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Amyloid Deposits (amyloid + deposit)

Distribution by Scientific Domains

Medical Sciences	73%
Chemistry	17%
Life Sciences	8%

Distribution within Medical Sciences

Pathology	27%
Dermatology	15%

Selected Abstracts

PAINFUL NEUROPATHY, MONOCLONAL GAMMOPATHY AND AMYLOID DEPOSITS: RESPONSE TO THERAPY IN 3 CASES

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2002
Article first published online: 11 MAR 200
Siciliano G.1, D'Avino C.1, Panichi V.2, Azzarà A.3, Del Corona A.1, Pollina L.3, Murri L.1 1Department of Neuroscience, 2Department of Internal Medicine and 3Department of Oncology,University of Pisa-Italy Amyloidosis is a systemic disease with a wide organic involvement. Amyloidotic polyneuropathies may be genetic in their origin or present in association with a number of chronic inflammatory dysimmune disorders. We report on three patients affected by predominantly sensitive polyneuropathy, monoclonal gammopathy and amyloidosis. Patient 1. Woman, 72 years old, with a one year history of painful paraesthesias, ataxic gait and demyelinating predominantly sensitive polyneuropathy at 4 limbs also with involvement of sympathetic fibres. Blood protein electrophoresis showed a monoclonal gammopahty (IgG-k) with normal bone marrow biopsy and positivity for amyloid at fat biopsy. The patient has been treated with melphalan 0.2 mg/Kg/day+prednisone 100 mg/day for 7 days each month for 6 months with good efficacy and only a transient reduction in platelet and white blood cells count. Patient 2. Man, 60 years old, new diagnosis of diabetes with a 9 month history of painful paraesthesias and hyposthenia, a demyelinating sensory-motor polyneuropathy at 4 limbs. The patient presented an IgG-, monoclonal gammopathy with normal bone marrow biopsy, fat biopsy but not sural nerve biopsy positive for amyloid. The patient underwent melphalan+prednisone therapy, with insulinic control of glycemia. He presented a clear-cut improvement in sensitive-motor symptomatology. Patient 3. Man, 72 years old, with a 15 year history of ulcerous rectocolites. Since 1998 started complaining of paraesthesias and disaesthesias at four limbs associated with gait disturbances. The patient presented an IgG-, monoclonal gammopathy with normal bone marrow aspiration and elevated serum Interleukin-6 levels, fat biopsy positive for amyloid, and high anti-MAG antibodies titer (1:100000). Because of RCU, melphalan therapy was excluded and the patient is at the moment under fludarabine (25 mg/m2/day) ev for 5 days each 6 weeks for 6 bouts. [source]

Immunohistochemical study of cytokeratins in amyloid deposits associated with squamous cell carcinoma and dysplasia in the oral cavity, pharynx and larynx

PATHOLOGY INTERNATIONAL, Issue 5 2003
Tohru Ueno
The frequency of amyloid deposits associated with squamous cell carcinoma (SCC) and dysplasia in the oral cavity, pharynx and larynx was examined. In addition, the origin of amyloid proteins by immunohistochemical staining with a panel of anticytokeratin monoclonal antibodies was investigated. Amyloid deposits were found in eight of 73 (11.0%) SCC and one of seven (14.3%) dysplasias in the oral cavity, in eight of 22 (36.4%) SCC and zero of two (0%) dysplasias in the pharynx, and in 22 of 37 (59.5%) SCC and four of 10 (40.0%) dysplasias in the larynx. Eight of 12 different cytokeratin (CK) antibodies reacted with these deposits: 34,E12 (CK1, -5, -10, -14) reacted with amyloid deposits in 19 of 19 cases (100%), LL002 (CK14) in eight of 18 cases (44.4%), MNF116 (CK5, -6, -8, -17) in eight of 19 cases (42.1%), D5/16B4 (CK5, -6) in five of 18 cases (27.8%), DE-K10 (CK10) in four of 17 cases (23.5%), RCK108 (CK19) in three of 18 cases (16.7%), 34,B4 (CK1) in three of 19 cases (15.8%) and AE8 (CK13) in two of 17 cases (11.8%). These antibodies always reacted with the cytoplasm of squamous cell lesions. Amyloid deposits in two cases contained a CK5 and CK14 pair, and in another two cases they contained both a CK5 and CK14 pair, and a CK1 and CK10 pair. Anti-CK antibodies, including OV-TL12/30 (CK7), c-51 (CK8), DC10 (CK18) and IT-Ks20.8 (CK20) did not react with the amyloid deposits. We conclude that the amyloid deposits associated with SCC or dysplasia in the oral cavity, pharynx or larynx were derived from CK of cancer cells and that some amyloid deposits might be assembled by two or more different CK. [source]

Dystrophia Smolandiensis: a novel morphological picture of recurrent corneal erosions

ACTA OPHTHALMOLOGICA, Issue 4 2010
Björn Hammar
Abstract. Purpose:, The aim of this study was to describe morphological changes in Dystrophia Smolandiensis, a corneal disease that is characterized by recurrent corneal erosive episodes and the formation of central corneal keloid-like opacities in approximately half of those affected. Methods:, The corneas of seven affected individuals were examined using in-vivo confocal microscopy. Specimens of one primary corneal graft, one regraft and one biopsied keloid-like region , all obtained from members of a large family with the disease , were re-examined with a light microscope. Sections were stained with Congo red and analysed immunohistochemically for fibronectin and S100A4. Results:, Light microscopic examination revealed epithelial hyperplasia, absence of Bowman's layer and subepithelial fibrosis. Fibronectin was expressed in the area of subepithelial fibrosis, and the keratocytes in this area generally expressed S100A4. The biopsy specimen stained positive for Congo red, suggesting an amyloid deposit. In-vivo confocal microscopy confirmed epithelial abnormalities, loss of Bowman's layer and significant alterations of the subbasal nerve plexus in affected individuals. Conclusion:, The morphological picture in Dystrophia Smolandiensis is novel for a condition dominated by recurrent corneal erosions at the clinical level. Although no single morphological feature unique to the disease could be found, the general morphological pattern of pathology (true keloid formation, absence of Bowman's layer, subepithelial fibrosis and abnormal subbasal nerves) probably reflects a novel phenotypic expression of the healing response to recurrent erosion of the corneal epithelium. However, the pathogenesis of Dystrophia Smolandiensis remains to be elucidated fully. [source]

Insulitis in type 2 diabetes

DIABETES OBESITY & METABOLISM, Issue 2008
M. Böni-Schnetzler
Islets of patients with type 2 diabetes have the feature of an inflammatory process reflected by the presence of cytokines, immune cells, ,-cell apoptosis, amyloid deposits and fibrosis. Indeed, ,-cells from patients with type 2 diabetes display inflammatory markers, including increased interleukin (IL)-1, expression. Furthermore, increased islet-associated macrophages are observed in human type 2 diabetic patients and in most animal models of diabetes. Importantly, increased numbers of macrophages are detectable very early in high fat,fed mice islets, before the onset of diabetes. These immune cells are most likely attracted by islet-derived chemokines, produced in response to metabolic stress, and under the control of IL-1,. It follows that modulation of intra-islet inflammatory mediators, in particular IL-1,, may prevent insulitis in type 2 diabetes and therefore presents itself as a possible causal therapy with disease-modifying potential. [source]

Reduced intensity allogeneic stem cell transplantation for systemic primary amyloidosis refractory to high-dose melphalan

EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2004
Yasukazu Kawai
Abstract: Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity. [source]

Alzheimer's disease: Mechanisms and development of therapeutic strategies

GERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 4 2003
Takeshi Tabira
Senile plaques are the most characteristic change in Alzheimer's disease (AD). In senile plaques, , amyloid is deposited, which is composed of aggregated amyloid , protein (A,) derived from amyloid precursor protein (APP). Therefore, it is suggested that there exists a mechanism of increase of A, production or a decrease of A, degradation and/or clearance of , amyloid in AD. Mutations in familial Alzheimer's disease (FAD) genes such as APP, presenilin 1 (PS1) and presenilin 2 (PS2) result in an increase of A, production. Apolipoprotein E (ApoE), a genetic risk factor for AD, is involved in A, production and/or its clearance. Thus, it is suggested that an inhibition of A, production and a facilitation of , amyloid degradation and clearance delay the clinical onset and progression of AD, and it is possible to cure AD even after an onset of the disease, if it is still at an early phase. Researchers studied the fine mechanisms of A, production and identified enzymes that cleave-out A, from APP. Inhibitors of the cleaving enzymes are proven to be effective in ameliorating AD-like conditions in its animal models and are now being applied to humans. Researchers also found an efficient way of clearing , amyloid deposits using the immune system, which was effective in animal models. When it was applied to humans, some patients developed meningoencephalitis as a side-effect. Therefore, safer vaccines are now being developed. It did not require 20 years for researchers to develop therapeutic strategies since the discovery of A, in 1984. Now that AD is becoming a treatable disease, early diagnosis and early treatment will soon become the rule. Notably, AD may not be a psychiatric disorder any more, and mainly neurologists and geriatricians will see patients. Thus, neurogeriatrics will become more and more important. [source]

ALys amyloidosis caused by compound heterozygosity in Exon 2 (Thr70Asn) and Exon 4 (Trp112Arg) of the lysozyme gene,,

HUMAN MUTATION, Issue 1 2006
Christoph Röcken
Abstract Hereditary amyloidoses are caused by germline mutations, which increase the propensity of a protein to form cross-, aggregates and deposit as amyloid. Hereditary amyloidoses are particularly interesting as they help to understand how changes in the primary structure of an otherwise non-amyloidogenic protein contribute to amyloidogenesis. Here we report on a novel form of systemic ALys amyloidosis, caused by compound heterozygosity in exon 2 (p.T70N) and exon 4 (p.W112R) of the lysozyme gene (LYZ), with both mutations being present on the same allele. This type of hereditary ALys amyloidosis is characterized by extended amyloid deposits in the upper gastrointestinal tract, entire colon, and kidney, leading to gastrointestinal bleeding. Both mutations are probably effective in disease manifestation. The novel mutation at position 112 in the mature protein is located within the ,-helical domain of the protein and therefore outside the cluster of residues that has so far been implicated in ALys amyloidosis. Taken together with the p.T70N mutation, this results in a lysozyme species where the correct folding of various protein domains is probably impaired and increases the propensity of amyloid fibril formation. Interestingly, this form of ALys amyloidosis is also characterized by the occurrence of proteolytic fragments of lysozyme in the amyloid deposits. © 2005 Wiley-Liss, Inc. [source]

Notalgia paresthetica: a study on pathogenesis

INTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 10 2000
avk MD
Background Notalgia paresthetica is a sensory neuropathy involving the dorsal spinal nerves. The characteristic symptom is pruritus on the back, occasionally accompanied by pain, paresthesia, and/or hyperesthesia, which results in a well-circumscribed hyperpigmented patch in the symptomatic area. The etiology of this condition has not yet been completely defined. Objective Possible mechanisms that could explain the pathogenesis of notalgia paresthetica were investigated through clinical examination and various diagnostic tests. Methods Ten cases of notalgia paresthetica underwent dermatologic, neurologic, and orthopedic examination. This was followed by skin biopsy, electrodiagnostic investigation, and radiography of the spine. Results All patients had a typical symptomatology and dermatologic picture. Neurologic examination and standard electrodiagnostic investigation results were normal in all cases. Histopathology was compatible with postinflammatory hyperpigmentation; there were no amyloid deposits. In seven cases, degenerative changes in the vertebrae were observed and, in all of these cases, these changes were most prominent in the vertebrae which corresponded to the dermatome of the cutaneous lesion. Conclusions The striking correlation of notalgia paresthetica localization with degenerative changes in the spine suggests that spinal nerve impingement may contribute to the pathogenesis of this entity. [source]

Imbalance of plasma membrane ion leak and pump relationship as a new aetiological basis of certain disease states

JOURNAL OF INTERNAL MEDICINE, Issue 6 2003
G. Ronquist
Abstract. The basis for life is the ability of the cell to maintain ion gradients across biological membranes. Such gradients are created by specific membrane-bound ion pumps [adenosine triphosphatases (ATPases)]. According to physicochemical rules passive forces equilibrate (dissipate) ion gradients. The cholesterol/phospholipid ratio of the membrane and the degree of saturation of phospholipid fatty acids are important factors for membrane molecular order and herewith a determinant of the degree of non-specific membrane leakiness. Other operative principles, i.e. specific ion channels can be opened and closed according to mechanisms that are specific to the cell. Certain compounds called ionophores can be integrated in the plasma membrane and permit specific inorganic ions to pass. Irrespective of which mechanism ions leak across the plasma membrane the homeostasis may be kept by increasing ion pumping (ATPase activity) in an attempt to restore the physiological ion gradient. The energy source for this work seems to be glycolytically derived ATP formation. Thus an increase in ion pumping is reflected by increased ATP hydrolysis and rate of glycolysis. This can be measured as an accumulation of breakdown products of ATP and end-products of anaerobic glycolysis (lactate). In certain disease entities, the balance between ATP formation and ion pumping may be disordered resulting in a decrease in inter alia (i.a.) cellular energy charge, and an increase in lactate formation and catabolites of adenylates. Cardiac syndrome X is proposed to be due to an excessive leakage of potassium ions, leading to electrocardiographic (ECG) changes, abnormal Tl-scintigraphy of the heart and anginal pain (induced by adenosine). Cocksackie B3 infections, a common agent in myocarditis might also induce an ionophore-like effect. Moreover, Alzheimer's disease is characterized by the formation of extracellular amyloid deposits in the brain of patients. Perturbation of cellular membranes by the amyloid peptide during the development of Alzheimer's disease is one of several mechanisms proposed to account for the toxicity of this peptide on neuronal membranes. We have studied the effects of the peptide and fragments thereof on 45Ca2+ -uptake in human erythrocytes and the energetic consequences. Treatment of erythrocytes with the ,1,40 peptide, results in qualitatively similar nucleotide pattern and decrease of energy charge as the treatment with Ca2+ -ionophore A23187. Finally, in recent studies we have revealed and published in this journal that a rare condition, Tarui's disease or glycogenosis type VII, primarily associated with a defect M-subunit of phosphofructokinase, demonstrates as a cophenomenon an increased leak of Ca2+ into erythrocytes. [source]

Advanced glycation end product in familial amyloidotic polyneuropathy (FAP)

JOURNAL OF INTERNAL MEDICINE, Issue 4 2000
N. Nyhlin
Abstract. Nyhlin N, Ando Y, Nagai R, Suhr O, El Sahly M, Terazaki H, Yamashita T, Ando M, Horiuchi S (Umeå University Hospital, Umeå, Sweden and Kumamoto University School of Medicine, Kumamoto, Japan). Advanced glycation end product in familial amyloidotic polyneuropathy (FAP). J Intern Med 2000; 247: 485,492. Objectives. Advanced glycation end products (AGE) are present in amyloid deposits in ,2 -microglobulin amyloidosis, and it has been postulated that glycation of ,2 -microglobulin may be involved in fibril formation. The aim of this paper was to ascertain whether AGE occur in amyloid deposits in familial amyloidotic polyneuropathy (FAP). Setting. Department of Medicine, Umeå University Hospital and First Department of Internal Medicine, Kumamoto University School of Medicine. Design. The presence of AGE was sought immunohistochemically and biochemically in amyloid-rich tissues from patients with FAP. Subjects. Biopsy specimens from nine patients and 10 controls were used for the immunohistochemical analysis. For amyloid preparation, vitreous samples from three FAP patients were used. Results. Immunohistochemical studies using a polyclonal anti-AGE antibody revealed positive immunoreactivity in intestinal materials, but the pattern of reactivity was unevenly distributed; it was often present in the border of amyloid deposits, or surrounding them. Non-amyloid associated immunoreactivity was also observed in a few regions of the specimens, although the AGE-positive structures were situated in areas containing amyloid deposits. Western blotting of purified amyloid from the vitreous body of FAP patients revealed a significant association of AGE with amyloid fibrils. Conclusion. The immunoreactivity for the AGE antibody suggests that AGE may be involved in fibril formation in FAP. [source]

Synthesis and 11C-labelling of (E,E)-1-(3,,4,-dihydroxystyryl)-4-(3,-methoxy-4,-hydroxystyryl) benzene for PET imaging of amyloid deposits,,

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, Issue 8 2002
Yanming Wang
Abstract Carboxylic acid derivatives of the amyloid-binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid-imaging agents. A neutral amyloid probe, (E,E)-1-(3,,4,-dihydroxystyryl)-4-(3,-methoxy-4,-hydroxystyryl)benzene (3), devoid of any carboxylate groups has been designed and synthesized via a 12-step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C-11 via [11C]methyl iodide ([11C]CH3I) methylation of a symmetric 4,4,-dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post-mortem AD brain, and exhibited good binding affinity (Ki=38±8 nM) for A,(1,40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [11C]3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [11C]3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR-beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits. Copyright © 2002 John Wiley & Sons, Ltd. [source]

Cystatin C colocalizes with amyloid-, and coimmunoprecipitates with amyloid-, precursor protein in sporadic inclusion-body myositis muscles

JOURNAL OF NEUROCHEMISTRY, Issue 6 2003
Gaetano Vattemi
Abstract Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid-, (A,) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo-morphologic muscle phenotype of sporadic inclusion-body myositis (s-IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of A, deposits, we studied expression and localization of CC in muscle biopsies of 10 s-IBM, and 16 disease- and five normal-control muscle biopsies. Physical interaction of CC with amyloid-, precursor protein (A,PP) was studied by a combined immunoprecipitation/immunoblotting technique in the s-IBM muscle biopsies and in A,PP-overexpressing cultured human muscle fibers. In all s-IBM muscle biopsies, CC-immunoreactivity either colocalized with, or was adjacent to, the A,-immunoreactive inclusions in 80,90% of the vacuolated muscle fibers, mostly in non-vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity-colocalized with A, on 6,10 nm amyloid-like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with A,PP, both in s-IBM muscle and in A,PP-overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with A,PP, and (ii) suggest that CC may play a novel role in the s-IBM pathogenesis, possibly by influencing A,PP processing and A, deposition. [source]

Characterizing bathocuproine self-association and subsequent binding to Alzheimer's disease amyloid ,-peptide by NMR

JOURNAL OF PEPTIDE SCIENCE, Issue 4 2004
Shenggen Yao
Abstract Aggregated amyloid ,-peptide (A,) is the primary constituent of the extracellular plaques and perivascular amyloid deposits associated with Alzheimer's disease (AD). Deposition of the cerebral amyloid plaques is thought to be central to the disease progression. One such molecule that has previously been shown to ,dissolve' deposited amyloid in post-mortem brain tissue is bathocuproine (BC). In this paper 1H NMR chemical shift analysis and pulsed field gradient NMR diffusion measurements were used to study BC self-association and subsequent binding to A,. The results show that BC undergoes self-association as its concentration increases. The association constant of BC dimerization, Ka, was estimated to be 0.64 mM,1 at 25°C from 1H chemical shift analysis. It was also found that dimerization of BC appeared to be essential for its binding to A,. From the self-association constant of BC, Ka, the fraction of dimeric BC in the complex was obtained and the dissociation constant, Kd, of BC bound to A,40 peptide was then determined to be ,1 mM. Copyright © 2003 European Peptide Society and John Wiley & Sons, Ltd. [source]

Abstracts of the 8th Meeting of the Italian Peripheral Nerve Study Group: 14

JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2003
A Toscano
Transthyretin-derived familial amyloid polyneuropathy (TTR-FAP) is the most common form of hereditary amyloidosis, often associated with multisystemic involvement and a poor prognosis. We studied four patients, aged between 43 and 68 yrs, with TTR-FAP. A severe somatic and autonomic polyneuropathy was seen in three patients, whereas one was at onset of the disease. In addition 2/4, aged 43 and 63 years old, had a mild central nervous system (CNS) involvement. Neurophysiological studies showed an axonal polyneuropathy and amyloid deposits were found in all sural nerve biopsies. Combined conventional MRI and proton MR spectroscopic imaging (MRSI) were performed in our patients and in 14 age-matched normal controls. Conventional MRI was normal in two patients and showed minimal white matter and subcortical lesions in the other two, who were 63 and 68 years old. Proton MRSI of the periventricular brain regions showed a large reduction in N-acetylaspartate/creatine (NAA/Cr) resonance intensity (mean NAA/Cr in patients: 2.45 ± 0.04; mean NAA/Cr in normal controls: 2.9 ± 0.1; p < 0.003). Our findings suggest that, despite minimal or no abnormalities on conventional MRI, evidence of diffuse axonal damage can be demonstrated in brain of patients with TTR-FAP by proton MRSI examination, even in patients with no or mild CNS involvement. [source]

Transthyretin-derived amyloid deposition on the gastric mucosa in domino recipients of familial amyloid polyneuropathy liver

LIVER TRANSPLANTATION, Issue 2 2007
Yo-ichi Takei
Familial amyloid polyneuropathy (FAP) is a form of hereditary generalized amyloidosis. Liver tissue explanted from FAP patients has normal structure and function, except for the production of amyloidogenic variant transthyretin (TTR), and domino liver transplantation (DLT) using grafts from FAP patients was first performed in 1995. FAP symptoms usually develop in genetically determined individuals after the age of 20, but it is difficult to estimate when FAP symptoms will appear in domino recipients. Concerning this problem, histological findings showing amyloid deposition have recently been obtained in a few domino recipients of FAP livers. This study investigated the presence of de novo amyloid deposition in the gastroduodenal mucosa of domino recipients transplanted at our institution. Biopsy of gastroduodenal mucosa was carried out in 5 recipients of FAP livers and TTR-derived amyloid deposits were detected in 2 patients, both of whom had undergone DLT 47 months previously. In FAP liver recipients, de novo systemic amyloid deposition may begin much sooner than previously supposed. Therefore, careful follow-up of domino recipients of FAP livers is required. Liver Transpl, 2006. © 2006 AASLD. [source]

Immunohistochemical study of the expression of cytokines and nitric oxide synthases in brains of patients with dementia with Lewy bodies

NEUROPATHOLOGY, Issue 1 2003
Omi Katsuse
Regional expression of cytokines (IL-1,, TNF-,), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) was immunohistochemically investigated in the brains of patients with dementia with Lewy bodies (DLB), compared with those of patients with Alzheimer's disease (AD) and non-demented elderly persons. It has been reported that inflammatory responses by cytokines and oxygen free radicals such as nitric oxide (NO) are associated with damaged neurons, degenerative neurites or amyloid deposits in AD brains. In the present study, overexpression of IL-1,, TNF-, and iNOS was demonstrated in the amygdala, hippocampus, entorhinal and insular cortices of DLB brains, which are pathologically the most vulnerable regions in DLB brains as well as AD brains. In addition, some Lewy body (LB)-bearing neurons were involved by the processes of IL-1,- and TNF-,-positive microglia, and most extracellular LB were associated with the processes of TNF-,- and iNOS-positive astroglia. Glial involvement was also found around neuritic plaques and extracellular neurofibrillary tangles. In contrast, the expression of nNOS was reduced in the amygdala of DLB brains showing severe Lewy pathology. These findings suggest that cytokines and NO are significantly implicated in neuronal damage and death including LB formation in DLB brains. [source]

Selective PrP-like protein, doppel immunoreactivity in dystrophic neurites of senile plaques in Alzheimer's disease

NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2004
I. Ferrer
Doppel (Dpl) is a prion-like protein encoded by the gene PRND, which has been found downstream of the prion gene PRNP in several species. The present study examines by immunohistochemistry Dpl expression in brain samples from 10 patients with Alzheimer's disease (AD), three patients with Pick's disease, four patients with Parkinson's disease, eight patients with diffuse Lewy body disease (DLBD), six patients with sporadic Creutzfeldt,Jakob disease (CJD) methionine/methionine at the codon 129, two patients with sporadic CJD methionine/valine at the codon 129 and numerous kuru plaques in the cerebellum, one patient with fatal familial insomnia (FFI), and 10 age-matched controls. In the adult human brain, Dpl immunoreactivity was restricted to scattered granule cells of the cerebellum and scattered small granules in the cerebral cortex. Dpl immunoreactivity was seen around ,A4 amyloid deposits in neuritic plaques, but not in diffuse plaques, AD and the common form of DLBD. Neurofibrillary tangles, Pick bodies and Lewy bodies were not stained with anti-Dpl antibodies. No modifications in Dpl immunoreactivity were observed in CJD excepting those associated with accompanying senile plaques. No Dpl-positive deposits were seen in FFI. Whether Dpl in neuritic plaques may attenuate amyloid-induced oxidative stress and participate in the glial response around amyloid cores is discussed in light of the few available data on Dpl functions. [source]

Immunohistochemical study of cytokeratins in amyloid deposits associated with squamous cell carcinoma and dysplasia in the oral cavity, pharynx and larynx

Vascular amyloid of unknown origin and senile transthyretin amyloid in the lung and gastrointestinal tract of old age: Histological and immunohistochemical studies

PATHOLOGY INTERNATIONAL, Issue 5 2001
Hironobu Matsutani
The histological and immunohistochemical characteristics and the incidence of amyloid deposits in the tissues of the lung and gastrointestinal tract were investigated in 64 autopsied individuals who were 80 years and older (age range: 80,92 years; mean: 83.3 years). Immunohistochemical examination was performed with antibodies against amyloid A, transthyretin, immunoglobulin , and , light chain amyloid fibril proteins, ,2 -microglobulin, , protein, apolipoprotein AI, apolipoprotein AII, atrial natriuretic peptide, apolipoprotein E, and amyloid P component. Transthyretin amyloid fibril protein (ATTR) deposits were observed in five cases (7.8%). Gastrointestinal amyloid deposits of unknown origin were observed in the veins of the gastrointestinal tract in 26 cases (40.6%). This amyloid was regarded as portal amyloid with respect to distribution pattern. Pulmonary vascular amyloid deposits of unknown origin were observed in 12 cases (18.8%). These amyloid deposits were found mainly in medium-sized veins in the lungs and did not react with any antibodies against amyloid fibril proteins except apolipoprotein E and amyloid P component. Eleven of the 26 cases (42.3%) showing portal amyloid also showed pulmonary vascular amyloid of unknown origin. The pulmonary vascular amyloid deposits were similar to the portal amyloid deposits with respect to their morphological features and their relation to elastic fibers in the vessels. Further morphological investigation and biochemical analysis of the pulmonary vascular amyloid and portal amyloid will resolve questions of their origins and relation. [source]

Hyperkeratotic variant of porokeratosis Mibelli with dermal amyloid deposits

THE JOURNAL OF DERMATOLOGY, Issue 5 2010
Toshiaki UENISHI
Abstract We report a case of hyperkeratotic variant of porokeratosis Mibelli with dermal amyloid deposits. A 66-year-old man presented with multiple brownish keratotic lesions on the lower extremities, a verrucous nodule on the third toe of the left foot and brownish verrucous plaques on the buttocks for several years. Histopathological examination of the hyperkeratotic plaque in the right gluteal region revealed extreme hyperkeratosis and cornoid lamella. In the papillary dermis, there were prominent eosinophilic amorphous materials which were positive to Dylon staining. Treatment with oral etretinate resulted in a remission of the skin lesions in this case. [source]

Sjögren's syndrome and localized nodular cutaneous amyloidosis: Coincidence or a distinct clinical entity?

ARTHRITIS & RHEUMATISM, Issue 7 2008
Jiska M. Meijer
Objective To report 8 patients with Sjögren's syndrome (SS) and localized nodular cutaneous amyloidosis and to examine serologic and immunohistologic findings that may link the 2 diseases. Methods The databases for 3 amyloidosis centers were searched for patients with localized nodular cutaneous amyloidosis and SS. Eight patients with this combination were identified, and clinical, serologic, and histologic parameters were retrospectively evaluated. Results Among the 8 patients with a clinical diagnosis of SS, 6 fulfilled the American,European Consensus Group criteria for SS. All of the patients were women in whom SS had been diagnosed at a median age of 47 years (range 30,61 years) and amyloid had been diagnosed at a median age of 60 years (range 42,79 years). The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients. In 3 of these 4 patients as well as 2 other patients, a light chain,restricted plasma cell population was observed near the amyloid deposits. Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years. Conclusion SS should be considered in patients with cutaneous amyloidosis. The combination of cutaneous amyloidosis and SS appears to be a distinct disease entity reflecting a particular and benign part of the polymorphic spectrum of lymphoproliferative diseases related to SS. [source]

X-ray crystallographic studies of two transthyretin variants: further insights into amyloidogenesis

ACTA CRYSTALLOGRAPHICA SECTION D, Issue 3 2005
Ricardo M. Neto-Silva
Transthyretin (TTR) is a homotetrameric plasma protein that, as a result of a set of not yet fully characterized conformational changes, forms fibrillar aggregates that are the major protein component of amyloid deposits. More than 80 mutations associated with TTR amyloid deposition have been described in the literature. X-ray crystallography was used to elucidate the three-dimensional structure of two important TTR variants: TTR Y78F, an amyloidogenic protein, and TTR R104H, which is associated with a protective effect over the amyloidogenic V30M mutation. The structures of those two TTR variants have been determined in space group P21212 to 1.55 and 1.60,Å resolution, respectively, using molecular-replacement techniques. Detailed analysis of the protein model for TTR Y78F indicates a destabilization of the contacts between the ,-helix and AB loop and the body of the molecule, intimately related to the amyloidogenic nature; contrastingly, in the TTR R104H variant new contacts involving the N-terminal region and His104 are clearly antagonists of amyloid formation. [source]

Greasing the wheels of A, clearance in Alzheimer's Disease: The role of lipids and apolipoprotein E

BIOFACTORS, Issue 3 2009
Jianjia Fan
Abstract Although apolipoprotein E (apoE) is the most common genetic risk factor for Alzheimer's Disease (AD), how apoE participates in AD pathogenesis remains incompletely understood. ApoE is also the major carrier of lipids in the brain. Here, we review studies showing that the lipidation status of apoE influences the metabolism of A, peptides, which accumulate as amyloid deposits in the neural parenchyma and cerebrovasculature. One effect of apoE is to inhibit the transport of A, across the blood-brain-barrier (BBB), particularly when apoE is lipidated. A second effect is to facilitate the proteolytic degradation of A, by neprilysin and insulin degrading enzyme (IDE), which is enhanced when apoE is lipidated. We also describe how apoE becomes lipidated and how this impacts A, metabolism. Specifically, genetic loss of the cholesterol transporter ABCA1 impairs apoE lipidation and promotes amyloid deposition in AD mouse models. ABCA1 catalyses the ATP-dependent transport of cholesterol and phospholipids from the plasma membrane to lipid-free apolipoproteins including apoE. Conversely, selective overexpression of ABCA1 increases apoE lipidation in the central nervous system (CNS) and eliminates the formation of amyloid plaques in vivo. Deficiency of Liver-X-Receptors (LXRs), transcription factors that stimulate ABCA1 and apoE expression, exacerbates AD pathogenesis in vivo, whereas treatment of AD mice with synthetic LXR agonists reduces amyloid load and improves cognitive performance. These studies provide new insights into the mechanisms by which apoE affects A, metabolism, and offer opportunities to develop novel therapeutic approaches to reduce the leading cause of dementia in the elderly. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source]

A variant TGFBI corneal dystrophy from G623D mutation with an unusual amyloidogenic phenotype

ACTA OPHTHALMOLOGICA, Issue 2009
HT AGOSTINI
Purpose To present a unique corneal dystrophy never before described in a German family carrying the Gly623Asp mutation of the TGFBI gene with late clinical onset. Methods Clinical documentation and isolation of genomic DNA from peripheral blood leucocytes were obtained from each family member examined. Exons 3, 4, 5, and 11 to 14 of the TGFBI gene were sequenced. 5 corneal buttons of 3 affected siblings were excised at the time of penetrating keratoplasty. Light and electron microscopic examination were performed including immunohistochemistry with antibodies against Keratoepithelin (KE) 2 and 15. Results Specimens showed changes in Bowman's layer and the adjacent stroma. Congo red-positive amyloid deposits were found within the epithelium in one cornea, in Bowman's layer and in the anterior stroma of all specimens, also showing KE2- but not KE15-immunostaining. EM revealed deposits located in the anterior stroma and Bowman's layer and the basal area of some epithelial cells. These areas were strongly Alcian blue-positive but negative in the Masson-Trichrom-stain. Only affected patients had a heterozygous missense mutation in exon 14 of the TGFBI gene (G->A transition at nucleotide 1915) with the change Gly623Asp in the keratoepithelin protein. Conclusion In contrast to the patient carrying the Gly623Asp mutation of the TGFBI gene described by Afshari et al., our cases presented with Salzmann nodular degeneration like clinical features with KE2 positive amyloid. The reason for this now "meeting the expectation histological phenotype" is unclear. The histological findings emphasize that this is a unique corneal dystrophy which shares no clinical characteristics with Reis-Bücklers dystrophy and should be treated as a distinct entity. [source]

Distribution of amyloid and BIG-H3 in the cornea and limbus of a patient with lattice corneal dystrophy.

ACTA OPHTHALMOLOGICA, Issue 2009
Unique findings in donated eyes
Purpose The lattice corneal dystrophies (LCDs) are hereditary diseases involving the formation of opaque or refractile, amyloid-containing filaments in the corneal stroma. We report the distribution of amyloid and big-h3 protein in cornea and limbus in a patient suffering with LCD. Methods An 84 year-old patient with lattice corneal dystrophy died and donated her eyes for further study. The corneal and limbal tissue of the patient processed for light and electron microscopy. The primary polyclonal antibody big-h3 was located by secondary, goat anti-rabbit antibody conjugated with gold. Results In cornea amyloid deposits were observed below epithelium, and in the anterior and middle stroma. The epithelium was thin and invaginated by the amyloid deposits. In the limbus, large numbers of amyloid deposits were observed in sub-epithelial region, and in the mid and deep stroma. Subepithelial amyloid was also present in the substantia propria beneath the bulbar conjunctival epithelium. The amyloid deposits contained very thin amyloid fibrils and strongly stained with big-h3 antibody. There were also numerous long spacing collagen fibrils observed in the mid stroma, which also labelled with the antibody. Conclusion This is the first report of structural changes in the peripheral cornea and limbus in LCD. It is thought that mutated big-h3 protein diffuse into the stroma from the corneal epithelium to form amyloid deposits. The presence of amyloid and big-h3 at the limbus and in the adjacent bulbar conjunctiva and perilimbal cornea, suggests that Big-h3 is overproduced in these regions, which are normally free from clinically detectable disease. [source]

Ocular manifestations in liver transplant recipients with familial amyloid polyneuropathy

ACTA OPHTHALMOLOGICA, Issue 5 2008
Ola Sandgren
Abstract. Purpose:, To evaluate postoperative ocular involvement in Swedish liver transplant (LT) recipients with familial amyloid polyneuropathy (FAP). Methods:, Routine ophthalmological examinations were performed in 48 LT recipients, with particular attention given to amyloid deposition in the anterior segment and the vitreous body. Medical records were scrutinized for information regarding neurological impairment at the time of the LT. The diagnosis was secured in all cases by examining for amyloid deposits in biopsy specimens and positive genetic testing for amyloidogenic transthyretin (ATTR) Val30Met mutation. Results:, Six patients (12.5%) developed vitreous opacities within the post-LT observation period. The first opacities were seen 40 months after transplantation, 8 years after the onset of systemic disease. Four patients (8%) developed secondary glaucoma, the first of which was observed 18 months after the procedure and 6.5 years after the onset of disease. Sixteen patients (33%) developed deposits on the anterior surface of the lens. Scalloped pupillary margins were noted in 10 patients (21%). Conclusion:, The prevalence of eye complications increases with time after LT and regular follow-up is necessary, especially to disclose the development of glaucoma , a complication with insidious symptoms of which patients are normally unaware. [source]

Self-Assembly of Amylin(20,29) Amide-Bond Derivatives into Helical Ribbons and Peptide Nanotubes rather than Fibrils

CHEMISTRY - A EUROPEAN JOURNAL, Issue 14 2006
Ronald C. Elgersma
Abstract Uncontrolled aggregation of proteins or polypeptides can be detrimental for normal cellular processes in healthy organisms. Proteins or polypeptides that form these amyloid deposits differ in their primary sequence but share a common structural motif: the (anti)parallel , sheet. A well-accepted approach for interfering with ,-sheet formation is the design of soluble ,-sheet peptides to disrupt the hydrogen-bonding network; this ultimately leads to the disassembly of the aggregates or fibrils. Here, we describe the synthesis, spectroscopic analysis, and aggregation behavior, imaged by electron microscopy, of several backbone-modified amylin(20,29) derivatives. It was found that these amylin derivatives were not able to form fibrils and to some extent were able to inhibit fibril growth of native amylin(20,29). However, two of the amylin peptides were able to form large supramolecular assemblies, like helical ribbons and peptide nanotubes, in which ,-sheet formation was clearly absent. This was quite unexpected since these peptides have been designed as soluble ,-sheet breakers for disrupting the characteristic hydrogen-bonding network of (anti)parallel , sheets. The increased hydrophobicity and the presence of essential amino acid side chains in the newly designed amylin(20,29) derivatives were found to be the driving force for self-assembly into helical ribbons and peptide nanotubes. This example of controlled and desired peptide aggregation may be a strong impetus for research on bionanomaterials in which special shapes and assemblies are the focus of interest. [source]

Hypopigmented macular amyloidosis with or without hyperpigmentation

CLINICAL & EXPERIMENTAL DERMATOLOGY, Issue 8 2009
M. S. L. Ho
Summary Primary cutaneous amyloidosis (PCA) is a chronic pruritic skin disorder with characteristic amyloid deposits in the papillary dermis. We report three cases of PCA, which shared common features of hypopigmentation as a predominant feature with or without reticular hyperpigmentation, no itching, adult onset and dermal papillary amyloid deposition. These cases did not conform to the usual features of PCA. [source]