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PubMed1996

Potential for imaging cerebral amyloid deposits using 123I-labelled serum amyloid P component and SPET.

The systemic and cerebral accumulation of 123I-labelled serum amyloid P component (123I-SAP) was studied in patients with hereditary cerebral amyloid angiopathy-Dutch type (HCHWA-D) to determine the usefulness of 123I-SAP imaging in cerebral amyloidosis. Whole-body and SPET scintigraphic imaging was performed in two patients with HCHWA-D and four controls after the intraveous injection of 123I-SAP. Venous 123I-SAP clearance was also determined. Accumulation of the tracer was observed in the cerebral cortex of both patients, whereas no accumulation was seen in the controls. Blood clearance of radioactivity was similar in the patients and controls, suggesting that the amount of uptake of 123I-SAP in the cerebral amyloid deposits is relatively small. We believe this to be the first demonstration of cerebral amyloid deposits in vivo. Our findings indicate that 123I-SAP scintigraphy has possibilities for the diagnosis of patients with cerebral amyloid diseases, in addition to its use in patients with systemic amyloid deposition.

Brain↗
PubMed2000

Amyloid in human islets of Langerhans: immunologic evidence that islet amyloid polypeptide is modified in amyloidogenesis.

Amyloid derived from the beta-cell product islet amyloid polypeptide (IAPP) has been implicated for a beta-cell lesion in Type II diabetes mellitus. The pathogenesis of islet amyloid is poorly understood, and in addition to an amyloidogenic IAPP molecule and possibly increased concentration of IAPP, other unknown factors seem to be included. It was shown previously that polyclonal rabbit IAPP antisera label beta cells close to amyloid only weakly. Whether this lack of immunoreactivity depends on lack of IAPP or on hidden epitopes is in question. In the present study, we show that the IAPP immunoreactivity of these beta cells is possible to retrieve. On the other hand, the monoclonal IAPP antibody 4A5, which labels IAPP in beta cells, does not label IAPP in its native amyloid form. We show evidence that this lack of immunoreactivity is not dependent on conformational change of the IAPP molecules in the amyloidogenesis but is likely owing to glycation of IAPP in human islet amyloid deposits.

Amyloid↗
PubMed1996

Islet amyloid and islet amyloid polypeptide in cynomolgus macaques (Macaca fascicularis): an animal model of human non-insulin-dependent diabetes mellitus.

To further characterize spontaneous diabetes mellitus in cynomolgus macaques (Macaca fascicularis) as a model for human non-insulin-dependent diabetes mellitus (NIDDM), we evaluated the morphologic characteristics of the endocrine pancreas of 4 diabetic and 12 age-matched nondiabetic cynomolgus macaques. In addition, the cDNA-predicted amino acid sequence for islet amyloid polypeptide (IAPP) of this species was determined. Islet amyloid deposits exhibiting typical congophilia and green birefringence were found in 4/4 diabetic animals and in 8/12 nondiabetics. Islet amyloid deposits were significantly more extensive in the diabetic macaques (P = 0.001), in which they occupied a mean of 60% of the islet area. In contrast, in the nondiabetic group the maximum islet area occupied by amyloid was 24% (group mean = 6.8%), with four animals having no detectable islet amyloid. Amyloid deposits consistently showed immunoreactivity for IAPP but not for insulin. Comparisons between group means for diabetic versus nondiabetic macaques showed significantly greater islet area (P = 0.01, 85,390 versus 36,540 microns 2) and significantly greater islet area fraction (P = 0.02, 0.065 versus 0.032) for the diabetic group. The cDNA-predicted amino acid sequence for cynomolgus IAPP was identical to that previously reported for pig-tail macaques (M. nemestrina) and had 92%, 86%, and 84% amino acid sequence identity with human, domestic cat, and murine IAPPs, respectively. These findings support the use of cynomolgus macaques as an animal model of human NIDDM.

Amino Acid Sequence↗
PubMed2006

Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy.

BACKGROUND: Microvascular brain injury, typically measured by extent of white matter hyperintensity (WMH) on MRI, is an important contributor to cognitive impairment in the elderly. Recent studies suggest a role for circulating beta-amyloid peptide in microvascular dysfunction and white matter disease. METHODS: The authors performed a cross-sectional study of clinical, biochemical, and genetic factors associated with WMH in 54 subjects with Alzheimer disease (AD) or mild cognitive impairment (AD/MCI) and an independent group of 42 subjects with cerebral amyloid angiopathy (CAA). Extent of WMH was determined by computer-assisted volumetric measurement normalized to intracranial size (nWMH). Biochemical measurements included plasma concentrations of the 40- and 42-amino acid species of beta-amyloid (Abeta40 and Abeta42) detected by specific enzyme-linked immunosorbent assays. RESULTS: Plasma Abeta40 concentrations were associated with nWMH in both groups (correlation coefficient = 0.48 in AD/MCI, 0.42 in CAA, p < or = 0.005). Plasma Abeta40 remained independently associated with nWMH after adjustment for potential confounders among age, hypertension, diabetes, homocysteine, creatinine, folate, vitamin B12, and APOE genotype. The presence of lacunar infarctions was also associated with increased Abeta40 in both groups. nWMH was greater in CAA (19.8 cm3) than AD (11.1 cm3) or MCI (10.0 cm3; p < 0.05 for both comparisons). CONCLUSIONS: Plasma beta-amyloid 40 concentration is independently associated with extent of white matter hyperintensity in subjects with Alzheimer disease, mild cognitive impairment, or cerebral amyloid angiopathy. If confirmed in longitudinal studies, these data would suggest circulating beta-amyloid peptide as a novel biomarker or risk factor for microvascular damage in these common diseases of the elderly.

Aged↗
PubMed1981

Amyloid fibril protein in familial amyloid polyneuropathy.

Amyloid fibril protein was purified from organs of patients with familial amyloid polyneuropathy (Nagano prefecture, Japan). When compared with amyloid fibril protein from primary amyloidosis and secondary amyloidosis, the protein from familial amyloid polyneuropathy was shown to differ in the molecular weight of the subunit. This protein subunit had the same molecular weight as the prealbumin subunit, but had a different amino acid composition: It did not contain tryptophan and cysteine. Amyloid fibril protein from familial amyloid polyneuropathy therefore differed from IgG, AA protein, and prealbumin.

Amyloid↗
PubMed2001

Enhanced in vitro production of amyloid-like fibrils from mutant (S20G) islet amyloid polypeptide.

UNLABELLED: Islet amyloid polypeptide (IAPP, "amylin") is the amyloid-fibril-forming polypeptide in the islets of Langerhans associated with type 2 diabetes mellitus. A missense mutation in the IAPP gene associated with early-onset type 2 diabetes has been identified in the Japanese population. This mutation results in a glycine for serine substitution at position 20 of the mature IAPP molecule. Whether or not formation of islet amyloid with resulting destruction of islet tissue is the cause of this diabetes is yet not known. The present in vitro study was performed in order to investigate any influence of the amino acid substitution on the fibril formation capacity. Synthetic full-length wild type (IAPPwt) and mutant (IAPPS20G) as well as corresponding truncated peptides (position 18-29) were dissolved in dimethylsulfoxide (DMSO) or in 10% acetic acid at a concentration of 10 mg/mL and their fibril forming capacity was checked by Congo red staining, electron microscopy, a Congo red affinity assay and Thioflavine Tfluorometric assay. It was found that full-length and truncated IAPPS20G both formed more amyloid-like fibrils and did this faster compared to IAPPwt. The fibril morphology differed slightly between the preparations. CONCLUSION: The amino acid substitution (S20G) is situated close to the region of the IAPP molecule implicated in the IAPP fibrillogenesis. The significantly increased formation of amyloid-like fibrils by IAPPS20G is highly interesting and may be associated with an increased islet amyloid formation in vivo and of fundamental importance in the pathogenesis of this specific form of diabetes.

Amyloid↗
PubMed1998

Ultrastructural evidence for the formation of amyloid fibrils within cardiomyocytes in isolated atrial amyloid.

Isolated atrial amyloid (IAA) frequently affects elderly human hearts in which only the atria are involved by the deposits. Biochemical analysis has indicated that the major subunit protein of IAA is alpha-human atrial natriuretic peptide (alpha-ANP), which is synthesized by the atrial muscle cells. To define the exact location of the formation of IAA fibrils, right atria from 25 patients undergoing cardiac surgery have been examined by an immunohistochemistry and immunoelectron microscopy with anti-alpha-ANP, apolipoprotein E, amyloid P component, transthyretin, and cathepsin B antisera. Of 25 patients, 19 were involved with IAA deposits which reacted with anti-alpha-ANP, apolipoprotein E, amyloid P component antisera but not with anti-transthyretin antiserum. In 8 of them, amyloid fibrils were seen not only in the interstitium of the atrial myocardium but also in the dilated transverse tubules of the cardiomyocytes. In some cardiomyocytes, amyloid fibrils were also demonstrated within the organelles such as coated and uncoated secretory vesicles or lysosomes. These findings lead to the inescapable conclusion that the polymerization of amyloid fibrils in IAA occurs within the cytoplasm of cardiomyocytes under some conditions.

Adult↗
PubMed1995

Immunoreactivity against tau, amyloid precursor protein, and beta-amyloid in the human retina.

PURPOSE: Increased immunoreactivity (IR) of beta-amyloid and the amyloid-associated proteins tau and amyloid precursor protein (APP) in the brain have been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. However, the expression of these proteins has not been investigated in the normal or diseased human retina. METHODS: Using immunohistochemical techniques, we examined the distribution and age-related changes of anti-tau-1, anti-tau-2, anti-APP, and anti-beta-amyloid IR in the human retina at various ages (n = 24), in retinitis pigmentosa (RP, n = 6), and in age-related macular degeneration (ARMD, n = 10). RESULTS: Tau-1 immunoreactivity was intense in the inner retinal layers and did not change with age or in RP. Eyes with ARMD showed less intense staining but exhibited a similar distribution. Tau-2 IR was faint and did not change with age but was mildly increased in the retinal pigment epithelium (RPE) of eyes with RP and in the retina of eyes with ARMD. APP IR was most prominent in the ganglion cell and nerve fiber layer, and it appeared to increase in ganglion cells of older persons and in RPE cells of eyes with RP and ARMD. Beta-amyloid IR was only detected focally in sub-RPE deposits in eyes from older persons. CONCLUSIONS: The proteins investigated in this study are present in the human retina. The staining pattern of tau is different from the brain, but it shows no age-related changes. The increased immunoreactivity of APP in retinal ganglion cells of older eyes and in RPE cells of eyes with RP and ARMD, as well as the patchy staining of beta-amyloid within sub-RPE deposits, might indicate a relationship of these proteins to retinal aging and possibly to retinal degeneration in RP.

Adolescent↗
PubMed1996

Amyloid load and neural elements in Alzheimer's disease and nondemented individuals with high amyloid plaque density.

The amyloid burden and relationship between amyloid deposits and neural elements were investigated in sections of prefrontal neocortex from eight Alzheimer's disease (AD) patients and four age-matched nondemented controls with high amyloid plaque density (HPND). Computer-based image analysis revealed that the total area occupied by betaA4 immunoreactivity was significantly greater (P < 0.031) in AD (27.1%) than in HPND (14.5%) sections. The total betaA4-positive area occupied by nondiffuse plaques was significantly greater (P < 0.05) in AD (13.6%) than in HPND (5.2%) sections. The percentage of diffuse (DPs) and nondiffuse plaques (NDPs) which contained neurons, astrocytes, microglia, dystrophic neurites, and amyloid precursor protein (APP) was also determined. The frequency of association between betaA4 and these neural elements was similar between AD and HPND cases in both diffuse and nondiffuse plaques. Forty percent of DPs in AD and HPND sections contained neuronal perikarya. Microglia, dystrophic neurites, and APP were detected in most nondiffuse plaques in both AD and HPND sections. While astrocyte cell bodies were not present in either diffuse or nondiffuse plaques, their processes were detected in most. These findings indicate that amyloid deposition and nondiffuse plaques are greater in AD than in HPND sections. The association between microglia and nondiffuse plaques supports the hypothesis that these resident immune cells participate in aggregation and redistribution of amyloid deposits and possibly formation of dystrophic neurites.

Age Factors↗
PubMed1983

Ultrastructural morphology of amyloid fibrils from neuritic and amyloid plaques.

The structure of partially purified, CNS amyloid fibrils from three different sources have been compared by negative stain EM. The fibrils isolated from brains with senile dementia of Alzheimer type were 4-8 nm in diameter, narrowing every 30-40 nm and apparently composed of two 2-4 nm filaments. The fibrils from a Gerstmann-Sträussler syndrome brain were 7-9 nm in diameter, narrowing every 70-80 nm and with a suggestion that they are composed of two 3-5 nm filaments. The fibrils isolated from 87V scrapie-affected mouse brains were 4-8 nm in diameter with a twist every 15-25 nm presumably composed of two 2-4 nm filaments. The fibrils from the scrapie brains were usually observed in pairs. The shape of the clusters of the isolated amyloid fibrils observed in each disease was similar in negative stain and thin section EM preparations and was related to the characteristic morphology of the amyloid fibrils in the neuritic and amyloid plaques in situ. The structural differences between the CNS amyloid fibrils from the various diseases studied by us may reflect differences in the polypeptides which comprise the fibril and/or a different pathogenesis in the formation of the amyloid fibrils.

Alzheimer Disease↗
PubMed1999

Mouse senile amyloid deposition is suppressed by adenovirus-mediated overexpression of amyloid-resistant apolipoprotein A-II.

Apolipoprotein A-II (apoA-II), the second most abundant apolipoprotein of serum high density lipoprotein, deposits as an amyloid fibril (AApoAII) in old mice. Mouse strains with a high incidence of senile amyloidosis have the type C apoA-II gene (Apoa2(c)), whereas the strains with a low incidence of amyloidosis have the type B apoA-II gene (Apoa2(b)). In this study, to investigate whether the type B apoA-II protein inhibits the extension of amyloid fibrils, we constructed an adenovirus vector bearing the Apoa2(b) cDNA (Adex1CATApoa2(b)), which is expressed under the control of a hepatocyte-specific promoter. The mice were infected with Adex1CATApoa2(b) before induction of amyloidosis by the injection of AApoAII amyloid fibril seeds. Compared with the mice infected with the control virus, amyloid deposition was suppressed significantly in the mice infected with Adex1CATApoa2(b). Fluorometry using thioflavine T also revealed that AApoAII fibril extension was inhibited by the addition of type B apoA-II in vitro. Thus, we propose that Apoa2(b) contributes as an active inhibitor of amyloid fibril extension and overexpression of amyloid-resistant gene variant may be an attractive therapeutic target in amyloidosis.

Adenoviridae↗
PubMed1996

Overexpressions of cDNAs for beta-amyloid precursor proteins 695, 751, and 770 enhance the secretion of beta-amyloid precursor protein derivatives and the survival of P19-derived neurons.

P19 is a C3H mouse-derived line of multipotent embryonic carcinoma cells that differentiate into neural cells. P19 cell clones overexpressing the three major forms of beta-amyloid precursor protein from their cDNA constructs were established. Unlike a previous study in which P19-derived neurons had a limited alpha-secretase activity, all of these clones produced significant amounts of secreted beta-amyloid precursor protein. When treated with retinoic acid, these transformed lines differentiated into neurons and survived better than did nontransformed parental P19 cells. Furthermore, P19-derived neurons survived better in medium conditioned by the transformed P19 line, and survival was reduced by immunoabsorption with an antibody to beta-amyloid precursor protein. These results suggest neurotrophic effects of secreted beta-amyloid precursor protein and contrast with a previous report in which overexpression of a full-length cDNA for beta-amyloid precursor protein led to degeneration of P19-derived neurons. Western blot analysis suggested that this difference might result from different levels of expression of putative neurotoxic C-terminal fragments of beta-amyloid precursor protein; moreover, P19-derived neurons differ from P19 stem cells in the processing of these C-terminal fragments.

Amyloid beta-Protein Precursor↗
PubMed1996

The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-beta 1-42 in Alzheimer's disease.

In hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), a genetic variant (E22Q) of amyloid beta (Abeta) accumulates predominantly in the small vessels of leptomeninges and cerebral cortex, leading to fatal strokes in the fifth or sixth decade of life. Abeta deposition in the neuropil occurs mainly in the form of preamyloid, Congo red negative deposits, while mature neuritic plaques and neurofibrillary tangles, hallmark lesions in Alzheimer's disease (AD), are characteristically absent. A recent hypothesis regarding the pathogenesis of AD states that Abeta extending to residues 42-43 (as opposed to shorter species) can seed amyloid formation and trigger the development of neuritic plaques followed by neuronal damage in AD. We characterized biochemically and immunohistochemically Abeta from three cases of HCHWA-D to determine its length in vascular and parenchymal deposits. Mass spectrometry of formic acid-soluble amyloid, purified by size-exclusion gel chromatography, showed that Abeta 1-40 and its carboxyl-terminal truncated derivatives were the predominant forms in leptomeningeal and cortical vessels. Abeta 1-42 was a minor component in these amyloid extracts. Immunohistochemistry with antibodies S40 and S42, specific for Abeta ending at Val-40 or Ala-42, respectively, were consistent with the biochemical data from vascular amyloid. In addition, parenchymal preamyloid lesions were specifically stained with S42 and were not labeled by S40, in agreement with the pattern reported for AD, Down's syndrome, and aged dogs. Our results suggest that in HCHWA-D the carboxyl-terminal Abeta heterogeneity is due to limited proteolysis in vivo. Moreover, they suggest that Abeta species ending at Ala-42 may not be critical for the seeding of amyloid formation and the development of AD-like neuritic changes.

Alzheimer Disease↗
PubMed2003

Amyloid fibril formation in the context of full-length protein: effects of proline mutations on the amyloid fibril formation of beta2-microglobulin.

Beta2-microglobulin (beta2-m), a typical immunoglobulin domain made of seven beta-strands, is a major component of amyloid fibrils formed in dialysis-related amyloidosis. To understand the mechanism of amyloid fibril formation in the context of full-length protein, we prepared various mutants in which proline (Pro) was introduced to each of the seven beta-strands of beta2-m. The mutations affected the amyloidogenic potential of beta2-m to various degrees. In particular, the L23P, H51P, and V82P mutations significantly retarded fibril extension at pH 2.5. Among these, only L23P is included in the known "minimal" peptide sequence, which can form amyloid fibrils when isolated as a short peptide. This indicates that the residues in regions other than the minimal sequence, such as H51P and V82P, determine the amyloidogenic potential in the full-length protein. To further clarify the mutational effects, we measured their stability against guanidine hydrochloride of the native state at pH 8.0 and the amyloid fibrils at pH 2.5. The amyloidogenicity of mutants showed a significant correlation with the stability of the amyloid fibrils, and little correlation was observed with that of the native state. It has been proposed that the stability of the native state and the unfolding rate to the amyloidogenic precursor as well as the conformational preference of the denatured state determine the amyloidogenicity of the proteins. The present results reveal that, in addition, stability of the amyloid fibrils is a key factor determining the amyloidogenic potential of the proteins.

Amyloid↗
PubMed1977

Characterization of an amyloid fibril protein from senile cardiac amyloid.

A protein, ASCA, is isolated from amyloid fibrils extracted from heart tissue of five different patients with senile cardiac amyloidosis (SCA). The proteins of all five patients showed immunological identity when reacted with an antiserum raised against one of the proteins. In contrast, no reaction was obtained with antisera against a variety of other amyloid proteins. The antiserum against the subunit protein of senile cardiac amyloid did not react with any other amyloid preparations tested, nor with extracts of normal heart tissue. Thus, the subunit protein appeared to be unique to senile heart amyloid. The protein could form fibrils in vitro, had a mol wt of about 6,000 daltons and the amino acid compositions investigated in two cases showed extensive similarities but were clearly different from that of protein AA of secondary amyloid fibrils.

Aged↗
PubMed1977

Amyloid production by dermal fibroblasts. Electron microscopic studies on the origin of amyloid in various dermatoses and skin tumours.

Electron microscopic investigations in 7 patients with different dermatoses or skin tumours containing amyloid showed that amyloid is synthesized in the cytoplasm of dermal cells. In 3 cases of localized primary amyloidosis of the skin highly active cells were demonstrated, showing grossly dilated cisternae of rough endoplasmic reticulum, resembling fibroblasts. Their intracellular product seemed amorphous, later filamentous, and was then released into the extracellular space. Extracellular aggregations of typical amyloid filaments were found partially surrounded by thin cytoplasmic remnants of the cells producing them. Subclinical amounts of amyloid found in porokeratosis of Mibelli, in superficial basal-cell carcinoma, in senile skin, and in clinically normal skin of a patient with malignant melanoma showed the same characteristics. Other cell types such as plasma cells and mast cells were well preserved and seemed stimulated; however, no amyloid precursors were found in their cytoplasm and no release was seen. We, therefore, conclude that dermal amyloid is generally produced by falsely programmed fibroblasts.

Adult↗
PubMed2002

Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease.

The deposition of amyloid-beta (Abeta) peptides into amyloid plaques precedes the cognitive dysfunction of Alzheimer's disease (AD) by years. Biomarkers indicative of brain amyloid burden could be useful for identifying individuals at high risk for developing AD. As in AD in humans, baseline plasma Abeta levels in a transgenic mouse model of AD did not correlate with brain amyloid burden. However, after peripheral administration of a monoclonal antibody to Abeta (m266), we observed a rapid increase in plasma Abeta and the magnitude of this increase was highly correlated with amyloid burden in the hippocampus and cortex. This method may be useful for quantifying brain amyloid burden in patients at risk for or those who have been diagnosed with AD.

Alzheimer Disease↗
PubMed1985

Feline insular amyloid: immunohistochemical and immunochemical evidence that the amyloid is insulin-related.

Utilizing islet amyloid-laden pancreatic tissues from six diabetic cats, we demonstrated substantial immunoreactivity (peroxidase-antiperoxidase technique) of the islet amyloid with antiserum to a B chain-rich insulin fraction, but no reactivity with antisera to insulin, glucagon, or somatostatin. Islet amyloid was purified from two cats and a protein unique to the diabetic and islet amyloid-laden cats was separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Immunoreactivity of this protein with antiserum to the B chain-rich insulin fraction was also shown by immunoblotting. Attempts to obtain the amino acid composition of the purified unique protein (represented by a single 25,000 dalton band on gel electrophoresis) were not successful because the amount of protein was too small. These results provide important additional evidence that an insulin-related protein is involved in the formation of islet amyloid. Our study also shows that the diabetic cat provides several advantages for the continued study of the etiopathogenic relationship of islet amyloid and diabetes mellitus.

Amino Acids↗