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PubMed1991

Isolation and characterization of the integral glycosaminoglycan constituents of human amyloid A and monoclonal light-chain amyloid fibrils.

Amyloid fibrils were isolated by extraction in water from the livers and spleens of four patients who had died of monoclonal, light-chain (AL)-type, systemic amyloidosis and one with reactive systemic, amyloid A protein (AA)-type amyloidosis. Each fibril preparation contained 1-2% by weight of glycosaminoglycan (GAG) which was tightly associated with the fibrils and not just co-isolated from the tissues with them. After exhaustive digestion of the fibrils with papain and Pronase, the GAGs were specifically precipitated with cetylpyridinium chloride and were identified by cellulose acetate electrophoresis and selective susceptibility to specific glycosidases. All the preparations contained approximately equal amounts of heparan sulphate and dermatan sulphate. There was no evidence for the presence of chondroitin sulphate or other GAGs. Fine structural analysis by oligosaccharide mapping in gradient polyacrylamide gels, following partial digestion with specific glycosidases, showed very similar structures among the heparan sulphates and the dermatan sulphates, respectively. GAGs were also extracted by solubilizing amyloid fibrils in 4 M-guanidinium chloride followed by CsCl density-gradient ultracentrifugation. Although a minor proportion of the GAG material obtained in this way was apparently in the form of proteoglycan molecules, most of it was free GAG chains. The presence in amyloid fibrils of different types, in different organs and from different patients of particular GAG classes with similar structures supports the view that these molecules may be of pathogenic significance.

Amyloidosis↗
PubMed1998

A novel assay in vitro of human islet amyloid polypeptide amyloidogenesis and effects of insulin secretory vesicle peptides on amyloid formation.

Human islet amyloid polypeptide (IAPP) is a 37-residue peptide that is co-secreted with insulin by the beta-cell and might be involved in the pathogenesis of non-insulin-dependent diabetes mellitus. We developed an improved assay in vitro based on the fluorescence of bound thioflavin T to study factors affecting amyloidogenesis. Monomeric IAPP formed amyloid fibrils, as detected by increased fluorescence and by electron microscopy. Fluorimetric analysis revealed that the initial rate of amyloid formation was: (1) proportional to the peptide monomer concentration, (2) maximal at pH 9.5, (3) maximal at 200 mMKCl, and (4) proportional to temperature from 4 to 37 degreesC. We found that 5-fold and 10-fold molar excesses of proinsulin inhibited fibril formation by 39% and 59% respectively. Insulin was somewhat more potent with 5-fold and 10-fold molar excesses inhibiting fibril formation by 69% and 73% respectively, whereas C-peptide had no effect at these concentrations. Thus at physiological ratios of IAPP to insulin, insulin and proinsulin, but not C-peptide, can retard amyloidogenesis. Because insulin resistance or hyperglycaemia increase the IAPP-to-insulin ratio, increased intracellular IAPP compared with insulin expression in genetically predisposed individuals might contribute to intracellular amyloid formation, beta-cell death and the genesis of non-insulin-dependent diabetes mellitus.

Amyloid↗
PubMed2004

Amyloid-beta protofibrils differ from amyloid-beta aggregates induced in dilute hexafluoroisopropanol in stability and morphology.

The brains of Alzheimer's disease (AD) patients contain large numbers of amyloid plaques that are rich in fibrils composed of 40- and 42-residue amyloid-beta (Abeta) peptides. Several lines of evidence indicate that fibrillar Abeta and especially soluble Abeta aggregates are important in the etiology of AD. Recent reports also stress that amyloid aggregates are polymorphic and that a single polypeptide can fold into multiple amyloid conformations. Here we demonstrate that Abeta-(1-40) can form soluble aggregates with predominant beta-structures that differ in stability and morphology. One class of aggregates involved soluble Abeta protofibrils, prepared by vigorous overnight agitation of monomeric Abeta-(1-40) at low ionic strength. Dilution of these aggregation reactions induced disaggregation to monomers as measured by size exclusion chromatography. Protofibril concentrations monitored by thioflavin T fluorescence decreased in at least two kinetic phases, with initial disaggregation (rate constant approximately 1 h(-1)) followed by a much slower secondary phase. Incubation of the reactions without agitation resulted in less disaggregation at slower rates, indicating that the protofibrils became progressively more stable over time. In fact, protofibrils isolated by size exclusion chromatography were completely stable and gave no disaggregation. A second class of soluble Abeta aggregates was generated rapidly (<10 min) in buffered 2% hexafluoroisopropanol (HFIP). These aggregates showed increased thioflavin T fluorescence and were rich in beta-structure by circular dichroism. Electron microscopy and atomic force microscopy revealed initial globular clusters that progressed over several days to soluble fibrous aggregates. When diluted out of HFIP, these aggregates initially were very unstable and disaggregated completely within 2 min. However, their stability increased as they progressed to fibers. Relative to Abeta protofibrils, the HFIP-induced aggregates seeded elongation by Abeta monomer deposition very poorly. The techniques used to distinguish these two classes of soluble Abeta aggregates may be useful in characterizing Abeta aggregates formed in vivo.

Alzheimer Disease↗
PubMed2005

Amyloid fibril formation of alpha-synuclein is accelerated by preformed amyloid seeds of other proteins: implications for the mechanism of transmissible conformational diseases.

Alpha-synuclein is one of the causative proteins of familial Parkinson disease, which is characterized by neuronal inclusions named Lewy bodies. Lewy bodies include not only alpha-synuclein but also aggregates of other proteins. This fact raises a question as to whether the formation of alpha-synuclein amyloid fibrils in Lewy bodies may occur via interaction with fibrils derived from different proteins. To probe this hypothesis, we investigated in vitro fibril formation of human alpha-synuclein in the presence of preformed fibril seeds of various different proteins. We used three proteins, Escherichia coli chaperonin GroES, hen lysozyme, and bovine insulin, all of which have been shown to form amyloid fibrils. Very surprisingly, the formation of alpha-synuclein amyloid fibril was accelerated markedly in the presence of preformed seeds of GroES, lysozyme, and insulin fibrils. The structural characteristics of the natively unfolded state of alpha-synuclein may allow binding to various protein particles, which in turn triggers the formation (extension) of alpha-synuclein amyloid fibrils. This finding is very important for understanding the molecular mechanism of Parkinson disease and also provides interesting implications into the mechanism of transmissible conformational diseases.

Amyloid↗
PubMed1999

Primary amyloid tumor (amyloidoma) of the jejunum with spheroid type of amyloid.

The present report documents an incidentally discovered, solitary amyloidoma of the jejunum in a 70 year old man with no predisposing disorder or other sites of deposition of amyloid, as was demonstrated at autopsy. Amyloid tumors of the intestine have been reported only rarely. In those reports the deposits were conventional in type, forming large masses of acellular, eosinophilic, homogeneous material. In the case described here the deposits were in the form of corpora amylacea-like structures, or spheroids. To the best of our knowledge, the corpora amylacea-like structures, or spheroid amyloid, have not been previously described in bowel amyloidoma. This rare form of amyloid deposition should be recognized so as to prevent misdiagnosis.

Aged↗
PubMed1995

Correlation among secondary structure, amyloid precursor protein accumulation, and neurotoxicity of amyloid beta(25-35) peptide as analyzed by single alanine substitution.

Structure-neurotoxicity relationships of amyloid beta (25-35) peptide were studied by replacing each amino acid with Ala. In contrast to the general tendency in hydrophobicity-toxicity relationships, replacement of Asn27 yielded a more hydrophobic but less toxic analog and that of Met35 gave a less hydrophobic but more toxic one. Sedimentation profiles and CD spectra indicated that peptide aggregation via intermolecular beta-sheet formation is essential for the neurotoxicity of amyloid beta (25-35) peptide. The correlation between neurotoxicity and amyloid precursor protein accumulation suggested that the latter is one of the pathways of the neuronal death caused by amyloid beta protein.

Alanine↗
PubMed1999

Molecular modeling of the amyloid-beta-peptide using the homology to a fragment of triosephosphate isomerase that forms amyloid in vitro.

The main component of the amyloid senile plaques found in Alzheimer's brain is the amyloid-beta-peptide (A beta), a proteolytic product of a membrane precursor protein. Previous structural studies have found different conformations for the A beta peptide depending on the solvent and pH used. In general, they have suggested an alpha-helix conformation at the N-terminal domain and a beta-sheet conformation for the C-terminal domain. The structure of the complete A beta peptide (residues 1-40) solved by NMR has revealed that only helical structure is present in A beta. However, this result cannot explain the large beta-sheet A beta aggregates known to form amyloid under physiological conditions. Therefore, we investigated the structure of A beta by molecular modeling based on extensive homology using the Smith and Waterman algorithm implemented in the MPsrch program (Blitz server). The results showed a mean value of 23% identity with selected sequences. Since these values do not allow a clear homology to be established with a reference structure in order to perform molecular modeling studies, we searched for detailed homology. A 28% identity with an alpha/beta segment of a triosephosphate isomerase (TIM) from Culex tarralis with an unsolved three-dimensional structure was obtained. Then, multiple sequence alignment was performed considering A beta, TIM from C.tarralis and another five TIM sequences with known three-dimensional structures. We found a TIM segment with secondary structure elements in agreement with previous experimental data for A beta. Moreover, when a synthetic peptide from this TIM segment was studied in vitro, it was able to aggregate and to form amyloid fibrils, as established by Congo red binding and electron microscopy. The A beta model obtained was optimized by molecular dynamics considering ionizable side chains in order to simulate A beta in a neutral pH environment. We report here the structural implications of this study.

Algorithms↗
PubMed2004

Generation of amyloid A protein by the cell lines from amyloid-susceptible and -resistant mice.

It has been proposed that impaired degradation is the cause of amyloid A (AA) formation in reactive amyloidosis (Ham et al., Scand J Immunol 1997; 45: 354-60). The current SDS-PAGE of the culture medium showed that the macrophage cell line from the amyloid-susceptible mouse strain (ANA1) degraded amyloid precursor protein serum amyloid A into the AA-like amyloidogenic product of approximately 8.6 kDa but went no further, whereas cells from the resistant strain (A/J10) cleared the AA-like derivates proceeding to approximately 7.7 kDa products within the incubation period. Degradation occurred in the chemically defined medium at a slower rate than in the medium with serum. This may imply that a lack of the serum components as well as impaired degradation could contribute to the development of amyloidosis.

Amyloidosis↗
PubMed2006

The functions of mammalian amyloid precursor protein and related amyloid precursor-like proteins.

It is well established that proteolytic processing of the beta-amyloid precursor protein (APP) generates beta-amyloid which plays a central role in the pathogenesis of Alzheimer's disease. In contrast, the physiological role of APP and the question of whether a loss of these functions contributes to Alzheimer's disease are still unclear. For a long time, the characterization of APP functions was markedly hampered by the high redundancy between APP and the related APP family members amyloid precursor-like proteins 1 and 2. The generation and analyses of combined gene deficiencies for APP and amyloid precursor-like proteins in mice finally marked the beginning of uncovering the in vivo roles of these proteins in mammals. In the current review, we summarize recent insights into the functions of the APP gene family from mice lacking one, two or all three family members.

Amyloid beta-Protein Precursor↗
PubMed1982

Gastrointestinal amyloid deposition in familial amyloid polyneuropathy.

We found degeneration of enteric nerve plexuses in two patients with type I familial amyloid polyneuropathy. Amyloid deposition was more severe in the wall of the stomach than in the rectum. Hypomotility of the upper gastrointestinal tract, resulting from both amyloid deposition in the stomach and upper bowel and degeneration of the intrinsic autonomic nerves, may be responsible for anorexia, nausea, and vomiting. Diarrhea and constipation may be caused by degeneration of the enteric nerve plexuses. Gastric biopsy is valuable and safe in the diagnosis to type I familial amyloid polyneuropathy.

Adolescent↗
PubMedDate not supplied

Amyloidosis (AA type) with gastrointestinal involvement: resolution of gastric amyloid deposition in parallel with disappearance of the serum component of amyloid A protein.

The prognosis for secondary amyloidosis is better than that for the primary form. With arrest of the triggering disease, clinical improvement can be expected. Dramatic resolution of amyloid deposits, as proven by repeated biopsies, has been reported. We report on the effectiveness of amputation of the left thigh with chronic osteomyelitis in a patient with AA amyloidosis presenting with extensive amyloid involvement of the gastrointestinal tract and kidneys. Clinical improvement associated with reversibility of gastric amyloid deposition was observed in accordance with disappearance of the serum component of amyloid A protein.

Adult↗
PubMed2002

Conformational changes preceding amyloid-fibril formation of amyloid-beta and stefin B; parallels in pH dependence.

Amyloid beta (A beta) protein is the key component of amyloid plaques in Alzheimer's disease brain whereas stefin B is an intracellular cysteine proteinase inhibitor, broadly distributed in different tissue and recently reported to form amyloid fibrils in vitro. By reducing the pH to 4.6, the native conformation of both polypeptides are changed into less ordered metastable intermediates that are stabilized by formation of the more stable fibrils. In A beta, the Glu at position 11 was found to be responsible for the conformational change at pH 4.6. Metal ions, including copper and zinc, could also induce conformational changes of A beta at neutral pH. The acid modified A beta conformer exhibited protease K resistance, preferential internalization and accumulation in the human glial cells. In stefin B, reducing the pH to pH 3.3 results in another intermediate of the molten-globule type which also leads to amyloid fibril formation. Multiple sequence alignment revealed distinct similarities of A beta (1-42) peptide, stefin B (13 to 61 residues) and prion fragment (90 to 144 residues).

Amino Acid Sequence↗
PubMed2002

Amyloid-associated neuron loss and gliogenesis in the neocortex of amyloid precursor protein transgenic mice.

APP23 transgenic mice express mutant human amyloid precursor protein and develop amyloid plaques predominantly in neocortex and hippocampus progressively with age, similar to Alzheimer's disease. We have previously reported neuron loss in the hippocampal CA1 region of 14- to 18-month-old APP23 mice. In contrast, no neuron loss was found in neocortex. In the present study we have reinvestigated neocortical neuron numbers in adult and aged APP23 mice. Surprisingly, results revealed that 8-month-old APP23 mice have 13 and 14% more neocortical neurons compared with 8-month-old wild-type and 27-month-old APP23 mice, respectively. In 27-month-old APP23 mice we found an inverse correlation between amyloid load and neuron number. These results suggest that APP23 mice have more neurons until they develop amyloid plaques but then lose neurons in the process of cerebral amyloidogenesis. Supporting this notion, we found more neurons with a necrotic-apoptotic phenotype in the neocortex of 24-month-old APP23 mice compared with age-matched wild-type mice. Stimulated by recent reports that demonstrated neurogenesis after targeted neuron death in the mouse neocortex, we have also examined neurogenesis in APP23 mice. Strikingly, we found a fourfold to sixfold increase in newly produced cells in 24-month-old APP23 mice compared with both age-matched wild-type mice and young APP23 transgenic mice. However, subsequent cellular phenotyping revealed that none of the newly generated cells in neocortex had a neuronal phenotype. The majority were microglial and to a lesser extent astroglial cells. We conclude that cerebral amyloidosis in APP23 mice causes a modest neuron loss in neocortex and induces marked gliogenesis.

Aging↗
PubMed1991

Immunohistochemical colocalization of amyloid precursor protein with cerebrovascular amyloid of Alzheimer's disease.

Molecular cloning and cDNA sequencing have indicated that the fibril-forming, amyloidogenic beta/A4 peptide of cerebrovasculature and plaque core in AD is encoded as part of a larger precursor, amyloid precursor protein (APP). A panel of antibodies directed against synthetic peptides, which correspond to distinct domains of this putative APP molecule (i.e., amino acid residues 45-62, 587-596, 597-606, 597-638 [beta/A4 peptide], 638-658 and 653-661), were used to probe immunohistochemically serial sections of formalin-fixed, paraffin-embedded Alzheimer's disease (AD) brains for the presence of APP and/or its derivatives. Histochemical staining of adjacent sections with Bielschowsky's silver impregnation and with Congo red or thioflavin S-staining techniques was also done to identify the structures with amyloid deposition. All these antibodies exhibited intense immunoreactivity with amyloidotic cerebral vessels, including meningeal and parenchymal. This observation indicates that the amyloidotic vasculature of AD brain contains, in addition to the fibril-forming beta/A4 protein, nonamyloidogenic APP and/or its derivatives. More importantly, this APP immunoreactivity colocalized with angiopathic amyloid, which is characterized by phenol-resistant, birefringent congophilia. Parallel analyses with a dual SABC/silver impregnation procedure further confirmed that APP and/or its derivatives, including the amyloidogenic beta/A4, colocalized with argentophilic amyloid in the cerebrovasculature of AD.

Alzheimer Disease↗
PubMed1991

The primary structure of serum amyloid A protein in the rabbit: comparison with serum amyloid A proteins in other species.

Rabbit serum amyloid A (SAA) protein was isolated from acute-phase serum by ultracentrifugation, molecular seive chromatography, and ion-exchange chromatography. The complete amino acid sequence of the protein was established by sequence analysis of peptides derived from trypsin and Staphylococcus proteinase digestion of the protein. The molecule consisted of 104 amino acids and had an amino terminus that was blocked by pyrrolidonecarboxylic acid. Heterogeneity was not observed at any residue, which suggests that the material sequenced consisted of a single serum amyloid A species. The protein is highly homologous to serum amyloid A from humans and other animals, particularly in the middle portion of the molecule (positions 33 to 63), which suggests that this region may be important in its function. This highly conserved region may also contain the determinants for amyloid formation.

Amino Acid Sequence↗
PubMed1989

Differential induction of the serum amyloid A gene family in response to an inflammatory agent and to amyloid-enhancing factor.

The murine serum amyloid A1 (SAA1), SAA2, and SAA3 genes are expressed in various tissues in response to acute inflammation. Prolonged expression may be accompanied by amyloid deposition in liver, spleen, and kidney. Shortly before and during deposition, an amyloid-enhancing factor (AEF) can be extracted from these tissues which accelerates amyloid formation when administered with an inflammatory agent. We have investigated the ability of liver AEF to alter expression of the three SAA genes in liver, spleen, and kidney when administered to normal mice or to mice in which inflammation was created with the injection of silver nitrate. In liver, both AEF and silver nitrate induce SAA1 and SAA2 mRNA accumulation. However, AEF elicits a more rapid response and also acts as a potent inducer of hepatic SAA3 mRNA. Silver nitrate does not induce any SAA mRNA species in kidney, whereas AEF induces all three species. In contrast, AEF induces only SAA3 mRNA in the spleen. We also show that the elevation in hepatic SAA mRNA levels induced by either AEF or silver nitrate is associated with a transient increase in the length of the poly(A) tail.

Animals↗
PubMed1989

Serum amyloid A gene expression and AA amyloid formation in A/J and SJL/J mice.

Serum amyloid A (SAA) gene expression and AA amyloid fibril formation were studied in A/J and SJL/J mice, two strains which have been reported to possess defects in AA fibril formation. Four types of inflammatory stimulation were employed: acute inflammation stimulated with lipopolysaccharide (LPS), chronic inflammation with casein in complete Freund's adjuvant, amyloidosis with injection of amyloid enhancing factor (AEF) together with casein in complete Freund's adjuvant, and non-amyloidogenic inflammation in the presence of AEF with injection of AEF together with LPS. Both A/J and SJL/J mice developed splenic amyloidosis 1 day after initiation of chronic inflammation in the presence of AEF. No amyloid deposits were detected during any of the other types of inflammation. Amyloidotic mice exhibited decreased amounts of SAA mRNA in liver and spleen concomitant with decreased amounts of SAA in serum. Alpha-I-acid glycoprotein mRNA was present in liver throughout the course of AEF accelerated amyloidosis, indicating that decreased SAA gene expression and AA fibril formation is not part of a general inhibitory effect of AEF on protein synthesis.

Animals↗
PubMed1996

Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency.

Experimental thiamine deficiency (TD) is a classical model of a nutritional deficit associated with a generalized impairment of oxidative metabolism and selective cell loss in the brain. In rats, TD-induced cell degeneration is accompanied by an accumulation of amyloid precursor protein (APP)/amyloid precursor-like protein 2 (APLP2) immunoreactivity in abnormal neurites and perikarya along the periphery of, or scattered within, the lesion. Prompted by these data and our previous findings of a genetic variation in the development of TD symptoms, we extended our studies to mice. C57BL/6, ApoE knockout, and APP YAC transgenic mice received thiamine-deficient diet and pyrithiamine injections. Unlike rats, APP/APLP2-immunoreactive neurites in all strains of mice were sparsely scattered within damaged areas and did not delimit the thalamic lesion. In addition, abnormal clusters of intensely immunoreactive neurites occurred only in areas of damage including the thalamus, mammillary body, and inferior colliculus. The clusters appeared as either irregular clumps or round or oval rosettes that strikingly resembled the neuritic component of Alzheimer amyloid plaques. However, immunostaining using various antisera to synthetic amyloid beta-protein (A beta 1-40) and thioflavine S histochemistry failed to show evidence of a component of A beta Neither APP/APLP2-immunoreactive clusters nor amyloid plaques were observed in the brain from patients with Wernicke-Korsakoff syndrome, the clinical manifestation of TD in man. Our results demonstrate species (i.e., genetic) differences in the response to TD-induced damage and support a role for APP and APLP2 in the response to brain injury. This is the first report that chronic oxidative deficits can lead to this novel pathology.

Amyloid beta-Protein Precursor↗