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PubMed1988

Amyloid in the horse: a report of nine cases.

Out of approximately 16,000 horses referred for clinical examination, nine had amyloidosis. Six of these horses had localised amyloid deposits in the wall of the nasal meatus and ventral turbinates associated with epistaxis. Horse 1 also developed malignant histiolymphocytic lymphosarcomas. The amyloid deposits were potassium permanganate-resistant and tryptophan-positive. Gel filtration of solubilised amyloid fibrils from Horse 1 revealed a major retarded fraction with an apparent molecular weight of 20 kD. This protein had an amino acid composition similar to human AL-amyloid proteins and horse immunoglobulin light chains. On Western blot a strong cross-reaction was observed between horse 1gG2a light chains and the Horse 1 amyloid. Horses 7 to 9 had suppurative verminous aneurysm, tuberculosis and an adrenal cortical adenoma, respectively, and had generalised amyloid deposits in liver and spleen. These amyloid deposits were found to be potassium permanganate-sensitive and positive for tryptophan. Gel filtration of solubilised amyloid fibrils from Horse 8 revealed a major retarded fraction (protein AA) with an apparent molecular weight of 10 kD. Immunoperoxidase-antiperoxidase staining showed the localised deposits to be negative or only weakly positive with antisera against bovine, hamster, dog and human protein AA and to be positive with anti-horse-one amyloid protein. The generalised deposits were found to be positive with the antisera against allogenic protein AA. The results of the potassium permanganate incubation, biochemistry, immunoblotting and immunochemistry, indicate that the localised amyloid of Horse 1 and most likely the amyloid of Horses 2 to 6, is of the AL-type. The generalised amyloid deposits were found to be of the AA type.

Amyloid↗
PubMed1997

Light microscopic, immunohistochemical, and electron microscopic features of amyloid arthropathy in chickens.

Amyloid arthropathy has been recently recognized as a spontaneous syndrome in chickens. Predominantly, femorotibial and tarsometatarsal joints were affected, showing (peri) articular orange amyloid deposits. Immunohistochemical evaluation revealed the amyloid to be of the reactive type. Induction of amyloid arthropathy in chickens was carried out using a single intravenous injection of Enterococcus faecalis cultures. In the naturally occurring and the induced cases, amyloid deposits were found in the hypertrophic synovial villi and in the articular cartilage, particularly in the superficial layer and in the nutritional blood vessel walls. Highly sulfated glycosaminoglycans (GAGs) were found in the amyloid deposits. Ultrastructurally, bundles of amyloid fibrils were seen in invaginations of synoviocytes and chondrocytes. Immunogold electron microscopy failed to reveal signs of intracellular amyloid formation. The predilection site for amyloid deposition in the major leg joints of the chickens with reactive amyloid could be explained by the arthritic condition caused by Enterococcus faecalis bacteriaemia. The polyarthritis triggers hepatic acute phase protein synthesis and increases the vascular serum amyloid A (SAA) supply to the joint. Inflammatory and degenerative changes in the articular cartilage and adjoining tissues result in an increase of highly sulphated GAGs, which are considered to enhance deposition of SAA as amyloid.

Amyloid↗
PubMed2005

Development of novel amyloid imaging agents based upon thioflavin S.

To date, small-molecule amyloid-imaging agents for in vivo detection and quantitation of amyloid deposits in Alzheimer's disease (AD) have been developed and successfully applied to human subjects. Preliminary studies have indicated that these amyloid-imaging agents were accumulated in the AD brains in a pattern that is relatively consistent with AD pathology, at least in the regions of amyloid-rich grey matter. These studies have also proven the concept that amyloid dyes, normally too hydrophilic to enter the brain, can be chemically modified to enhance brain permeability, binding affinity, as well as improve binding specificity for amyloid deposits. Related studies have suggested that structurally different agents can be developed that bind to different sites on amyloid deposits. In fact, in vivo cross-referencing studies based upon different amyloid-imaging agents may permit better characterization of AD pathology. But more importantly, novel amyloid imaging agents are required that will allow direct correlation between the results of animal models and human subjects based upon identical imaging modalities. Thus far, amyloid stains such as Congo red and thioflavin T have been extensively studied. However, another widely used amyloid dye, thioflavin S, has not been previously explored. This is in part due to the fact that thioflavin S exists as a mixture, not a pure chemical entity, albeit that the major component has been characterized. We hypothesized that neutral analogs, based upon the major component, could be developed as novel amyloid imaging agents, that exhibit complementary binding properties and pharmacokinetic profiles compatible with potential human studies.

Amyloid↗
PubMed1985

Temporal relationship between glycosaminoglycan accumulation and amyloid deposition during experimental amyloidosis. A histochemical study.

The temporal relationship between glycosaminoglycan (GAG) accumulation and amyloid deposition was determined in two models of amyloid induction. In the first model amyloid was induced rapidly using amyloid-enhancing factor and AgNO3 as an inflammatory stimulus. In the second model amyloid was induced by daily injections of azocasein. Congo red staining was used to demonstrate amyloid, and both the sulfated Alcian blue and Alcian blue (pH 5.7)-MgCl2 methods were used to demonstrate GAGs. In the rapid model, amyloid was first detected in the splenic perifollicular areas 36 hours after induction. The initial presence of GAGs was also seen at 36 hours and in the exact locale where the amyloid was found. Amyloid was first seen in the liver about the central veins at 48 hours. GAGs in the liver appeared coincidentally with and in the same location as the amyloid. In the traditional model (azocasein injections) amyloid did not appear in the spleen until day 6 to 7, again with coincidental GAG deposition. The present study shows that amyloid-associated GAGs appear in the tissues together with the AA protein and are not a function of the tissue type. The appearance of the GAGs is also not a function of the nature of the inflammatory agent or its length of action but appears to be part of the process involved in the deposition of the AA protein.

Amyloid↗
PubMed2004

Ginkgolide B inhibits the neurotoxicity of prions or amyloid-beta1-42.

BACKGROUND: Neuronal loss in Alzheimer's or prion diseases is preceded by the accumulation of fibrillar aggregates of toxic proteins (amyloid-beta1-42 or the prion protein). Since some epidemiological studies have demonstrated that the EGb 761 extract, from the leaves of the Ginkgo biloba tree, has a beneficial effect on Alzheimer's disease, the effect of some of the major components of the EGb 761 extract on neuronal responses to amyloid-beta1-42, or to a synthetic miniprion (sPrP106), were investigated. METHODS: Components of the EGb 761 extract were tested in 2 models of neurodegeneration. SH-SY5Y neuroblastoma cells were pre-treated with ginkgolides A or B, quercetin or myricetin, and incubated with amyloid-beta1-42, sPrP106, or other neurotoxins. After 24 hours neuronal survival and the production of prostaglandin E2 that is closely associated with neuronal death was measured. In primary cortical neurons apoptosis (caspase-3) in response to amyloid-beta1-42 or sPrP106 was measured, and in co-cultures the effects of the ginkgolides on the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia was tested. RESULTS: Neurons treated with ginkgolides A or B were resistant to amyloid-beta1-42 or sPrP106. Ginkgolide-treated cells were also resistant to platelet activating factor or arachidonic acid, but remained susceptible to hydrogen peroxide or staurosporine. The ginkgolides reduced the production of prostaglandin E2 in response to amyloid-beta1-42 or sPrP106. In primary cortical neurons, the ginkgolides reduced caspase-3 responses to amyloid-beta1-42 or sPrP106, and in co-culture studies the ginkgolides reduced the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia. CONCLUSION: Nanomolar concentrations of the ginkgolides protect neurons against the otherwise toxic effects of amyloid-beta1-42 or sPrP106. The ginkgolides also prevented the neurotoxicity of platelet activating factor and reduced the production of prostaglandin E2 in response to platelet activating factor, amyloid-beta1-42 or sPrP106. These results are compatible with prior reports that ginkgolides inhibit platelet-activating factor, and that platelet-activating factor antagonists block the toxicity of amyloid-beta1-42 or sPrP106. The results presented here suggest that platelet-activating factor antagonists such as the ginkgolides may be relevant treatments for prion or Alzheimer's diseases.

Journal Article↗
PubMed1996

Apolipoprotein E is associated with islet amyloid and other amyloidoses: implications for Alzheimer's disease.

Apolipoprotein E (ApoE) has recently been proposed as an aetiological factor of Alzheimer's disease (AD): ApoE is co-localized to amyloid plaques and neurofibrillary tangles in the brain and binds to A beta-protein in vitro. An association of ApoE epsilon 4 allele with the development of AD has been reported. Islet amyloid is formed from islet amyloid polypeptide (IAPP) in pancreatic islets of 90 per cent of patients with non-insulin-dependent diabetes mellitus (NIDDM) which, like AD, is an age-dependent pathology. The relationship of ApoE to islet amyloid and other amyloidoses is largely unknown. In this study, ApoE was localized by immunocytochemistry on pancreatic specimens from non-diabetic man, monkey, and mouse, and on amyloid-containing human tissues from pancreas, heart, brain, and intestine. All types of amyloid deposits, irrespective of the constituent peptide, site of deposition, or species, showed immunoreactivity for ApoE (ApoE-IR). Quantitative morphometry showed that similar proportions of islet amyloid were labelled for IAPP and ApoE in monkey islets. ApoE-IR was observed in pancreatic islet cells of non-diabetics. These results suggest that the association of ApoE with amyloid is non-specific for AD or to the component peptide of amyloid fibrils. If ApoE promotes amyloid formation, its synthesis in pancreatic islets could be important for the initiation or the development of pancreatic amyloid in NIDDM.

Alzheimer Disease↗
PubMed2001

Dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type is associated with cerebral amyloid angiopathy but is independent of plaques and neurofibrillary tangles.

Cerebral amyloid angiopathy is frequently found in demented and nondemented elderly persons, but its contribution to the causation of dementia is unknown. Therefore, we investigated the relation between the amount of cerebral amyloid angiopathy and the presence of dementia in 19 patients with hereditary cerebral hemorrhage with amyloidosis-Dutch type. The advantage of studying hereditary cerebral hemorrhage in amyloidosis-Dutch type is that patients with this disease consistently have severe cerebral amyloid angiopathy with minimal neurofibrillary pathology. The amount of cerebral amyloid angiopathy, as quantified by computerized morphometry, was strongly associated with the presence of dementia independent of neurofibrillary pathology, plaque density, or age. The number of cortical amyloid beta-laden severely stenotic vessels, vessel-within-vessel configurations, and cerebral amyloid angiopathy-associated microvasculopathies was associated with the amount of cerebral amyloid angiopathy and dementia. A semiquantitative score, based on the number of amyloid beta-laden severely stenotic vessels, completely separated demented from nondemented patients. These results suggest that extensive (more than 15 amyloid beta-laden severely stenotic vessels in five frontal cortical sections) cerebral amyloid angiopathy alone is sufficient to cause dementia in hereditary cerebral hemorrhage with amyloidosis-Dutch type. This may have implications for clinicopathological correlations in Alzheimer's disease and other dementias with cerebral amyloid angiopathy.

Aged↗
PubMed2004

Glycosylphosphatidylinositol-specific phospholipase D immunoreactivity is present in islet amyloid in type 2 diabetes.

Numerous apolipoproteins associate with amyloid plaques. A minor high-density lipoprotein-associated protein, glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD), has recently been described by the authors and others. Since GPI-PLD is synthesized by, and secreted from, pancreatic islet beta cells, the present study examined the hypothesis that GPI-PLD associates with islet amyloid. GPI-PLD immunoreactivity was examined in pancreatic tissues from type 2 diabetic and non-diabetic humans. GPI-PLD binding to heparan sulphate proteoglycan was determined in the absence or presence of heparan sulphate or heparin. Fibril formation from human islet amyloid polypeptide was determined in the absence or presence of GPI-PLD. In non-diabetics, GPI-PLD immunoreactivity was present and co-localized with insulin, as opposed to co-localizing with amyloid in diabetics. No immunoreactivity for apolipoprotein A-I was present in islet cells or islet amyloid. Heparan sulphate proteoglycan, which is commonly present in most amyloid, bound GPI-PLD in vitro. GPI-PLD inhibited the formation of amyloid fibrils from synthetic islet amyloid polypeptide in vitro. GPI-PLD is therefore present in islet amyloid and appears to derive from local production from islets. This localization likely derives from interaction between GPI-PLD and heparan sulphate proteoglycan. Since GPI-PLD also inhibited islet amyloid polypeptide fibril formation in vitro, it is concluded that GPI-PLD may play a role in islet amyloid formation in type 2 diabetes.

Amyloid↗
PubMed2000

Review: history of the amyloid fibril.

Rudolph Virchow, in 1854, introduced and popularized the term amyloid to denote a macroscopic tissue abnormality that exhibited a positive iodine staining reaction. Subsequent light microscopic studies with polarizing optics demonstrated the inherent birefringence of amyloid deposits, a property that increased intensely after staining with Congo red dye. In 1959, electron microscopic examination of ultrathin sections of amyloidotic tissues revealed the presence of fibrils, indeterminate in length and, invariably, 80 to 100 A in width. Using the criteria of Congophilia and fibrillar morphology, 20 or more biochemically distinct forms of amyloid have been identified throughout the animal kingdom; each is specifically associated with a unique clinical syndrome. Fibrils, also 80 to 100 A in width, have been isolated from tissue homogenates using differential sedimentation or solubility. X-ray diffraction analysis revealed the fibrils to be ordered in the beta pleated sheet conformation, with the direction of the polypeptide backbone perpendicular to the fibril axis (cross beta structure). Because of the similar dimensions and tinctorial properties of the fibrils extracted from amyloid-laden tissues and amyloid fibrils in tissue sections, they have been assumed to be identical. However, the spatial relationship of proteoglycans and amyloid P component (AP), common to all forms of amyloid, to the putative protein only fibrils in tissues, has been unclear. Recently, it has been suggested that, in situ, amyloid fibrils are composed of proteoglycans and AP as well as amyloid proteins and thus resemble connective tissue microfibrils. Chemical and physical definition of the fibrils in tissues will be needed to relate the in vitro properties of amyloid protein fibrils to the pathogenesis of amyloid fibril formation in vivo.

Amyloid↗
PubMed1990

The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down's syndrome and Alzheimer's disease.

The extent of amyloid deposition within the cerebellum and the cerebral cortex was assessed and compared, using anti-amyloid protein (A4) immunostaining and a novel methenamine silver method, in 20 patients aged between 60 and 77 years with Alzheimer's disease (AD), 29 patients aged between 13 and 71 years with Down's syndrome (DS), 26 demented patients with disorders other than AD and DS and in 20 non-demented elderly individuals of age range 60-102 years. In AD, amyloid deposits were noted in the cerebellar cortex in 90% of patients and in the meningeal vessels of the cerebellum in 80% of patients. In DS, amyloid deposits were seen in the cerebellar cortex in 82% of patients over 30 years of age and was universal in patients over 50 years of age. Overall, in DS, amyloid deposits were present in the meningeal vessels of the cerebellum in 79% of patients, but were present in 94% of those patients over 50 years of age. The sites of amyloid deposition in the cerebellar cortex were (poorly) detected by lectin histochemistry (Concanavalin A binding) in only 40% of patients with AD and 43% of all patients with DS (69% of those over 50 years of age). No amyloid deposits were seen in either the cerebellar cortex or its meningeal vessels in any of the 20 non-demented elderly individuals nor in any of the non-Alzheimer demented patients. The cerebellar amyloid deposits were never associated with a neuritic change [i.e. as characterised by the presence of (tau-positive) paired helical filaments (PHF)] and neurofibrillary tangles were seen only in a few cells of the dentate nucleus in a single patient with AD and in three of the elderly DS patients. Amyloid deposits were numerous in the cerebral cortex of all patients with AD and in all, except the 13-year-old patient, with DS. In all the AD patients and in most of the DS patients over 30 years of age, many of the cerebral cortical amyloid deposits were associated with neurites and were strongly recognised by lectin histochemistry. Amyloid deposits were present within the meningeal vessels of the cerebral cortex in 75% patients with AD and 72% of patients, over 30 years of age, with DS (82% of those over 50 years of age). These data indicate that the process of amyloidosis in AD and in elderly DS patients is not restricted to the cerebral cortex and may affect other grey matter regions, particularly the cerebellum.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1990

Islet amyloid polypeptide (amylin): no evidence of an abnormal precursor sequence in 25 type 2 (non-insulin-dependent) diabetic patients.

Islet amyloid polypeptide is the major protein component of the islet amyloid of patients with Type 2 (non-insulin-dependent) diabetes mellitus. Since the synthesis of a structurally abnormal or mutant protein may contribute to the formation of amyloid deposits, we have examined the possibility that a mutant form of islet amyloid polypeptide or its precursor contributes to the formation of islet amyloid in Type 2 diabetic patients. We have sequenced the islet amyloid polypeptide precursor coding regions of the gene of 25 patients with Type 2 diabetes. Genomic DNA fragments corresponding to exon 2 and 3 of the islet amyloid polypeptide gene were amplified from patients' peripheral blood leucocyte DNAs using the polymerase chain reaction and specific oligonucleotide primer sets, and then directly sequenced. The nucleotide sequences of the amplified regions of both alleles of the islet amyloid polypeptide gene of these 25 patients were identical to one another and to the sequence of an islet amyloid polypeptide allele isolated from a human fetal liver genomic library. These findings suggest that a primary structural abnormality of islet amyloid polypeptide or its precursor is unlikely to play a significant role in the formation of islet amyloid in Type 2 diabetic patients.

Amyloid↗
PubMed1999

Amyloid fibril formation is progressive and correlates with beta-cell secretion in transgenic mouse isolated islets.

AIMS/HYPOTHESIS: Amyloid fibrils are formed in islets isolated from transgenic mice expressing the gene for human islet amyloid polypeptide (IAPP) by an unknown mechanism. This model of islet amyloidosis in Type II (non-insulin-dependent) diabetes mellitus has been used to investigate the temporal and glucose dependency of fibril formation. METHODS: To determine the time course and nature of amyloid-like accumulations and the role of glucose, transgenic mouse islets were cultured for 2-12 days in medium containing glucose (4.2 mmol/l, 11.1 mmol/l or 16.7 mmol/l) or 3.3 mmol/l glucose plus non-glucose secretagogues, 10 mmol/l leucine, 10 mmol/l leucine + 0.1 mmol/l tolbutamide, 10 mmol/l alpha-ketoisocaproic acid + 10 mmol/l glutamine. The extent of fibril formation was determined by quantitative immuno-electron microscopy. Insulin and islet amyloid polypeptide secretion into the media was measured by radioimmunoassay. RESULTS: Extracellular amyloid fibrils immunoreactive for islet amyloid polypeptide were visible initially after 6 days of culture in 11.1 mmol/l glucose and formed 2.3 +/- 0.8 % of the islet area after 12 days; small accumulations of intracellular fibrils and amorphous extracellular islet amyloid polypeptide-immunoreactive material were present at 6-12 days. Beta-cell secretion was increased significantly by 16.7 mmol/l glucose and by alpha-ketoisocaproic acid + glutamine. The proportion of fibrillar amyloid (amyloid area/islet area%) correlated with the amount of insulin (r = 0.55, p < 0.05) and IAPP (r = 0.5, p < 0.05) in the culture media. Evidence of cellular damage was present in less than 10 % cells and correlated with the degree of fibril deposition (r = 0.8, p < 0.0001). CONCLUSION/INTERPRETATION: These data suggest that islet amyloid polypeptide amyloid is formed primarily at extracellular sites in isolated transgenic mouse islets and progressive fibril formation correlates with beta-cell secretion. [Diabetologia (1999) 42: 1219-1227]

Amyloid↗
PubMed2001

Islet amyloid polypeptide promotes beta-cell proliferation in neonatal rat pancreatic islets.

AIMS/HYPOTHESIS: We aimed to clarify the role of islet amyloid polypeptide, which is expressed at early embryonic onset, in the proliferation and cell death of neonatal islet cells. METHODS: Fetal islets were prepared from pregnant rats on gestational day 21. Islets were cultured in RPMI 1640 (11.1 mmol/l glucose) + 10 % fetal calf serum (FCS) for 48 h, followed by a 24-h culture period in RPMI 1640 (5.6 mmol/l glucose) + 1 % FCS. The islets were then exposed to rat islet amyloid polypeptide (1-10 nmol/l) for 24 h. RESULTS: Islet amyloid polypeptide increased islet DNA synthesis (dpm/microg of DNA. 6 h) (control 1 % FCS: 3634 +/- 662; 1 nmol/l 6347 +/- 1535; 10 nmol/l 5157 +/- 769; p < 0.05 islet amyloid polypeptide vs control). In accordance with this, a doubling of the autoradiographic labelling index was seen in immunocytochemically stained islet beta cells after exposure to 1 and 10 nmol/l islet amyloid polypeptide. Islet amyloid polypeptide at 1 nmol/l increased the islet insulin content (202 +/- 25 % of control; p < 0.01) and the 24-h medium insulin concentration (1 nmol/l islet amyloid polypeptide: 143 +/- 19 % of control; p < 0.05) but at 10 nmol/l islet amyloid polypeptide these changes did not attain statistical difference. Islet amyloid polypeptide did not have any marked effect on the islet cell death frequency, suggesting that islet amyloid polypeptide is a more potent promoter of proliferation than of programmed cell death. CONCLUSION/INTERPRETATION: Our data indicate islet amyloid polypeptide is a potential regulator of proliferation in neonatal pancreatic islet cells, an effect which can partly be attributed to the proliferation of beta cells.

Amyloid↗
PubMed1989

Alpha 1-antichymotrypsin is present together with the beta-protein in monkey brain amyloid deposits.

The recent finding that the serine protease inhibitor, alpha 1-antichymotrypsin, is tightly associated with the amyloid deposits in brains of normal aged individuals and patients with Alzheimer's disease [Abraham C. R., Selkoe D. J. and Potter H. (1988) Cell 52, 487-501], suggests a role for this inhibitor in the progressive deposition of brain amyloid in humans. We have used immunocytochemistry to detect alpha 1-antichymotrypsin in the amyloid that accumulates in brains of aged monkeys, a naturally occurring animal model of Alzheimer-like neuropathology. In monkeys of increasing age, the earliest alpha 1-antichymotrypsin immunoreactivity was found in cortical perivascular cells, before the appearance of either Thioflavin S-detectable amyloid deposits or beta-protein reactivity in the vessel walls. Subsequently, amyloid deposits appeared in small meningeal blood vessels and cortical neuritic plaques. The oldest monkeys also showed microvascular amyloid in the cortical gray matter. Amyloid was never seen in white matter. The amyloid deposits in meningeal vessels were always positive for both beta-protein and alpha 1-antichymotrypsin, whereas in the cortex, alpha 1-antichymotrypsin immunoreactivity seemed to appear somewhat later than that of beta-protein. These findings demonstrate that two of the brain amyloid components of human senescence and Alzheimer's disease--the beta-protein and the protease inhibitor alpha 1-antichymotrypsin--are also present in the amyloid deposits of normal aged monkey brain. The extended molecular parallels between normal brain aging and Alzheimer's disease suggest that similar biochemical mechanisms may underlie progressive amyloid deposition in both situations.

Aging↗
PubMed2002

Amyloid fibril proteins.

Amyloidosis refers to a group of protein folding diseases. Various innocuous and soluble proteins in physiological conditions polymerize to insoluble amyloid fibrils in several serious diseases, including Alzheimer's disease (AD) and prion diseases. In addition, senile amyloidosis is a form of amyloidosis in which the incidence and severity of amyloid deposition increases with age without any apparent predisposing conditions and it was thought that the amyloidosis was related to some physiological changes which accompany ageing. Although the etiology and pathogenesis of amyloid disease are not fully understood, drastic structural changes of the amyloid proteins from the normal forms to the unique beta-sheet fibrils is the most important event in amyloid diseases. The present article introduces the three amyloid diseases, AD, prion diseases and mouse senile amyloidosis in which Abeta, PrP(Sc) and AApoAII amyloid fibrils deposit respectively. We discuss the nucleation dependent polymerization model as a model that explains the kinetics of fibrillization of these amyloid proteins. Exogenous amyloid fibrils may act as templates (nuclei) and change the conformation of endogenous amyloid protein to polymerize into amyloid fibrils. This hypothesis makes the boundary between transmissible and non-transmissible amyloidosis ambiguous and proposes the common pathogenesis for them.

Aging↗
PubMed1995

Interaction of the anthracycline 4'-iodo-4'-deoxydoxorubicin with amyloid fibrils: inhibition of amyloidogenesis.

All types of amyloidosis are structurally characterized by the cross beta-pleated sheet conformation of the fibrils, irrespective of their biochemical composition. The clinical observation that the anthracycline 4'-iodo-4'-deoxy-doxorubicin (IDOX) can induce amyloid resorption in patients with immunoglobulin light chain amyloidosis was the starting point for this investigation of its possible mechanism of action. IDOX binds strongly to all five types of natural amyloid fibrils tested: immunoglobulin light chains, amyloid A, transthyretin (methionine-30 variant), beta-protein (Alzheimer), and beta 2-microglobulin. Quantitative binding studies showed that IDOX, but not doxorubicin, binds strongly to amyloid fibrils. This binding is saturable and involves two apparently distinct binding sites with Kd values of 5.9 x 10(-11) M and 3.4 x 10(-9) M. IDOX inhibited in vitro insulin amyloid fibrillogenesis. In vivo studies using the experimental amyloid murine model confirmed the specific targeting of IDOX to amyloid deposits. Preincubation of amyloid enhancing factor with IDOX significantly reduced the formation of amyloid deposits. It is hypothesized that IDOX exerts its beneficial effects through the inhibition of fibril growth, thus increasing the solubility of existing amyloid deposits and facilitating their clearance. IDOX may represent the progenitor of a class of amyloid-binding agents that could have both diagnostic and therapeutic potential in all types of amyloidoses.

Amyloid↗
PubMed1996

Beta-amyloid precursor protein. Location of transmembrane domain and specificity of gamma-secretase cleavage.

The formation of beta-amyloid by processing of its precursor protein is a characteristic of Alzheimer's disease. Two proteolytic cleavages produce the amino and carboxyl termini of beta-amyloid, with the latter cleavage site located within the transmembrane domain. Using DNA mutagenesis, we investigated the membrane position and sequence requirements for carboxyl-terminal processing of the beta-amyloid domain. Substitution of negatively charged residues across positions 40-46 of the beta-amyloid domain precluded both beta-amyloid formation and precursor maturation associated with secretory protein transport. In contrast, identical substitutions from positions 48-50 had no adverse effects. Since charged residues typically prevent protein membrane insertion, these data define the membrane boundary to position 46/47, a location allowing greater access to carboxyl-terminal processing of beta-amyloid, possibly without membrane destruction. Deletions within the carboxyl-terminal domain, including 4 residues spanning positions 39-42 of beta-amyloid, resulted in formation of the beta-amyloid peptide. Substituting residues 38-47 or 39-56 of the beta-amyloid domain in the precursor with a transmembrane sequence from another protein yielded a approximately 4-kDa beta-amyloid peptide, reflecting a loose residue specificity for carboxyl-terminal processing to beta-amyloid.

Amino Acid Sequence↗
PubMed1990

Immunohistochemical characterization of cerebrovascular amyloid in 46 autopsied cases using antibodies to beta protein and cystatin C.

Using immunohistochemical staining methods with antibodies to amyloid beta protein and human cystatin C, we examined cerebrovascular amyloid protein in the brains from 46 cases with cerebral amyloid angiopathy (seven with Alzheimer's disease, one with Down's syndrome, 18 with intracranial hemorrhage, 10 with cerebral infarction, and 10 elderly patients without any neurologic disorder). All cerebrovascular amyloid deposits in these 46 cases were consistently immunoreactive to anti-beta protein antibody. However, in nine cases some vascular walls with strong beta protein immunoreactivity also reacted less intensely with the anti-cystatin C antiserum. Of these nine cases, seven showed relatively heavy cerebrovascular amyloid deposition, and all seven had suffered a fatal subcortical hemorrhage presumably caused by cerebral amyloid angiopathy. Previous limited studies have suggested that the amyloid protein seen in elderly individuals with cerebral amyloid angiopathy is composed of beta protein. However, subcortical hemorrhage rarely occurs in such individuals. Our study shows that aged patients with different brain disorders commonly suffer from beta protein-type cerebral amyloid angiopathy, and we also suggest that the severity of beta protein-type cerebrovascular amyloid deposition is a fundamental factor in cerebral amyloid angiopathy-induced brain hemorrhage in the elderly. The nature of the cystatin C-immunoreactive substance in some of these vascular lesions is uncertain, but it might conceivably play an additional important role in the pathogenesis of brain hemorrhage in these cases.

Adult↗