusion Abstract Amyloid , protein (A,) has been associated with Alzheimer's disease (AD) because it is a major component of the extracellular plaque found in AD brains. Increased A, levels correlate with the cognitive decline observed in AD. Sporadic AD cases are thought to be chiefly associated with lack of A, clearance from the brain, unlike familial AD which shows increased A, production. A, aggregation leading to deposition is an essential event in AD. However, the factors involved in A, aggregation and accumulation in sporadic AD have not been completely characterized. This review summarizes studies that have examined the factors that affect A, aggregation and toxicity. By necessity these are studies that are performed with recombinant-derived or chemically synthesized A,. The studies therefore are not done in animals but in cell culture, which includes neuronal cells, other mammalian cells and, in some cases, non-mammalian cells that also appear susceptible to A, toxicity. An understanding of A, oligomerization may lead to better strategies to prevent AD. [source]

Amyloid-,(1-42) alters structure and function of retinal pigmented epithelial cells

AGING CELL, Issue 2 2009
Julien Bruban
Summary Age-related macular degeneration (AMD) is characterized by the formation of drusen, extracellular deposits associated with atrophy of the retinal pigmented epithelium (RPE), disturbance of the transepithelial barrier and photoreceptor death. Amyloid-, (A,) is present in drusen but its role during AMD remains unknown. This study investigated the in vitro and in vivo effects of the oligomeric form of A,(1-42) , OA,(1-42) , on RPE and found that it reduced mitochondrial redox potential and increased the production of reactive oxygen species, but did not induce apoptosis in RPE cell cultures. It also disorganized the actin cytoskeleton and halved occludin expression, markedly decreasing attachment capacity and abolishing the selectivity of RPE cell transepithelial permeability. Antioxidant pretreatment partially reversed the effects of OA,(1-42) on mitochondrial redox potential and transepithelial permeability. Subretinally injected OA,(1-42) induced pigmentation loss and RPE hypertrophy but not RPE cell apoptosis in C57BL/6 J mice. Rapid OA,(1-42)-induced disorganization of cytoskeletal actin filaments was accompanied by decreased RPE expression of the tight junction proteins occludin and zonula occludens-1 and of the visual cycle proteins cellular retinaldehyde-binding protein and RPE65. The number of photoreceptors decreased by half within a few days. Our study pinpoints the role of A, in RPE alterations and dysfunctions leading to retinal degeneration and suggests that targeting A, may help develop selective methods for treating diseases involving retinal degeneration, such as AMD. [source]

Spontaneous pancreatic islet amyloidosis in 40 baboons

JOURNAL OF MEDICAL PRIMATOLOGY, Issue 2 2002
G.B. Hubbard
Spontaneous amyloidosis occurs in many nonhuman primate species but remains difficult to diagnose and treat. Nonhuman primates continue to offer promise as animal models in which to study amyloidosis in humans. Amyloidosis was not diagnosed clinically but was found histologically in four male and 36 female baboons. The baboons averaged 18 years of age at death (range, 7,28 years). Clinical signs, if present, were hyperglycemia and cachexia. Blood glucose values were elevated in 12 of 30 baboons with available clinical pathology data. Four baboons had been clinically diagnosed as diabetic and three were treated with insulin. Amyloid was found in the islets of Langerhans of the pancreas in 40 baboons; 35 baboons had amyloid only in the islets of Langerhans. Amyloid was found in nonislet tissue of baboons as follows: five, nonislet pancreas; four, intestine and adrenal; three, kidney; two, prostate and spleen; and one each, lymph node, liver, gall bladder, stomach, tongue, urinary bladder, and salivary gland. Sections of paraffin-embedded tissues were evaluated for amyloid with hematoxylin and eosin (HE) and congo red (CR) staining, and using immunohistochemistry for human islet amyloid polypeptide (IAPP), calcitonin gene-related peptide (CGRP), glucagon, pancreatic polypeptide (PP), somatostatin (SS), and porcine insulin. Islet amyloid was positive with HE in 40 baboons, with CR in 39 baboons, and with IAPP and CGRP in 35 baboons. IAPP and CGRP only stained islet amyloid. PP, SS, glucagon, and porcine insulin did not stain amyloid. Islet amyloidosis in the baboon appears to be difficult to diagnose clinically, age-related, and similar to islet amyloidosis in other species. The baboon may be a good model for the study of islet amyloidosis in humans. [source]

Spontaneous amyloidosis in twelve chimpanzees, Pan troglodytes

JOURNAL OF MEDICAL PRIMATOLOGY, Issue 5 2001
Gene B. Hubbard
Spontaneous amyloidosis was diagnosed in 11 male and 1 female chimpanzees and confirmed histologically and immunohistochemically. The chimpanzees were ,15 years of age when first diagnosed and averaged 22.4 years of age. The average survival time after diagnosis of systemic amyloidosis was 1.86 years with a standard deviation of 4.06 years (n=7). The chimpanzees with amyloidosis were asymptomatic except for hepatomegaly, which became more detectable with age. Significant increases in clinical chemistry values, as compared with referenced normals and established normals, of blood urea nitrogen (BUN), asparate aminotransferase (AST), gamma-glutamyltransferase (GGT), globulin, total protein, creatinine phosphokinase (CPK), sedimentation rate, and triglycerides were found in animals 7 years of age or older with amyloidosis. These serum chemistry values, while increased in chimpanzees with amyloidosis, were generally within normal limits. Immunohistochemistry for both amyloid A protein and amyloid P component-labeled extracellular amyloid in all chimpanzees with amyloidosis was determined. Amyloid was deposited primarily in the liver. Amyloidosis in the chimpanzee is a chronic, intractable, progressive, fatal disease, and appears to be similar to secondary amyloidosis in other species. [source]

22R -Hydroxycholesterol protects neuronal cells from ,-amyloid-induced cytotoxicity by binding to ,-amyloid peptide

JOURNAL OF NEUROCHEMISTRY, Issue 5 2002
Zhi-Xing Yao
Abstract 22R -hydroxycholesterol, a steroid intermediate in the pathway of pregnenolone formation from cholesterol, was found at lower levels in Alzheimer's disease (AD) hippocampus and frontal cortex tissue specimens compared to age-matched controls. ,-Amyloid (A,) peptide has been shown to be neurotoxic and its presence in brain has been linked to AD pathology. 22R -hydroxycholesterol was found to protect, in a dose-dependent manner, against A,-induced rat sympathetic nerve pheochromocytoma (PC12) and differentiated human Ntera2/D1 teratocarcinoma (NT2N) neuron cell death. Other steroids tested were either inactive or acted on rodent neurons only. The effect of 22R -hydroxycholesterol was found to be stereospecific because its enantiomer 22S -hydroxycholesterol failed to protect the neurons from A,-induced cell death. Moreover, the effect of 22R -hydroxycholesterol was specific for A,-induced cell death because it did not protect against glutamate-induced neurotoxicity. The neuroprotective effect of 22R -hydroxycholesterol was seen when using A,1,42 but not the A,25,35 peptide. To investigate the mechanism of action of 22R -hydroxycholesterol we examined the direct binding of this steroid to A, using a novel cholesterol-protein binding blot assay. Using this method the direct specific binding, under native conditions, of 22R -hydroxycholesterol to A,1,42 and A,17,40, but not A,25,35, was observed. These data suggest that 22R -hydroxycholesterol binds to A, and the formed 22R -hydroxycholesterol/A, complex is not toxic to rodent and human neurons. We propose that 22R -hydroxycholesterol offers a new means of neuroprotection against A, toxicity by inactivating the peptide. [source]

,-Amyloid inhibits integrated mitochondrial respiration and key enzyme activities

JOURNAL OF NEUROCHEMISTRY, Issue 1 2002
C. S. Casley
Abstract Disrupted energy metabolism, in particular reduced activity of cytochrome oxidase (EC 1.9.3.1), ,-ketoglutarate dehydrogenase (EC 1.2.4.2) and pyruvate dehydrogenase (EC 1.2.4.1) have been reported in post-mortem Alzheimer's disease brain. ,-Amyloid is strongly implicated in Alzheimer's pathology and can be formed intracellularly in neurones. We have investigated the possibility that ,-amyloid itself disrupts mitochondrial function. Isolated rat brain mitochondria have been incubated with the ,-amyloid alone or together with nitric oxide, which is known to be elevated in Alzheimer's brain. Mitochondrial respiration, electron transport chain complex activities, ,-ketoglutarate dehydrogenase activity and pyruvate dehydrogenase activity have been measured. ,-Amyloid caused a significant reduction in state 3 and state 4 mitochondrial respiration that was further diminished by the addition of nitric oxide. Cytochrome oxidase, ,-ketoglutarate dehydrogenase and pyruvate dehydrogenase activities were inhibited by ,-amyloid. The Km of cytochrome oxidase for reduced cytochrome c was raised by ,-amyloid. We conclude that ,-amyloid can directly disrupt mitochondrial function, inhibits key enzymes and may contribute to the deficiency of energy metabolism seen in Alzheimer's disease. [source]

Urokinase-type plasminogen activator inhibits amyloid-, neurotoxicity and fibrillogenesis via plasminogen

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2002
H. Michael Tucker
Abstract Amyloid-, (A,) appears central to Alzheimer's disease (AD), aggregates spontaneously, and is neurotoxic to neurons in vitro. Recently, several groups reported a familial AD locus on chromosome 10. Here, we note that urokinase-type plasminogen activator (uPA) is located within this locus. Previously, we reported that uPA and its functional homolog, tissue-type plasminogen activator, are induced by A, treatment of neurons in vitro as well as in a mouse model of A, accumulation in vivo. Moreover, the target of plasminogen activators, plasmin, degraded nonaggregated and aggregated A, and modulated A, toxicity and deposition. Here, we have evaluated the effects of uPA and plasminogen on A, fibril formation and neurotoxicity. We report that the combination of uPA and plasminogen, but neither alone, inhibits A, toxicity, reduces A, deposition in vitro, and inhibits A, fibrillogenesis. We interpret these observations as suggesting that uPA represents a possible candidate gene for the chromosome 10 familial AD locus. © 2002 Wiley-Liss, Inc. [source]

Serum Amyloid A and Haptoglobin Concentrations and Liver Fat Percentage in Lactating Dairy Cows with Abomasal Displacement

JOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2010
H. Guzelbektes
Background: There has been increased interest in measuring the serum concentration of acute phase reactants such as serum amyloid A [SAA] and haptoglobin [haptoglobin] in periparturient cattle in order to provide a method for detecting the presence of inflammation or bacterial infection. Objectives: To determine whether [SAA] and [haptoglobin] are increased in cows with displaced abomasum as compared with healthy dairy cows. Animals: Fifty-four adult dairy cows in early lactation that had left displaced abomasum (LDA, n = 34), right displaced abomasum or abomasal volvulus (RDA/AV, n = 11), or were healthy on physical examination (control, n = 9). Materials and Methods: Inflammatory diseases or bacterial infections such as mastitis, metritis, or pneumonia were not clinically apparent in any animal. Jugular venous blood was obtained from all cows and analyzed. Liver samples were obtained by biopsy in cattle with abomasal displacement. Results: [SAA] and [haptoglobin] concentrations were increased in cows with LDA or RDA/AV as compared with healthy controls. Cows with displaced abomasum had mild to moderate hepatic lipidosis, based on liver fat percentages of 9.3 ± 5.3% (mean ± SD, LDA) and 10.8 ± 7.7% (RDA/AV). [SAA] and [haptoglobin] were most strongly associated with liver fat percentage, rs=+0.55 (P < .0001) and rs=+0.42 (P= .0041), respectively. Conclusions and Clinical Importance: An increase in [SAA] or [haptoglobin] in postparturient dairy cows with LDA or RDA/AV is not specific for inflammation or bacterial infection. An increase in [SAA] or [haptoglobin] may indicate the presence of hepatic lipidosis in cattle with abomasal displacement. [source]

Randomization of Amyloid-,-Peptide(1-42) Conformation by Sulfonated and Sulfated Nanoparticles Reduces Aggregation and Cytotoxicity

MACROMOLECULAR BIOSCIENCE, Issue 10 2010
Ana M. Saraiva
Abstract The amyloid-, peptide (A,) plays a central role in the mechanism of Alzheimer's disease, being the main constituent of the plaque deposits found in AD brains. A, amyloid formation and deposition are due to a conformational switching to a ,-enriched secondary structure. Our strategy to inhibit A, aggregation involves the re-conversion of A, conformation by adsorption to nanoparticles. NPs were synthesized by sulfonation and sulfation of polystyrene, leading to microgels and latexes. Both polymeric nanostructures affect the conformation of A, inducing an unordered state. Oligomerization was delayed and cytotoxicity reduced. The proper balance between hydrophilic moieties and hydrophobic chains seems to be an essential feature of effective NPs. [source]

Proapoptotic Nitric Oxide Production in Amyloid , Protein-Treated Cerebral Microvascular Endothelial Cells

MICROCIRCULATION, Issue 2 2007
CHIWAKA KIMURA
ABSTRACT Objective: The objective of this study was to investigate the effects of amyloid , protein (A,) on cerebral microvascular endothelium, and their possible involvement in A,-induced apoptosis in the neighboring cells. Methods: Cultured bovine brain microvascular endothelial cells (BBECs) were incubated with A, for 24 h. Production of nitric oxide (NO) was assessed by nitric oxide-sensitive fluorescent dye, DAF-2, and the expression of NO synthase (NOS) proteins was examined by Western blotting. Effects of A,-treated microvascular endothelium on the DNA damage of the neighboring cells were assessed by single-cell gel electrophoresis. Results: A, increased the expression of iNOS protein, but did not affect eNOS and nNOS expressions in BBECs. A,-treated BBECs showed spontaneous NO production in the presence of L-arginine. The neural cell line PC12 showed marked apoptosis after being co-cultured with A,-treated BBECs for 48 h, and the apoptosis was as potent as that induced by the inflammatory stimuli lipopolysaccharide and interferon-,. The DNA damage of PC12 cells evoked by co-culture with A,-treated BBECs was prevented by L- NG -nitroarginine methyl ester, an inhibitor of NOS. Conclusions: These results indicate that A, induces the expression of iNOS in BBECs, and that microvascular endothelium-derived NO may induce apoptosis in neighboring neural cells. [source]

Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2008
R. O. Carare
Elimination of interstitial fluid and solutes plays a role in homeostasis in the brain, but the pathways are unclear. Previous work suggests that interstitial fluid drains along the walls of arteries. Aims: to define the pathways within the walls of capillaries and arteries for drainage of fluid and solutes out of the brain. Methods: Fluorescent soluble tracers, dextran (3 kDa) and ovalbumin (40 kDa), and particulate fluospheres (0.02 ,m and 1.0 ,m in diameter) were injected into the corpus striatum of mice. Brains were examined from 5 min to 7 days by immunocytochemistry and confocal microscopy. Results: soluble tracers initially spread diffusely through brain parenchyma and then drain out of the brain along basement membranes of capillaries and arteries. Some tracer is taken up by vascular smooth muscle cells and by perivascular macrophages. No perivascular drainage was observed when dextran was injected into mouse brains following cardiac arrest. Fluospheres expand perivascular spaces between vessel walls and surrounding brain, are ingested by perivascular macrophages but do not appear to leave the brain even following an inflammatory challenge with lipopolysaccharide or kainate. Conclusions: capillary and artery basement membranes act as ,lymphatics of the brain' for drainage of fluid and solutes; such drainage appears to require continued cardiac output as it ceases following cardiac arrest. This drainage pathway does not permit migration of cells from brain parenchyma to the periphery. Amyloid-, is deposited in basement membrane drainage pathways in cerebral amyloid angiopathy, and may impede elimination of amyloid-, and interstitial fluid from the brain in Alzheimer's disease. Soluble antigens, but not cells, drain from the brain by perivascular pathways. This atypical pattern of drainage may contribute to partial immune privilege of the brain and play a role in neuroimmunological diseases such as multiple sclerosis. [source]

Neuroprotective effects of Triticum aestivum L. against ,-Amyloid-induced cell death and memory impairments

PHYTOTHERAPY RESEARCH, Issue 1 2010
Jung-Hee Jang
Abstract ,-Amyloid (A,) is a key component of senile plaques, neuropathological hallmarks of Alzheimer's disease (AD) and has been reported to induce cell death via oxidative stress. This study investigated the protective effects of Triticum aestivum L. (TAL) on A,-induced apoptosis in SH-SY5Y cells and cognitive dysfunctions in Sprague-Dawley (SD) rats. Cells treated with A, exhibited decreased viability and apoptotic features, such as DNA fragmentation, alterations in mitochondria and an increased Bax/Bcl-2 ratio, which were attenuated by TAL extract (TALE) pretreatment. To elucidate the neuroprotective mechanisms of TALE, the study examined A,-induced oxidative stress and cellular defense. TALE pretreatment suppressed A,-increased intracellular accumulation of reactive oxygen species (ROS) via up-regulation of glutathione, an essential endogenous antioxidant. To further verify the effect of TALE on memory impairments, A, or scopolamine was injected in SD rats and a water maze task conducted as a spatial memory test. A, or scopolamine treatment increased the time taken to find the platform during training trials, which was decreased by TALE pretreatment. Furthermore, one of the active components of TALE, total dietary fiber also effectively inhibited A,-induced cytotoxicity and scopolamine-caused memory deficits. These results suggest that TALE may have preventive and/or therapeutic potential in the management of AD. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Protective effect of Toki-shakuyaku-san on amyloid ,25,35 -induced neuronal damage in cultured rat cortical neurons

PHYTOTHERAPY RESEARCH, Issue 5 2005
Nobuaki Egashira
Abstract Amyloid , protein (A,) is the major component of senile plaques, the pathological hallmark of the neurodegeneration associated with Alzheimer's disease (AD). This study investigated the effect of Toki-shakuyaku-san (TSS), a traditional medicine, on A,25,35 -induced neuronal death and lipid peroxidation assessed by measuring lactate dehydrogenase (LDH) and malondialdehyde (MDA), respectively. A,25,35 at 10 µM induced neuronal damage and increased the LDH and MDA. TSS at concentrations of 100 and 300 µg/mL significantly reduced the A,25,35 -induced neuronal death and the lipid peroxidation. These results suggest that TSS has a protective effect against A,25,35 -induced neuronal damage. TSS may be beneficial for the treatment of AD. Copyright © 2005 John Wiley & Sons, Ltd. [source]

Amyloid,a state in many guises: Survival of the fittest fibril fold

PROTEIN SCIENCE, Issue 1 2008
Jesper S. Pedersen
Abstract Under appropriate conditions, essentially all proteins are able to aggregate to form long, well-ordered and ,-sheet-rich arrays known as amyloid-like fibrils. These fibrils consist of varying numbers of intertwined protofibrils and can for any given protein exhibit a wealth of different forms at the ultrastructural level. Traditionally, this structural variability or polymorphism has been attributed to differences in the assembly of a common protofibril structure. However, recent work on glucagon, insulin, and the A, peptide suggests that this polymorphism can occur at the level of secondary structure. Simple variations in either solvent conditions such as temperature, protein concentration, and ionic strength or external mechanical influences such as agitation can lead to formation of fibrils with markedly different characteristics. In some cases, these characteristics can be passed on to new fibrils in a strain-specific manner, similar to what is known for prions. The preferred structure of fibrils formed can be explained in terms of selective pressure and survival of the fittest; the most populated types of fibrils we observe at the end of an experiment are those that had the fastest overall growth rate under the given conditions. Fibrillar polymorphism is probably a consequence of the lack of structural restraints on a nonfunctional conformational state. [source]

Redox proteomics studies of in vivo amyloid beta-peptide animal models of Alzheimer's disease: Insight into the role of oxidative stress

PROTEOMICS - CLINICAL APPLICATIONS, Issue 5 2008
Rukhsana Sultana
Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disease. AD is characterized by the presence of senile plaques, neurofibrillary tangles, and synaptic loss. Amyloid ,-peptide (A,), a component of senile plaques, has been proposed to play an important role in oxidative stress in AD brain and could be one of the key factors in the pathogenesis of AD. In the present review, we discuss some of the AD animal models that express A,, and compare the proteomics-identified oxidatively modified proteins between AD brain and those of A, models. Such a comparison would allow better understanding of the role of A, in AD pathogenesis thereby helping in developing potential therapeutics to treat or delay AD. [source]

The newly synthesized linoleic acid derivative DCP-LA ameliorates memory deficits in animal models treated with amyloid-, peptide and scopolamine

PSYCHOGERIATRICS, Issue 4 2005
Tetsu NAGATA
Abstract Background:, In our earlier study, 8-[2-(2-pentyl-cyclopropylmethyl)-cyclopropyl]-octanoic acid (DCP-LA), a newly synthesized linoleic acid derivative with cyclopropane rings instead of cis -double bonds, facilitated hippocampal synaptic transmission by stimulating glutamate release from presynaptic terminals as mediated via ,7 acetylcholine (Ach) receptors under the influence of protein kinase C. The present study assessed the possibility of using DCP-LA as a cognitive enhancer in animal models. Methods:, Amyloid-,1,40 peptide (300 pM/day) or saline was continuously injected in the right lateral ventricle of rats for 2 weeks. Then, the water maze test was carried out, once per day for 7 days, 1 h after the intraperitoneal injection with DCP-LA or saline. In a different set of experiments, rats were intraperitoneally injected with scopolamine (1 mg/kg) and the water maze test was performed twice per day, with the first test taking place 1 h after the intraperitoneal injection with DCP-LA, galantamine or saline, and the second test starting 2 min after the end of the first. Results:, Continuous intraventricular injection with amyloid-,1,40 peptide in the rat lateral ventricle prolonged the latency for acquisition in the water maze test. DCP-LA (1 mg/kg, intraperitoneal (i.p.)) significantly improved the impairment, which reached a level similar to the latency for sham. Furthermore, DCP-LA (1 mg/kg, i.p.) significantly ameliorated learning and memory deficits in rats treated with scopolamine and was, if not more, effective than galantamine, a modest inhibitor of acetylcholinesterase with nicotinic ACh receptor modulation. Conclusion:, The results of the present study show that DCP-LA ameliorates learning and memory deficits induced by amyloid-,1,40 peptide or scopolamine. DCP-LA may thus offer new hope for dementia patients. [source]

Laryngeal presentation of systemic apolipoprotein A-I,derived amyloidosis,

THE LARYNGOSCOPE, Issue 3 2009
Aldert J. C. Hazenberg MD
Abstract Objective: To study the clinical and pathological characteristics of two patients with laryngeal apolipoprotein A-I (apoA-I)-derived (AApoAI) amyloidosis with the apolipoprotein A-I variants Leu174Ser and Leu178Pro, respectively. The latter variant has not been associated with amyloid before. Study Design: Descriptive report of two patients who presented with laryngeal amyloid presumed to be of localized AL type, but in who further assessments demonstrated systemic amyloidosis. Methods: The larynx was examined by videolaryngostroboscopy. The voice was analyzed with the GRBAS system, phonation times, and phonetography. Laryngeal biopsies were stained with Congo red and analyzed immunohistochemically. Organ function was assessed and tissue involvement by amyloid further determined by rectal biopsy, abdominal fat tissue aspirate, and serum amyloid P component scintigraphy. Results: The appearance of the laryngeal amyloid was unusual in both patients, occurring as small, irregular floppy proliferations affecting the borders of both vocal folds. Amyloid was stained with antibodies to apoA-I and not with antibodies to immunoglobulin light chains. The 45-year-old woman with the previously described amyloidogenic apoA-I Leu174Ser variant had possible involvement by amyloid in joints, peripheral nerves, and heart. Whereas in the 67-year-old man with apoA-I Leu178Pro there was a clinical suggestion of autonomic and cardiac amyloid and histological corroboration of systemic amyloidosis in abdominal fat. Conclusions: Laryngeal symptoms may be the presenting feature of hereditary systemic AApoAI amyloidosis, and comprehensive investigations including apoA-I genotyping are warranted in patients who present with apparently localized laryngeal amyloidosis. The distinctive appearance of the amyloidotic vocal folds described here may further signal the possibility of hereditary AApoAI type. Laryngoscope, 119:608,615, 2009 [source]

Laryngeal Amyloidosis in 10 Patients,

THE LARYNGOSCOPE, Issue 10 2004
Herbert H. Dedo MD
Abstract Objectives: Review the location, symptoms, treatment, and outcomes in 10 consecutive laryngeal amyloid (LA) patients. Study Design: Pre and retrospective evaluation after treatment. Methods: Analysis of visual and phonatory pathology and detailed description of surgery. Results: Amyloid on the undersurface of both true vocal cords (TVCs) was found in two cases, uni- or bilaterally submucosally in the false vocal cords (FVCs) in eight cases, extending down into the lateral TVC in four cases, or on the undersurface of the TVCs as well in one case. The chief complaint was hoarseness and not shortness of breath. The amyloid was resected with a CO2 laser by way of microdirect laryngoscopy (MDL) on one side at a time to try to prevent anterior commissure scarring. Removal of most of the FVC improved the voice, but removal of the whole FVC to the inner thyroid perichondrium was found to be necessary to avoid recurrence from supraglottic deposits. Removal of at least 2 mm of the upper edge of a 3 to 4 mm thick submucosal deposit to the thyroarytenoid (TA) muscle along with the overlying mucosa on at least one side was necessary to improve hoarseness when amyloid was present on the undersurface of both TVCs. Partial regrowth occurred in a few months to years after partial removal. Seven patients had had one to seven prior removals. Any hard amyloid in the lateral TVC (floor of ventricle) as an inferior extension from FVC amyloid needed to be at least partially removed to avoid hoarseness from a convex vocal cord. The voice improved postoperatively in all patients. Follow-up after the first operation was 6 months to 16 years, with an average of 6.5 years. Four FVC patients required re-excision on the same side after the first operation, but none has required a third removal as of yet. [source]

Solid Organ Transplantation in AL Amyloidosis

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010
P. T. Sattianayagam
Vital organ failure remains common in AL amyloidosis. Solid organ transplantation is contentious because of the multisystem nature of this disease and risk of recurrence in the graft. We report outcome among all AL patients evaluated at the UK National Amyloidosis Centre who received solid organ transplants between 1984 and 2009. Renal, cardiac and liver transplants were performed in 22, 14 and 9 patients respectively, representing <2% of all AL patients assessed during the period. One and 5-year patient survival was 95% and 67% among kidney recipients, 86% and 45% among heart recipients and 33% and 22% among liver recipients. No renal graft failed due to recurrent amyloid during median (range) follow up of 4.8 (0.2,13.3) years. Median patient survival was 9.7 years among 8/14 cardiac transplant recipients who underwent subsequent stem cell transplantation (SCT) and 3.4 years in six patients who did not undergo SCT (p = 0.01). Amyloid was widespread in all liver transplant recipients. Solid organ transplantation has rarely been performed in AL amyloidosis, but these findings demonstrate feasibility and support a role in selected patients. [source]

Anaesthetics and postoperative cognitive dysfunction: a pathological mechanism mimicking Alzheimer's disease

ANAESTHESIA, Issue 4 2010
V. Fodale
Summary With longevity, postoperative cognitive decline in the elderly has emerged as a major health concern for which several factors have been implicated, one of the most recent being the role of anaesthetics. Interactions of anaesthetic agents and different targets have been studied at the molecular, cellular and structural anatomical levels. Recent in vitro nuclear magnetic resonance spectroscopy studies have shown that several anaesthetics act on the oligomerisation of amyloid , peptide. Uncontrolled production, oligomerisation and deposition of amyloid , peptide, with subsequent development of amyloid plaques, are fundamental steps in the generation of Alzheimer's disease. Amyloid , peptide is naturally present in the central nervous system, and is found at higher tissue concentrations in the elderly. We argue that administering certain general anaesthetics to elderly patients may worsen amyloid , peptide oligomerisation and deposition and thus increase the risk of developing postoperative cognitive dysfunction. The aim of this review is to highlight the clinical aspects of postoperative cognitive dysfunction and to find plausible links between possible anaesthetic effects and the molecular pathological mechanism of Alzheimer's disease. It is hoped that our hypothesis will stimulate further enquiry, especially triggering research into elucidating those anaesthetics that may be more suitable when cognitive dysfunction is a particular concern. [source]

Pulse EPR Spectroscopy Reveals the Coordination Sphere of Copper(II) Ions in the 1,16 Amyloid-, Peptide: A Key Role of the First Two N-Terminus Residues,

ANGEWANDTE CHEMIE, Issue 49 2009
Pierre Dorlet Dr.
Ligandensphäre aufgedeckt: Cu-Ionen sollen an der Aggregation des Amyloid-,-Peptids bei Alzheimer beteiligt sein, die eindeutige Identifizierung der Cu-Liganden ist jedoch schwierig. Mit EPR- und Isotopenmarkierungstechniken wurden nun die CuII -Liganden der beiden Komplexe, die bei physiologischen pH-Werten vorliegen, ermittelt (siehe Diagramme und Strukturen). Die ersten beiden Aminosäuren des Peptids sind für die Koordination und wahrscheinlich die Aggregation wichtig. [source]

Olfactory epithelium amyloid-, and paired helical filament-tau pathology in Alzheimer disease

ANNALS OF NEUROLOGY, Issue 4 2010
Steven E. Arnold MD
Objective Olfactory dysfunction is common in Alzheimer disease (AD) and other neurodegenerative diseases. Paired helical filament (PHF)-tau, ,-synuclein, and amyloid-, lesions occur early and severely in cerebral regions of the olfactory system, and they have also been observed in olfactory epithelium (OE). However, their frequency, abundance, and disease specificity, and the relationships of OE pathology to brain pathology have not been established. Methods We investigated the pathological expression of amyloid-,, PHFtau, ,-synuclein, and TDP-43 in postmortem OE of 79 cases with AD, 63 cases with various other neurodegenerative diseases, and 45 neuropathologically normal cases. Results Amyloid-, was present as punctate and small patchy aggregates in 71% of AD cases, compared with 22% of normal cases and 14% of cases with other diseases, and in greater amounts in AD than in either of the other 2 diagnostic categories. PHFtau was evident in dystrophic neurites in 55% of cases with AD, 34% with normal brains, and 39% with other neurodegenerative diseases, also at higher densities in AD. ,-Synuclein was present in dystrophic neurites in 7 cases, 6 of which also had cerebral Lewy bodies. Pathological TDP-43 inclusions were not observed in the OE in any cases. Amyloid-, and to a lesser degree, PHFtau ratings in OE significantly correlated with cortical A, and PHFtau lesion ratings in the brain. Interpretation These data demonstrate that AD pathology in the OE is present in the majority of cases with pathologically verified AD and correlates with brain pathology. Future work may assess the utility of amyloid-, and PHFtau measurement in OE as a biomarker for AD. ANN NEUROL 2010;67:462,469 [source]

Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects,

ANNALS OF NEUROLOGY, Issue 4 2009
Leslie M. Shaw PhD
Objective Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Methods Amyloid-, 1 to 42 peptide (A,1,42), total tau (t-tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy-confirmed AD cases and 52 age-matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t-tau and A,1,42 in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy-confirmed CSF data. Results CSF A,1,42 was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for A,1,42, t-tau, and APO,4 allele count provided the best assessment delineation of mild AD. An AD-like baseline CSF profile for t-tau/A,1,42 was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. Interpretation The CSF biomarker signature of AD defined by A,1,42 and t-tau in the autopsy-confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD. Ann Neurol 2009 [source]

Amyloid , protein toxicity mediated by the formation of amyloid-, protein precursor complexes

ANNALS OF NEUROLOGY, Issue 6 2003
Daniel C. Lu MD
The amyloid-, protein precursor, a type 1 transmembrane protein, gives rise to the amyloid ,-protein, a neurotoxic peptide postulated to be involved in the pathogenesis of Alzheimer's disease. Here, we show that soluble amyloid , protein accelerates amyloid precursor protein complex formation, a process that contributes to neuronal cell death. The mechanism of cell death involves the recruitment of caspase-8 to the complex, followed by intracytoplasmic caspase cleavage of amyloid precursor protein. In vivo, the levels of soluble amyloid , protein correlated with caspase-cleaved fragments of the amyloid precursor protein in brains of Alzheimer's disease subjects. These findings suggest that soluble amyloid , protein,induced multimerization of the amyloid precursor protein may be another mechanism by which amyloid , protein contributes to synapse loss and neuronal cell death seen in Alzheimer's disease. Ann Neurol 2003;54:781,789 [source]

Characterization of copper binding to the peptide amyloid-,(1,16) associated with Alzheimer's disease

BIOPOLYMERS, Issue 1 2006
Qing-Feng Ma
Abstract Amyloid-, peptide (A,) is the principal constituent of plaques associated with Alzheimer's disease (AD) and is thought to be responsible for the neurotoxicity associated with the disease. Copper binding to A, has been hypothesized to play an important role in the neruotoxicity of A, and free radical damage, and Cu2+ chelators represent a possible therapy for AD. However, many properties of copper binding to A, have not been elucidated clearly, and the location of copper binding sites on A, is also in controversy. Here we have used a range of spectroscopic techniques to characterize the coordination of Cu2+ to A,(1,16) in solution. Electrospray ionization mass spectrometry shows that copper binds to A,(1,16) at pH 6.0 and 7.0. The mode of copper binding is highly pH dependent. Circular dichroism results indicate that copper chelation causes a structural transition of A,(1,16). UV-visible absorption spectra suggest that three nitrogen donor ligands and one oxygen donor ligand (3N1O) in A,(1,16) may form a type II square-planar coordination geometry with Cu2+. By means of fluorescence spectroscopy, competition studies with glycine and L -histidine show that copper binds to A,(1,16) with an affinity of Ka , 107M,1 at pH 7.8. Besides His6, His13, and His14, Tyr10 is also involved in the coordination of A,(1,16) with Cu2+, which is supported by 1H NMR and UV-visible absorption spectra. Evidence for the link between Cu2+ and AD is growing, and this work has made a significant contribution to understanding the mode of copper binding to A,(1,16) in solution. © 2006 Wiley Periodicals, Inc. Biopolymers 83: 20,31, 2006 This article was originally published online as an accepted preprint. The "Published Online" date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com [source]