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At least 19 recordsLinked to original sources

PubMed1988

Systemic amyloid deposition in old age and dementia of Alzheimer type: the relationship of brain amyloid to other amyloid.

We investigated amyloid deposition in the brain and other organs in 105 consecutive autopsy cases, aged 59 to 101 years. They consisted of two groups; 15 patients with dementia of Alzheimer type (DAT) and 90 patients without DAT. Amyloid deposition was found in 93% of all cases. The incidence of amyloid deposition increased with age. The number of organs affected with amyloid deposition in each case also increased with age. The incidence of amyloid deposition in each organ was as follows; 88% in pituitary gland, 66% in brain [amyloid of senile plaque (SP) (61%) and/or cerebral amyloid angiopathy (CAA) (56%)], 33% in pancreas, 3% in heart, and less in others. In immunohistochemical studies using the antisera to the various kinds of amyloid or related proteins, amyloid beta protein was demonstrated in brain amyloids including SP and CAA, but not in others. Cardiac amyloid was positive for prealbumin. Pituitary amyloid and CAA were positive for amyloid P-component. The incidence of brain amyloids in DAT were significantly higher than that in non-DAT. There was no significant difference in the incidence of pituitary and pancreatic amyloid between DAT and non-DAT. In the non-DAT patients, there were significant positive correlations in amyloid deposition between the brain and pituitary gland and between the brain and pancreas. Acceleration of amyloid deposition would be a process confined to the brain in the patients with DAT. The pathogenesis of the accelerated deposition of brain amyloids is discussed from the point of view of amyloidosis.

Aged↗

PubMed1982

Immunohistochemical identification and cross reactions of amyloid fibril proteins in senile heart and amyloid in familial polyneuropathy. Lack of reactivity with cerebral amyloid in Alzheimer's disease.

Amyloid fibril proteins in senile cardiac amyloid (ASc1), in familial amyloid polyneuropathy (AF), in congophilic angiopathy, and in Alzheimer's disease were investigated in tissue sections by the indirect immunoperoxidase method using antisera against ASc1, AF, and serum prealbumin (PA). Control antisera were tested against amyloid fibril proteins of the AA- (serum amyloid A-derived), A lambda-, and A kappa-(immunoglobulin light chain-derived)amyloid types. Senile cardiac amyloid was specifically identified in tissue sections with antisera against ASc1, AF, and PA, but not with anti-AA, -A lambda, and -A kappa, thus showing cross-reactivity of ASc1 and AF with each other and with PA, but antigenic differences to the other amyloid types. Likewise, amyloid in AF syndromes, including the Japanese, the German, and the Portuguese types, were stained with anti-AF, anti-ASc1, and anti-PA, but not with the antisera against AA, A lambda, A kappa, again showing common antigenic determinants of AF and ASc1 and PA. This is in agreement with chemical and immunochemical data obtained by others. Cerebral amyloids in microangiopathy and in Alzheimer's disease have also been investigated with these antisera and no reaction was found. The cerebral amyloids, therefore, would appear to be antigenically different from ASc1, AF, AA, A lambda, and A kappa types of amyloid.

Adolescent↗

PubMed1999

A cell culture system for the study of amyloid pathogenesis. Amyloid formation by peritoneal macrophages cultured with recombinant serum amyloid A.

A murine macrophage culture system that is both easy to employ and amenable to manipulation has been developed to study the cellular processes involved in AA amyloid formation. Amyloid deposition, as identified by Congo red-positive, green birefringent material, is achieved by providing cultures with recombinant serum amyloid A2 (rSAA2), a defined, readily produced, and highly amyloidogenic protein. In contrast to fibril formation, which can occur in vitro with very high concentrations of SAA and low pH, amyloid deposition in culture is dependent on metabolically active macrophages maintained in neutral pH medium containing rSAA2 at a concentration typical of that seen in acute phase serum. Although amyloid-enhancing factor is not required, its addition to culture medium results in larger and more numerous amyloid deposits. Amyloid formation in culture is accompanied by C-terminal processing of SAA and the generation of an 8.5-kd fragment analogous to amyloid A protein produced in vivo. Consistent with the possibility that impaired catabolism of SAA plays a role in AA amyloid pathogenesis, treatment of macrophages with pepstatin, an aspartic protease inhibitor, results in increased amyloid deposition. Finally, the amyloidogenicity exhibited by SAA proteins in macrophage cultures parallels that seen in vivo, eg, SAA2 is highly amyloidogenic, whereas CE/J SAA is nonamyloidogenic. The macrophage culture model presented here offers a new approach to the study of AA amyloid pathogenesis.

Amyloid↗

PubMed1998

Serum amyloid P component scintigraphy in familial amyloid polyneuropathy: regression of visceral amyloid following liver transplantation.

Familial amyloid polyneuropathy (FAP) associated with transthyretin (TTR) mutations is the commonest type of hereditary amyloidosis. Plasma TTR is produced almost exclusively in the liver and orthotopic liver transplantation is the only available treatment, although the clinical outcome varies. Serum amyloid P component (SAP) scintigraphy is a method for identifying and quantitatively monitoring amyloid deposits in vivo, but it has not previously been used to study the outcome of visceral amyloid deposits in FAP following liver transplantation. Whole body scintigraphy following injection of iodine-123 labelled SAP was performed in 17 patients with FAP associated with TTR Met30 and in five asymptomatic gene carriers. Follow-up studies were performed in ten patients, eight of whom had undergone orthotopic liver transplantation 1-5 years beforehand. There was abnormal uptake of 123I-SAP in all FAP patients, including the kidneys in each case, the spleen in five cases and the adrenal glands in three cases. Renal amyloid deposits were also present in three of the asymptomatic carriers. Follow-up studies 1-5 years after liver transplantation showed that there had been substantial regression of the visceral amyloid deposits in two patients and modest improvement in three cases. The amyloid deposits were unchanged in two patients. In conclusion, 123I-SAP scintigraphy identified unsuspected visceral amyloid in each patient with FAP due to TTR Met30. The universal presence of renal amyloid probably underlies the high frequency of renal failure that occurs in FAP following liver transplantation. The variable capacity of patients to mobilise amyloid deposits following liver transplantation may contribute to their long-term clinical outcome.

Adult↗

PubMed1989

Absence of the cystatin C amyloid in the cerebral amyloid angiopathy, senile plaque, and extra-CNS amyloid deposits of aged Japanese.

Amyloid protein in Icelandic patients with hereditary cerebral amyloid angiopathy (CAA) is a variant of cystatin C. Immunoreactivities of the cystatin C and other amyloid proteins were investigated in CAA and other senile amyloid deposits in the Japanese sporadic aged cases including patients with dementia of Alzheimer type, and compared with those in Icelandic hereditary CAA. Compared with positive reaction of cystatin C in Icelandic hereditary CAA, no immunoreactivity of cystatin C was found in senile amyloid deposits of the Japanese aged including CAA. Immunoreactivity of the amyloid beta protein was negative in Icelandic hereditary CAA, for which CAA and senile plaque amyloid in the Japanese senile brains were positive. Our data suggest that the cystatin C amyloid would be present only in hereditary CAA, but not in the CAA and other senile amyloid deposits of the sporadic aged cases.

Aged↗

PubMed1992

Characterization of a transthyretin-related amyloid fibril protein from cerebral amyloid angiopathy in type I familial amyloid polyneuropathy.

Recently, it has been reported that transthyretin (TTR)-immunoreactive amyloid deposition with cerebral amyloid angiopathy in central nervous system is a common pathological finding in type I familial amyloid polyneuropathy (FAP). In the present study, we performed isolation and sequence analysis of TTR-related amyloid fibril protein from the meninges of a patient with type I FAP. Purified major amyloid fibril protein had a molecular weight of 15 kDa. Complete sequence analysis revealed that this amyloid fibril protein was a variant TTR with a single amino acid substitution of methionine for valine at position 30. This variant TTR is a previously unrecognized as cerebrovascular amyloid fibril protein. Furthermore, the patients with type I FAP are well known to have the variant TTR in the serum. These suggest that cerebrovascular amyloid fibril protein in type I FAP may derive from a serum precursor.

Amino Acid Sequence↗

PubMed1996

Degradation of serum amyloid A in amyloid-susceptible and amyloid-resistant mouse strains.

Degradation of serum amyloid A (apoSAA) by resident peritoneal cells (RPCS) and conditioned medium (CDM), prepared with RPCS, from amyloid-susceptible CBA/J mice, amyloid-resistant CE/J mice and their amyloid-resistant CBA/J x CE/J F1 progeny was investigated in vitro. Serum amyloid A was derived from murine acute phase (AP) plasma and associated with high density lipoprotein (HDL). Degradation of apoSAA by RPCS and CDM from CBA/J mice was complete while degradation by RPCS and CDM from CE/J mice did not occur. Degradation of apoSAA by RPCS and CDM from CBA/J x CE/J F1 hybrid mice was indistinguishable from that by RPCS and CDM from the CBA/J parent. Intermediate fragments were not detected with either RPCS or CDM from CBA/J mice or CBA/J x CE/J F1 hybrid mice. Degradation of apoSAA was inhibited by phenylmethanylsulfonyl fluoride (PMSF) indicating that the enzyme, secreted into the fluid phase, was a serine esterase. Unlike apoSAA, HDL-associated apoA-1 remained intact. It was thus concluded that while selective degradation of HDL-associated apoSAA (apoSAA-HDL) by RPCS from the CBA/J and CE/J mice was significantly different, the genetic study did not support the hypothesis that there was direct linkage between impaired degradation of apoSAA-HDL in the CE/J mouse strain and protection against amyloid fibril formation. As amyloid resistance in CBA/J x CE/J F1 hybrid mice is not attributable to failure to express the amyloidogenic isoform apoSAA2, the study supports the original hypothesis that amyloid resistance may be linked to expression of apoSAAcej.

Amyloid↗

PubMed1990

Isolation and characterization of cardiac amyloid in familial amyloid polyneuropathy type IV (Finnish): relation of the amyloid protein to variant gelsolin.

Amyloid subunit protein was isolated from familial amyloid polyneuropathy type IV (Finnish type) cardiac tissue and purified to homogeneity. N-terminal amino acid sequence analysis shows that the amyloid protein is a fragment of the inner region of human gelsolin. When compared with the predicted sequence of human plasma gelsolin, the amyloid protein contains an asparagine-for-aspartic acid substitution at position 15 corresponding to residue 187 of the secreted protein. Antibodies raised against the amyloidogenic region of gelsolin specifically stained the amyloid deposited in tissues in familial amyloidosis type IV. The results show that the subunit amyloid protein in familial amyloid polyneuropathy type IV represents a unique type of amyloid derived from a variant (Asn-187) gelsolin molecule by limited proteolysis.

Aged↗

PubMed2001

Analysis of the minimal amyloid-forming fragment of the islet amyloid polypeptide. An experimental support for the key role of the phenylalanine residue in amyloid formation.

The development of type II diabetes was shown to be associated with the formation of amyloid fibrils consisted of the islet amyloid polypeptide (IAPP or amylin). Recently, a short functional hexapeptide fragment of IAPP (NH(2)-NFGAIL-COOH) was found to form fibrils that are very similar to those formed by the full-length polypeptide. To better understand the specific role of the residues that compose the fragment, we performed a systematic alanine scan of the IAPP "basic amyloidogenic units." Turbidity assay experiments demonstrated that the wild-type peptide and the Asn(1) --> Ala and Gly(3) --> Ala peptides had the highest rate of aggregate formation, whereas the Phe(2) --> Ala peptide did not form any detectable aggregates. Dynamic light-scattering experiments demonstrated that all peptides except the Phe(2) --> Ala form large multimeric structures. Electron microscopy and Congo red staining confirmed that the structures formed by the various peptides are indeed amyloid fibrils. Taken together, the results of our study provide clear experimental evidence for the key role of phenylalanine residue in amyloid formation by IAPP. In contrast, glycine, a residue that was suggested to facilitate amyloid formation in other systems, has only a minor role, if any, in this case. Our results are discussed in the context of the remarkable occurrence of aromatic residues in short functional fragments and potent inhibitors of amyloid-related polypeptides. We hypothesize that pi-pi interactions may play a significant role in the molecular recognition and self-assembly processes that lead to amyloid formation.

Alanine↗

PubMed1982

The association of amyloid P-component (AP) with the amyloid fibril: an updated method for amyloid fibril protein isolation.

An amyloid fibril isolation procedure is proposed which uses citrate as well as saline washes to dissociate the calcium dependent linkage of amyloid P-component (AP) from the amyloid fibril. In two amyloid rich tissues, the amount of AP was quantitated in each saline and citrate wash and totalled 13.8% and 20.8% of the amyloid fibrils isolated. The amount of AP removed from these and 22 additional amyloid rich tissues was greater than had previously been recognized. AP protein was present in tissue only when amyloid fibrils were present. It could not be found in normal non-amyloidotic tissue, nor could it be found in tissue sediment after the fibrils were removed.

Amyloid↗

PubMed1986

Circulating serum amyloid P component is the precursor of amyloid P component in tissue amyloid deposits.

Intravenous administration of 125I-labelled isolated mouse serum amyloid P component (SAP) to mice with systemic amyloidosis was followed by specific deposition of the labelled protein in amyloidotic organs. Although only a small proportion of the total injected dose became localized in this way, the amount correlated with the quantity of amyloid present in different organs and was greatest in the spleen. No such localization was detected in the organs of control, untreated mice or animals which had received inflammatory stimuli but did not have amyloidosis. The labelled SAP was found by autoradiography to be present in the same distribution within the tissues as the Congophilic amyloid deposits. These observations establish directly, for the first time, that circulating SAP is the precursor of the amyloid P component (AP) in systemic amyloidosis. They were confirmed by the further finding that intravenous injection into amyloidotic mice of human SAP, either in whole human serum or in isolated pure form, was followed by appearance of the human SAP in the mouse amyloid deposits. In addition to elucidating one aspect of the pathogenesis of amyloid deposition and strengthening the homology of functional behaviour between SAP of different species, the present results suggest a means for selective targeting of diagnostic tracers and/or effector agents to amyloid deposits in vivo.

Amyloidosis↗

PubMed1978

[Amyloid transfer from a syngenous transplant of amyloid spleen in intact and amyloid mice].

Investigations were carried out on male CBA mice with casein-induced amyloidosis. Fragments of spleens from the amyloid and intact donors were transplanted simultaneously to the opposite kidney poles, subcapsularly, to the intact and amyloid recipients. Amyloid deposits were found in 40 per cent of intact recipients both in their own spleens and in the grafts from intact donors. In amyloid recipients amyloid deposits developed in the grafts from intact donors only in 5 per cent of the animals (observation periods from 5 days to 6 months after the transplantation). It is amyloidogenic cells migration and the depression of this mechanism in amyloid mice.

Amyloidosis↗

PubMed1996

C-terminal fragments of alpha- and beta-tubulin form amyloid fibrils in vitro and associate with amyloid deposits of familial cerebral amyloid angiopathy, British type.

Familial amyloidosis, British type, is an autosomal dominant disease characterized by progressive dementia, spastic paralysis and ataxia. The identity of the accumulating amyloid is not known, thus preventing the definitive classification of the disease. Biochemical methods were used to characterize the nature of the amyloid deposits from the brain tissue of one individual who died with this disease. The purified tissue material was subjected to trypsin digestion and subsequent N-terminal sequence analysis. Major tryptic fragments yielded the sequences VGINYQPPTVVPGGDLAK, FDLMYAK, GLTVPEL and GYLTVAAVFR, which are all tryptic fragments of the C-termini of human tubulin subunits alpha and beta. Synthetic peptides based on the sequences of these fragments formed amyloid fibrils in vitro fitting the characteristic definition of amyloid. These findings suggest that the C-terminal fragments of both alpha- and beta-tubulin are closely associated to the amyloid deposits of familial amyloidosis, British type.

Amino Acid Sequence↗

PubMed2003

The human amyloid-beta precursor protein770 mutation V717F generates peptides longer than amyloid-beta-(40-42) and flocculent amyloid aggregates.

One of the familial forms of Alzheimer's disease (AD) encodes the amyloid-beta precursor protein (AbetaPP) substitution mutation V717F. This mutation is relevant to AD research, since it has been utilized to generate transgenic mice models to study AD pathology and therapeutic interventions. Amyloid beta (Abeta) peptides were obtained from the cerebral tissue of three familial AD subjects carrying the AbetaPP V717F mutation. A combination of ultracentrifugation, size-exclusion, and reverse-phase high performance liquid chromatography, tryptic and cyanogen bromide hydrolysis, amino acid analysis, and matrix-assisted laser desorption ionization and surface-enhanced laser desorption ionization mass spectrometry was used to characterize the familial AD mutant Abeta peptides. The AbetaPP V717F mutation, located 4-6 residues beyond the wild-type AbetaPP gamma-secretase cleavage site, yielded longer Abeta peptides with C termini between residues 43 and 54. In the cerebral cortex these peptides aggregated into thin water- and SDS-insoluble amyloid bundles that condensed into flocculent spherical plaques. In the leptomeningeal arteries the amyloid was deposited in moderate amounts and was primarily composed of the shorter and more soluble Abeta species ending at residues 40, 42, and 44. The single V717F mutation in AbetaPP results in distinctive and drastic changes in the length and tertiary structure of Abeta peptides, which appear to be responsible for the earlier clinical manifestations of dementia and death of these patients.

Amino Acids↗

PubMed1995

Co-localization of amyloid-associated proteins with amyloid beta in rat soleus muscle in chloroquine-induced myopathy: a possible model for amyloid beta formation in Alzheimer's disease.

Chloroquine, a potent lysosomotropic agent, induces myopathy in experimental animals similar to rimmed vacuole (RV) myopathy in humans. The abnormal accumulation of amyloid beta protein (A beta), which is the invariable pathological alterations in the brains affected by Alzheimer's disease (AD), has been demonstrated in denervated soleus muscle fibers in chloroquine-induced myopathy in rats. In AD affected brains, a variety of additional proteins are associated with the extracellular deposition of A beta, which leads to the intracellular accumulation of neurofibrillary tangles and finally to neuronal death. In this study, we demonstrate that amyloid-associated proteins, alpha 1-antichymotrypsin, apolipoprotein E, SP-40,40 and ubiquitin co-localize with A beta in vacuolated muscle fibers in chloroquine-induced myopathy. There are striking similarities in immunopathology between experimental RV myopathy and AD. Chloroquine-induced myopathy in rats provides a suitable model not only to obtain insight into the basic mechanisms underlying RV formation in muscle, but also to understand amyloid precursor protein processing into A beta, and the role of amyloid-associated proteins in terms of the pathogenesis of AD.

Alzheimer Disease↗

PubMed1998

In vitro amyloid fibril formation by synthetic peptides corresponding to the amino terminus of apoSAA isoforms from amyloid-susceptible and amyloid-resistant mice.

Specific proteins of the apolipoprotein serum amyloid (apoSAA) family that are synthesized in large quantities during the acute, early phase of inflammation can serve as the proteinaceous precursors for amyloid fibrils. To model fibrillogenesis in such inflammatory diseases, we have used electron microscopy and X-ray diffraction to examine the structures formed by synthetic peptides corresponding in sequence to the 11 amino-terminal amino acids of murine apoSAA1, apoSAAcej, and apoSAA2 and to the 15 amino-terminal amino acids of apoSAA2. This region is reported to be the major fibrillogenic determinant of apoSAA isoforms. Both in 1 mM Tris buffer and in 35% acetonitrile, 0.1% trifluoracetic acid (ACN/TFA), all of the peptides formed macromolecular assemblies consisting of twisted, approximately 40- to 60-A-thick ribbons, which varied in width from around 40-70 A (for 11-mer apoSAA2 in Tris) up to 900 A (for the other peptides). X-ray diffraction patterns recorded from lyophilized peptides, vapor-hydrated samples, and solubilized/dried samples showed hydrogen bonding and intersheet reflections typical of a beta-pleated sheet conformation. The coherent lengths measured from the breadths of the X-ray reflections indicated that with hydration the growth of the assemblies in the intersheet stacking direction was comparable to that in the hydrogen-bonding direction, and analysis of oriented samples showed that the beta-strands were oriented perpendicular to both the long axis and the face of the assemblies. These X-ray results are consistent with the ribbon- or plate-like morphology of the individual aggregates and emphasize the polymorphic nature of amyloidogenic peptides. Our findings demonstrate that X-ray diffraction measurements on vapor-hydrated or solubilized/dried versus lyophilized, amyloidogenic peptides are a good indicator of their fibrillogenic potential. For example, from the highest to the lowest potential, the peptides examined here were ranked as: Abeta1-28 > Abeta1-40 > apoSAA1 approximately apoSAAcej > apoSAA2 > Abeta17-42. Experiments in which the three different 11-mer apoSAA isoforms were solubilized in ACN/TFA and then combined as binary mixtures showed that the ribbon morphology was not affected but that the extent of hydrogen bonding in the assemblies was substantially reduced. Our observations on the in vitro assembly of apoSAA analogs emphasize that amyloid fibril formation and morphology depend on primary sequence, length of polypeptide chain, the presence of additional fibrillogenic polypeptides, and solvent conditions.

Amino Acid Sequence↗

PubMed1998

A unique amyloidogenic apolipoprotein serum amyloid A (apoSAA) isoform expressed by the amyloid resistant CE/J mouse strain exhibits higher affinity for macrophages than apoSAA1 and apoSAA2 expressed by amyloid susceptible CBA/J mice.

CBA/J and other inbred strains of mice that express the amyloidogenic apolipoprotein serum amyloid A (apoSAA) apoSAA2, together with apoSAA1, are susceptible to amyloid A (AA) amyloidosis, whereas CE/J mice that express a single unique isoform, apoSAACEJ, are resistant. Studies indicate that CBA/JxCE/J hybrid mice that express apoSAA2 in the presence of apoSAACEJ are protected from amyloidogenesis. To define a mechanism by which expression of apoSAACEJ may protect from AA formation in the presence of apoSAA2, binding of recombinant apoSAA (r-apoSAA) isoforms, validated by N-terminal sequencing, to a murine macrophage cell line was investigated. Maximal specific binding occurred after incubation of radiolabeled apoSAA with IC-21 macrophages (1x105 cells/ml) for 30 min at 4 degreesC. The binding of 125I-r-apoSAA1, 125I-r-apoSAA2 and 125I-r-apoSAACEJ was specific and saturable, with an affinity (Kd) of about 2.8, 3.2 and 1.3 nM, respectively, and approximately 2-4x106 sites per cell. Competitive binding experiments indicate apoSAACEJ binds with higher affinity to macrophages than does either apoSAA1 or apoSAA2. We suggest that greater cellular affinity of apoSAACEJ compared to apoSAA2 may contribute to protection from AA amyloid in certain CBA/JxCE/J hybrid mice by interfering with interaction of apoSAA2 by macrophages and hence either membrane associated or intracellular degradation.

Amyloidosis↗

PubMed1999

Expression of beta-amyloid precursor protein-CD3gamma chimeras to demonstrate the selective generation of amyloid beta(1-40) and amyloid beta(1-42) peptides within secretory and endocytic compartments.

Amyloid beta-protein (Abeta) is the main constituent of amyloid fibrils found in senile plaques and cerebral vessels in Alzheimer's disease (AD) and is derived by proteolysis from the beta-amyloid precursor protein (APP). We have analyzed the amyloidogenic processing of APP using chimeric proteins stably transfected in Chinese hamster ovary cells. The extracellular and transmembrane domains of APP were fused to the cytoplasmic region derived from the CD3 gamma chain of the T cell antigen receptor (CD3gamma). CD3gamma contains an endoplasmic reticulum (ER) retention motif (RKK), in the absence of which the protein is targeted to lysosomes without going through the cell surface (Letourneur, F., and Klausner, R.D. (1992) Cell 69, 1143-1157). We used the wild-type sequence of CD3gamma to create an APP chimera predicted to remain in the ER (gammaAPP(ER)). Deletion of the RKK motif at the C terminus directed the protein directly to the lysosomes (gammaAPP(LYS)). A third chimera was created by removing both lysosomal targeting signals in addition to RKK (gammaAPP(DeltaDelta)). This last construct does not contain known targeting signals and consequently accumulates at the cell surface. We show by immunofluorescence and by biochemical methods that all three APP chimeras localize to the predicted compartments within the cell, thus providing a useful model to study the processing of APP. We found that Abeta(1-40) is generated in the early secretory and endocytic pathways, whereas Abeta(1-42) is made mainly in the secretory pathway. More importantly, we provide evidence that, unlike in neuronal models, both ER/intermediate compartment- and endocytic-derived Abeta forms can enter the secretable pool. Finally, we directly demonstrate that lysosomal processing is not involved in the generation or secretion of either Abeta(1-40) or Abeta(1-42).

Amino Acid Sequence↗