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PubMed1991

Amyloid beta-protein in cerebral amyloid angiopathy, senile plaques, and preamyloidotic lesions in subcortical arteriosclerotic encephalopathy (Binswanger disease).

Cerebral vascular amyloid deposits, senile plaques and neurofibrillary tangles have been found in subcortical arteriosclerotic encephalopathy (Binswanger disease). A mouse antiserum, prepared against a 43-amino acid synthetic peptide homologous to the amyloid beta-protein of Alzheimer disease (anti-SP43), revealed immunoreactive amyloid deposits in meningeal and intracortical blood vessels, senile plaques, intraneuronal amyloid and preamyloid in a neuropathologically confirmed case of Binswanger disease previously reported to have cerebral vascular amyloid deposits. These lesions contained sulfated glycosaminoglycans as determined by the Alcian blue/critical electrolyte concentration method. Similar findings were not observed in a case of Binswanger encephalopathy without cerebral amyloid deposits. Our study indicates that amyloidotic lesions in Binswanger encephalopathy with cerebral amyloid deposits contain amyloid beta-protein and sulfated glycosaminoglycans.

Amyloid beta-Peptides↗

PubMed2004

Does the cytotoxic effect of transient amyloid oligomers from common equine lysozyme in vitro imply innate amyloid toxicity?

In amyloid diseases, it is not evident which protein aggregates induce cell death via specific molecular mechanisms and which cause damage because of their mass accumulation and mechanical properties. We showed that equine lysozyme assembles into soluble amyloid oligomers and protofilaments at pH 2.0 and 4.5, 57 degrees C. They bind thioflavin-T and Congo red similar to common amyloid structures, and their morphology was monitored by atomic force microscopy. Molecular volume evaluation from microscopic measurements allowed us to identify distinct types of oligomers, ranging from tetramer to octamer and 20-mer. Monomeric lysozyme and protofilaments are not cytotoxic, whereas the oligomers induce cell death in primary neuronal cells, primary fibroblasts, and the neuroblastoma IMR-32 cell line. Cytotoxicity was accessed by ethidium bromide staining, MTT reduction, and TUNEL assays. Primary cultures were more susceptible to the toxic effect induced by soluble amyloid oligomers than the neuroblastoma cell line. The cytotoxicity correlates with the size of oligomers; the sample incubated at pH 4.5 and containing larger oligomers, including 20-mer, appears to be more cytotoxic than the lysozyme sample kept at pH 2.0, in which only tetramers and octamers were found. Soluble amyloid oligomers may assemble into rings; however, there was no correlation between the quantity of rings in the sample and its toxicity. The cytotoxicity of transient oligomeric species of the ubiquitous protein lysozyme indicates that this is an intrinsic feature of protein amyloid aggregation, and therefore soluble amyloid oligomers can be used as a primary therapeutic target and marker of amyloid disease.

Amyloid↗

PubMed2005

Selection of peptides binding to the amyloid b-protein reveals potential inhibitors of amyloid formation.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular amyloid plaques, cerebrovascular amyloid deposits, intracellular neurofibrillary tangles, and neuronal loss. Amyloid deposits are composed of insoluble fibers of a 39-43 amino acid peptide named the amyloid beta-protein (A beta). Neuropathological and genetic studies provide strong evidence of a key role for A beta amyloidosis in the pathogenesis of AD. Therefore, an obvious pharmacological target for treatment of AD is the inhibition of amyloid growth and/or inhibition of amyloid function. We took an unbiased approach to generate new inhibitors of amyloid formation by screening a FliTrx combinatorial peptide library for A beta binding peptides and identified four groups of peptides with different A beta binding motifs. In addition, we designed and examined peptides mimicking the A beta binding domain of transthyretin (TTR). Our results showed that A beta binding peptides selected from FliTrx peptide library and from TTR-peptide analogs are capable of inhibiting A beta aggregation and A beta deposition in vitro. These properties demonstrate that binding of selected peptides to the amyloid beta-protein may provide potent therapeutic compounds for the treatment AD.

Alzheimer Disease↗

PubMed1991

Widespread serum amyloid P immunoreactivity in cortical amyloid deposits and the neurofibrillary pathology of Alzheimer's disease and other degenerative disorders.

Amyloid P (AP) component is present in all types of systemic amyloid deposits. Recently, it has been shown to be also present in cerebral amyloid lesions of Alzheimer's disease (AD). In this study, we used immunocytochemical methods to extend these findings at the electron microscope level and characterize the spectrum of AP immunoreactivity in neurofibrillary pathology (NFP) of AD and other neurodegenerative disorders including Down's syndrome (DS), Creutzfeldt-Jakob, Parkinson's, Pick's and diffuse Lewy body diseases and progressive supranuclear palsy. In AD and DS, AP immunoreaction product was evident in all the classical amyloid lesions and NFP in a large sample of all cortical areas examined. The distribution and relative intensity of immunostaining was similar to that of thioflavin S staining in serial sections. In many cases, however, plaques and vessels stained by anti-AP serum were not apparent with thioflavin S. Serial sections immunostained with antiserum to amyloid A, C-reactive protein or to other proteins involved in systemic amyloidoses and the acute phase response showed no evidence of staining in any of the cerebral lesions. Electron microscopy confirmed that AP immunoreactivity was associated with the abnormal filaments characteristic of NFP as well as amyloid fibrils found in plaques and vessels showing congophilic amyloid angiopathy. Plaques of Creutzfeldt-Jakob disease, Pick bodies of Pick's disease, tangles and Lewy bodies in Parkinson's disease and a subpopulation of Lewy bodies in the diffuse Lewy body disease coexistent with AD were also stained. With the exception of vessels in two of the five cases, AP was not detected in age-matched controls. Our observations indicate AP to be a consistent feature of cerebral NFP and amyloid deposits.

Adult↗

PubMed1991

Glycosaminoglycans in extracts of cardiac amyloid fibrils from familial amyloid cardiomyopathy of Danish origin related to variant transthyretin Met 111.

We have previously demonstrated an association between secondary AA type amyloid fibrils and glycosaminoglycans (GAGs) in human liver. The present study was aimed at investigating whether a similar association could be demonstrated in isolated cardiac amyloid fibrils from a unique Danish family with amyloid cardiomyopathy related to variant transthyretin (TTR) with a single amino acid substitution of a methionin for leucine at position 111 (TTR Met 111). Using gel filtration and ion exchange chromatography, significant amounts of GAGs were detected in close association with purified myocardial amyloid fibrils, whereas only trace amounts of polysaccharides were present in the corresponding normal preparation. The GAGs were identified as 50% chondroitin sulfate, 33% heparin/heparan sulfate, and 17% hyaluronan. With the methods used the amyloid associated GAGs appeared as high molecular weight free polysaccharide chains, and not as part of intact proteoglycans (PGs) in the fibril extracts. We conclude that the association between purified amyloid fibrils and GAGs may be a general feature of amyloid deposits. Also, we suggest that the proportion of different GAGs in the amyloid deposits may depend both on the organ or tissues affected and the type of proteins making up the fibrils.

Adult↗

PubMed1981

Feline insular amyloid: histochemical distinction from secondary systemic amyloid.

Amyloid in islets of Langerhans from 48 domestic cats, one human, one non-human primate, and one raccoon was compared with secondary systemic amyloid from three domestic cats, one dog, one human, and one cow to determine affinity for Congo red dye after treatment of paraffin-embedded tissue sections with potassium permanganate and dilute sulfuric acid. Insular amyloid from all six species was resistant to pretreatment with potassium permanganate, i.e., affinity for Congo red was retained, whereas secondary systemic amyloid from all species was sensitive to the potassium permanganate pretreatment. Other stains did not distinguish between insular and secondary systemic amyloid. The potassium permanganate-Congo red staining procedure thus can be used to differentiate insular from secondary systemic amyloid in the cat and other species. The results also indicate that insular amyloid and secondary systemic amyloid are of different chemical composition and pathogenesis.

Adrenal Glands↗

PubMed1992

Immunohistochemical characterization of amyloid proteins in sural nerves and clinical associations in amyloid neuropathy.

To test whether immunohistochemical characterization of proteins in amyloid deposits in biopsied sural nerves gives reliable and useful diagnostic information using commercially available reagents, biopsy specimens of sural nerves from 38 patients with amyloid neuropathy were studied. Transthyretin (TTR) was detected in the amyloid deposits of 11 nerves, lambda light chains (LC) in 8 nerves, kappa LC in 7 nerves, and both lambda and kappa LC in 3 nerves. In 9 nerves, the amyloid deposits were too small to allow adequate immunohistochemical characterization of amyloid proteins in serial sections. Evidence that immunohistochemical characterization was correct came from: 1) evaluation of kin, 2) search for monoclonal proteins in the plasma, and 3) sequencing of the gene abnormalities in TTR+ cases. In 9 of 11 TTR+ cases, in which DNA could be obtained, sequencing of the gene showed that each of the 9 cases was heterozygous for a gene mutation; 7 had previously described mutations and 2 undescribed mutations. Therefore, in the nine sporadic cases without plasma monoclonal light chains, the immunohistochemical characterization correctly identified the protein in amyloid as transthyretin. Likewise, there was a high concordance between immunoglobulin light chains in plasma and light chains in amyloid in primary amyloidosis. Evaluation of the type, distribution, and severity of the neurologic symptoms and deficits showed: 1) the sensorimotor and autonomic neuropathy of amyloidosis characteristically affects proximal as well as distal limbs, and 2) the type of amyloidosis probably cannot be determined from the characteristics or severity of the neuropathy alone or from the location or size of amyloid deposits in nerve.

Aged↗

PubMed1992

[Amyloid in articular cartilage--a new type of amyloid?].

Hip and knee joints from 48 randomly selected autopsies have been investigated for amyloid deposits by means of conventional histology and immunohistology. 45 of 48 hip joints (93.75%) and 28 of 32 knee joints (87.5%) contained amyloid deposits. Amyloid has been found in a thin layer along the surface as well as infissures of the cartilage and around chondrocytes with increasing intensity towards the articular surface. Amyloid characteristically showed apple green birefringence in polarized light after staining with alkaline Congo red and pretreatment with potassium permanganate did not change intensity of reaction in most cases. None of the usual constituents of amyloid could be demonstrated by immunohistological methods. P-component (when present) kept the distribution of the amyloid material. It is possible that articular cartilage amyloid represents a new class of amyloid but its identity is to be proved by chemical analysis.

Adult↗

PubMed1991

Amyloid resistance in A/J mice is not determined by genetic variants at, or close to, the serum amyloid P component locus.

An experimental model to assess the utility of variants of the serum amyloid P component (SAP) gene in predicting resistance to amyloidosis resulting from chronic inflammation was developed. F2 mice were generated from amyloid resistant (A/J) and amyloid susceptible (C57BL/6J) progenitor strains. Mice were injected daily with azocasein for 30 days, a treatment protocol determined to produce little amyloid deposition in the A/J progenitor strain and substantial amyloid deposition in the C57BL/6J progenitor strain. In a blind study the F2 spleens were subjectively scored for amyloid deposition and DNA was isolated from F2 livers and subjected to Southern blot analysis to determine the inheritance of progenitor strain specific SAP restriction fragment length polymorphisms (RFLPs). No correlation between relative amyloid resistance and SAP genotype was observed, indicating that SAP RFLPs have no value in predicting predisposition to amyloid disease in the mouse model studied.

Amyloidosis↗

PubMed1998

Reduction in amyloid A amyloid formation in apolipoprotein-E-deficient mice.

Apolipoproteins have been implicated in the formation of amyloid fibrils. Recent studies have demonstrated that apolipoprotein E (apoE), alone or in combination with apolipoprotein J (apoJ), and other lipoproteins appear to enhance deposition of amyloid fibrils both in systemic and cerebral amyloids, especially Alzheimer's disease (AD). ApoE enhanced the ability of the amyloid beta-protein (1-40) fragment (A beta) to form fibrils in vitro, with apoE4 promoting the greatest fibril formation. ApoE was found associated with both human and mouse amyloid A (AA) deposits. To define the role of apoE in vivo, we utilized mice lacking the apoE gene by gene targeting. We used the AA model in mice to characterize the function of the apoE protein in amyloid fibrillogenesis. ApoE-deficient mice exhibited a decrease in deposition of AA when compared with heterozygous mutant or wild-type animals. In addition, apoE-deficient mice that were injected with an adenovirus that expressed the human apoE3 gene had restored AA deposition and the apoE was associated with the AA fibrils. These results are agreement with the in vitro studies using the beta-peptide and suggest that apoE is not essential for amyloid fibrillogenesis but can promote the development of amyloid deposition.

Acute-Phase Proteins↗

PubMed2005

Pharmacokinetic analysis of the blood-brain barrier transport of 125I-amyloid beta protein 40 in wild-type and Alzheimer's disease transgenic mice (APP,PS1) and its implications for amyloid plaque formation.

Amyloid plaques are formed in the extracellular space of Alzheimer's disease (AD) brain due to the accumulation of amyloid beta (Abeta) proteins such as Abeta40. The relationship between Abeta40 pharmacokinetics and its accumulation within and clearance from the brain in both wild-type (WT) and AD transgenic mice (APP,PS1) was studied to understand the mechanism of amyloid plaque formation and the potential use of Abeta40 as a probe to target and detect amyloid plaques. In both WT and APP,PS1 mice, the (125)I-Abeta40 tracer exhibited biexponential disposition in plasma with very short first and second phase half-lives. The (125)I-Abeta40 was significantly metabolized in the liver kidney > spleen. Coadministration of exogenous Abeta40 inhibited the plasma clearance and the uptake of (125)I-Abeta40 at the blood-brain barrier (BBB) in WT animals but did not affect its elimination from the brain. The (125)I-Abeta40 was shown to be metabolized within and effluxed from the brain parenchyma. The rate of efflux from APP,PS1 brain slices was substantially lower compared with WT brain slices. Since the Abeta40 receptor at the BBB can be easily saturated, the blood-to-brain transport of Abeta40 is less likely to be a primary contributor to the amyloid plaque formation in APP,PS1 mice. The decreased elimination of Abeta40 from the brain is most likely responsible for the amyloid plaque formation in the brain of APP,PS1 mice. Furthermore, inadequate targeting of Abeta40 to amyloid plaques, despite its high BBB permeability, is due to the saturability of Abeta40 transporter at the BBB and its metabolism and efflux from the brain.

Alzheimer Disease↗

PubMed1995

Formation of islet amyloid fibrils in beta-secretory granules of transgenic mice expressing human islet amyloid polypeptide/amylin.

To investigate the relationship between human islet amyloid polypeptide (IAPP)/amylin expression and islet amyloid deposits in the pathogenesis of human non-insulin-dependent diabetes mellitus (NIDDM), we developed transgenic mice using a human IAPP cDNA connected to an insulin promoter. Ribonucleic acid blotting and immunohistochemistry revealed the expression of the transgene in the pancreatic beta cells. Immunogold electron microscopy showed that beta-secretory granules contained the human C-terminal flanking peptide of the IAPP precursor. Reverse-phase HPLC demonstrated human and mouse IAPP amide in the pancreas. Electron microscopy showed the accumulation of fibril-like material in a considerable number of beta-secretory granules. These results suggest that in transgenic mice, the human IAPP precursor is expressed in beta cells and becomes normally sorted into beta-secretory granules in which normal conversion to mature human IAPP takes place. The human IAPP molecules, because of their amyloidogenesis, aggregate into amyloid fibrils in secretory granules. Glucose tolerance was normal at 7 months old and islet amyloid was not observed. A longer time may be required for islet amyloid deposits and hyperglycemia to develop in mice. Our working hypothesis is that in human NIDDM, IAPP aggregates into amyloid fibrils in beta-secretory granules, and that the fibrils are released into the extracellular space and islet amyloid deposits become substantial with time.

Amyloid↗

PubMed1990

Imaging of dialysis-related amyloid (AB-amyloid) deposits with 131I-beta 2-microglobulin.

The diagnosis of dialysis-related amyloid (AB-amyloid) has been based usually on clinical and radiological criteria. Following the discovery that beta 2-microglobulin was the major protein of this amyloid, we isolated and radiolabelled uremic plasma beta 2-microglobulin. After intravenous injection, gamma-camera images of selected joint areas were obtained from 42 patients who were on regular hemodialysis therapy. Positive scans involving the shoulder, hip, knee and carpal regions were found in 13 of 14 patients treated for more than 10 years and 10 of 16 patients treated for 5 to 10 years. Patients treated for less time had negative scans. Specificity was indicated by negative scans in non-amyloid inflammatory lesions in control hemodialysis patients. Up to 48-fold tracer enrichment was detected in excised AB-amyloid containing tissue as compared to amyloid-free tissue. These findings suggest that circulating radiolabelled beta 2-microglobulin is taken up by the amyloid deposits. This method may non-invasively detect tissue infiltrates of amyloid. It may also permit prospective evaluation of the efficacy of prophylactic dialysis strategies which are designed to prevent or delay the onset of this complication of long-term dialysis.

Amyloidosis↗

PubMed1981

Amyloid in hereditary amyloid polyneuropathy is related to prealbumin.

The origin of amyloid in the several subsets of hereditary amyloid polyneuropathy (HAP) is unknown. A recent biochemical study of extracted amyloid indicated that in the "portuguese" type of HAP it consists of a prealbumin-related protein. With the use of specific antibodies against human prealbumin, AA, and kappa and lambda type proteins, we demonstrated by indirect immunofluorescence that the amyloid in muscle biopsy specimens from five Americans and one Brazilian with HAP and one Brazilian without a family history (but with typical clinical disease and no plasma cell dyscrasia) was stained exactly and specifically only with antiprealbumin. In contrast, amyloid in muscle biopsy specimens from patients with plasma cell dyscrasic polyneuropathy and in amyloid-negative control muscle biopsy specimens from patients with nonamyloid neuropathies did not bind antiprealbumin antibodies. Our findings suggest that prealbumin-like protein may be a commonality of amyloid deposits in many, and possibly all, subsets of HAP.

Adolescent↗

PubMed1986

Diagnosis of the type of amyloid in paraffin wax embedded tissue sections using antisera against human and animal amyloid proteins.

Different histochemical techniques were compared on paraffin wax embedded tissue sections for routine classification of amyloid; the following methods were used: potassium permanganate, the indirect immunoperoxidase method using polyclonal anti-human amyloid antisera (anti-AA, anti-A lambda, anti-A kappa and anti-AF) and the peroxidase-antiperoxidase (PAP) method using antisera against human, bovine, hamster and canine AA amyloid. Anti-human AA antiserum appeared to be a useful tool in this respect. Polyclonal anti-AL antisera may be helpful in diagnosing AL amyloid, but were less of value than anti-AA serum. Strong cross reactivity between anti-bovine AA antiserum and human AA amyloid deposits was found. This indicates that animal amyloid AA antisera can also be used for the diagnosis of AA amyloid in human tissues.

Adult↗

PubMed1992

Intraperitoneal amyloid formation by amyloid enhancing factor--rich macrophages in ascitic fluid.

Although resident peritoneal cells from amyloidotic mice (amyloidotic peritoneal cells) are capable of processing the precursor protein of secondary amyloidosis, serum amyloid A (SAA) to amyloid fibrils, the peritoneum is a rare site for amyloid deposition. This is considered to be due to a deficiency of SAA in the peritoneum. To increase the supply of SAA to the peritoneum, ascitic fluid containing about the same protein constituents as in the serum was induced in mice. Amyloidotic peritoneal cells were packed in a microchamber which was shielded with filter membranes, and cultured in ascitic fluid supplemented with additional inflammatory factors. On the 7th day, Congo red-positive structures which showed green birefringence under polarized light were found inside and occasionally outside the chamber. By anti-AA or -SAA immunostaining, amyloid deposits and the cell surfaces of macrophages were positive. Immunologic depletion of T- and B-lymphocytes from the amyloidotic peritoneal cells did not adversely effect the amyloid formation in microchambers. These results suggest that either ascitic fluid containing sufficient amounts of SAA, or peritoneal macrophages with a high amyloid enhancing factor (AEF) activity are indispensable for AA amyloid fibrillogenesis in the peritoneum.

Amyloid↗

PubMed1990

Immunohistological study on the distribution of alpha 1-antichymotrypsin in Alzheimer's brain, compared to beta-amyloid precursor protein and beta-amyloid protein.

Distribution of alpha 1-antichymotrypsin was immunohistologically examined in Alzheimer's brains and compared with those of beta-amyloid precursor protein and beta-amyloid protein. Immunoblotting study revealed that alpha 1-antichymotrypsin existed in senile plaques extracted from Alzheimer's brain. Immunohistologically, rabbit polyclonal antiserum to alpha 1-antichymotrypsin reacted not only with well-defined amyloid deposits such as typical, primitive, core plaques and cerebrovascular amyloid, but also with so-called preamyloid deposits including large amorphous materials (diffuse plaques), subpial amorphous materials and granular deposits. The staining pattern of alpha 1-antichymotrypsin was almost the same as those of beta-amyloid precursor protein and beta-amyloid protein. The present study indicated that alpha 1-antichymotrypsin could play an important role in the formation of various kinds of amyloid deposits including preamyloid ones in Alzheimer's brain.

Aged↗

PubMed1989

Evidence for a diffusional model of Alzheimer amyloid A4 (beta-amyloid) deposition during neuritic plaque formation.

A recent study reported that Alzheimer senile plaques immunostained with monoclonal antibodies against the A4 (beta-amyloid) region of the amyloid precursor protein show gradients of density (Majocha R. E., Benes F. M., Reifel R. L., Rodenrys A. M. and Marotta C. A., Proc. natn. Acad. Sci. U.S.A. 85, 6182-6186, 1988). Although more than one explanation was suggested for this observation, the possible involvement of a diffusional process during plaque maturation was considered. In order to examine this hypothesis, specimens from prefrontal cortex, entorhinal area and hippocampal formation were immunoprocessed in a similar fashion and subjected to quantitative microdensitometric analyses of A4 amyloid reaction product. All plaques in the three brain areas examined showed a curvilinear relationship between the area of amyloid reaction product (expressed in pixel counts) and optical density (expressed as each of six grey scale levels). There was an increase in the area of amyloid at progressively lower density levels. When the area of amyloid reaction product at each density level was correlated with the overall size of individual plaques, it was found that there was a striking increase in the correlation coefficients at progressively lower grey scale levels, with r = 0.853 at the lowest level examined. When a second order derivation of these correlations was performed by expressing individual r-values with respect to an optical density index, an asymptotic relationship resulted with the lowest density levels showing an increasingly sharp rise toward unity. These data are consistent overall with a model for plaque maturation that involves diffusion of amyloid protein through the extracellular space from focal regions of high density where synthesis and/or release may occur.

Alzheimer Disease↗