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PubMed1994

An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants.

Normal processing of the amyloid beta protein precursor (beta APP) results in secretion of a soluble 4-kilodalton protein essentially identical to the amyloid beta protein (A beta) that forms insoluble fibrillar deposits in Alzheimer's disease. Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or the beta APP717 mutants linked to familial Alzheimer's disease were compared by (i) isolation of metabolically labeled 4-kilodalton A beta from conditioned medium, digestion with cyanogen bromide, and analysis of the carboxyl-terminal peptides released, or (ii) analysis of the A beta in conditioned medium with sandwich enzyme-linked immunosorbent assays that discriminate A beta 1-40 from the longer A beta 1-42. Both methods demonstrated that the 4-kilodalton A beta released from wild-type beta APP is primarily but not exclusively A beta 1-40. The beta APP717 mutations, which are located three residues carboxyl to A beta 43, consistently caused a 1.5- to 1.9-fold increase in the percentage of longer A beta generated. Long A beta (for example, A beta 1-42) forms insoluble amyloid fibrils more rapidly than A beta 1-40. Thus, the beta APP717 mutants may cause Alzheimer's disease because they secrete increased amounts of long A beta, thereby fostering amyloid deposition.

Alzheimer Disease↗
PubMed2002

[Sporadic cerebral amyloid angiopathy presenting with dementia and prominent capillary beta-amyloid deposition: a case report].

We report a sporadic case of unusual cerebral amyloid angiopathy (CAA) with prominent capillary involvement. A 67-year-old doctor developed gait disturbance, resting tremor and rigidity. He was diagnosed to have Parkinson's disease, for which the treatment with levodopa was effective. Four years later he began to exhibit progressive cognitive decline and behavioral abnormalities consisting of hallucination and agitation. Subsequently, his condition steadily worsened and became bedridden with severe dementia, and he died eight years after the disease onset. During the clinical course, there had been no episode of stroke. Postmortem examinations revealed the typical pathology of Parkinson's disease with frequent cortical Lewy bodies in the amygdala. The most striking pathological feature of this patient was widespread CAA where prominent beta-amyloid (A beta) deposition was observed in the capillaries of the neocortex, most pronouncedly in the occipital lobe, as well as leptomeningeal and cerebral medium-sized and small vessels. Further, perivascular plaques were found in half of the amyloid-laden capillaries. Tau-positive dystrophic neurites were only sparsely detectable within a few perivascular plaques. Despite the severe A beta pathology, there was no microaneurysmal dilatation, fibrinoid necrosis or vascular occlusion. There was only one small ischemic lesion in the brain. The cerebral white matter was unremarkable. Senile plaques of neuritic type and neurofibrillary tangles were mostly limited to the hippocampal regions and, to a lesser degree, in the amygdaloid nucleus, which did not meet the neuropathological criteria of Alzheimer's disease. On the gene analyses, his apolipoprotein E (ApoE) genotyping was verified to be heterozygous epsilon 3/epsilon 4, and no mutation was seen in exons 16 and 17 of the amyloid precursor protein gene. Severe A beta capillary angiopathy as seen in our patient is exceptional in sporadic CAA. Further, A beta angiopathy of this patient was notable in the absence of an associated cerebrovascular disease despite prominent A beta deposition in the vessel walls. Regarding the development of his severe dementia, the limbic pathology of Lewy body disease might be one of the potential causes, but A beta angiopathy appears more likely because of its severity. We speculate that widespread A beta deposition disregulates the blood-brain barrier of the capillaries leading to a disturbance of the microcirculation throughout the cerebral cortex without obvious ischemic disintegration of the neuropil. We should take into consideration that A beta angiopathy can present as progressive dementia without cerebrovascular disease.

Aged↗
PubMed1992

Development of a monoclonal antibody specific for beta/A4 amyloid in Alzheimer's disease brain for application to in vivo imaging of amyloid angiopathy.

We evaluated the efficacy of murine monoclonal antibodies (Mabs) targeted to beta/A4 amyloid for development of procedures for the in vivo identification of amyloid angiopathy (AA) in Alzheimer's disease (AD). Mabs to beta/A4 amyloid were prepared and screened for effectiveness in visualizing AA and senile plaques in postmortem AD brain sections. They were assessed again after enzymatic cleavage to produce Fab fragments and after labeling with 99mTc using a diamide dimercaptide ligand system. Modified and radiolabeled Fab fragments retained activity and specificity towards amyloid-laden blood vessels and senile plaques. A highly specific murine Mab, 10H3, was identified and characterized that fulfills criteria necessary for the development of a diagnostic imaging agent. Expansion and adaptation of these strategies may provide the methods and materials for the noninvasive analysis of AA in living patients, and permit assessment of the contribution of AA to the clinical and pathological features of AD.

Aged↗
PubMed1992

Ultrastructural immunohistochemical localization of polyclonal IgG, C3, and amyloid P component on the congo red-negative amyloid-like fibrils of fibrillary glomerulopathy.

Renal biopsies from seven patients with Congo red-negative amyloid-like fibrillary glomerulopathy (FGP) were examined by protein A gold immuno-electron microscopy. Ultrastructurally, the fibrils in all cases exhibited positive immunostaining for IgG, both Ig light chains, C3, and amyloid P component (AP), but did not show positive immunostaining for glomerular basement membrane (GBM)-associated proteins (collagen type IV and heparan-sulfate proteoglycans) or microfibril-associated proteins (fibronectin and fibrillin). In a triple-label study, AP and IgG were colocalized along the same fibril, whereas the gold probes for the detection of collagen type IV were absent. The results suggest that the fibrils are comprised of polyclonal IgG and C3 that bind AP. AP was immunolocalized sparsely but regularly along the lamina rara interna of normal GBM. AP was absent in the fibrils in a case of diabetic glomerulopathy, was scattered randomly without specificity for the electron-dense deposits in the GBM of membranous glomerulopathy, and lined up regularly along the fibrils in amyloid deposits. FGP is an entity in which the fibrils bind AP but lack the beta-pleated sheet structure necessary for Congo red staining that is typical of amyloid.

Amyloid↗
PubMed1990

Coexistence of Alzheimer's amyloid precursor protein and amyloid protein in cerebral vessel walls.

Polyclonal antibodies to synthetic peptides homologous to amino acid residues 45-62, 597-624, and 676-695 of the predicted sequence of Alzheimer's amyloid precursor protein (APP) were used to investigate the site of origin of APP, and the relationship between APP and amyloid protein in Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D). Cortical sections as well as homogenates of isolated leptomeningeal and cortical microvessels from three patients with AD, two patients with HCHWA-D, and two nondemented controls were probed. In vessel extracts of both groups of patients and the controls, APP was detected as a set of proteins with electrophoretic mobility of 105 to 135 kilodaltons. In cortical sections of all subjects, APP immunoreactivity was found in leptomeningeal and cortical vessel walls. In patients with AD and HCHWA-D, APP and amyloid fibrils coexisted in the same vessels. Moreover, APP immunoreactivity was found in association with 50% of senile plaques in AD brains, but was not evidenced in parenchymal amyloid deposits in patients with HCHWA-D. These data suggest that the vascular system is a source of APP and that the processing of APP into insoluble fibrils in AD and HCHWA-D may take place in situ.

Aged↗
PubMed1983

Kinetics of amyloid deposition. I. The effects of amyloid-enhancing factor and splenectomy.

It has long been recognized that amyloid AA deposition occurs in two phases, a predeposition and a deposition phase. The deposition phase has two distinct periods, a period of rapid deposition followed by a plateau stage. This kinetic pattern is seen in both liver and spleen and in animals in which the appearance of AA is accelerated by the administration of amyloid-enhancing factor. Amyloid-enhancing factor recipients have a shorter lag period before AA deposition is evident, but the kinetics of deposition and tissue level attained are similar to that seen in nonrecipients. It is also demonstrated that amyloid-enhancing factor activity may be generated in the liver of splenectomized animals.

Amyloid↗
PubMed1998

Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation.

Mutations at codons 717 and 670/671 in the amyloid precursor protein (APP) are rare genetic causes of familial Alzheimer's disease (AD). A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). We have reported a APP692Ala-->Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem examination of two demented patients with the APP692 mutation. The neuropathological findings support the diagnosis of AD. Leptomeningial and parenchymal vessels showed extensive deposition of Abeta amyloid protein. Numerous senile plaques consisted of large Abeta amyloid cores, often measuring more than 30 microm in diameter and were surrounded by a fine meshwork of dystrophic neurites. In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites. Our findings show that the APP692 mutation leads to morphological abnormalities that are similar to AD, but the morphology of senile plaques is clearly distinct from that described in sporadic and chromosome 14-linked AD patients, in patients with APP717 mutations causing familial, presenile AD and in patients with the APP693 mutation causing HCHWA-D.

Alzheimer Disease↗
PubMed2006

High sensitivity analysis of amyloid-beta peptide composition in amyloid deposits from human and PS2APP mouse brain.

Cortical amyloid-beta (Abeta) deposition is considered essential in Alzheimer's disease (AD) and is also detectable in nondemented individuals with pathologic aging (PA). The present work presents a detailed analysis of the Abeta composition in various plaque types from human AD and PA cases, compared with plaque Abeta isolated from PS2APP mice. To determine minute amounts of Abeta from 30 to 50 laser-dissected amyloid deposits, we used a highly sensitive mass spectrometry procedure after restriction protease lysyl endopeptidase (Lys-C) digestion. This approach allowed the analysis of the amino-terminus and, including a novel ionization modifier, for the first time the carboxy-terminus of Abeta at a detection limit of approximately 200 fmol. In addition, full length Abeta 40/42 and pyroglutamate 3-42 were analyzed using a highly sensitive urea-based Western blot procedure. Generally, Abeta fragments were less accessible in human deposits, indicative of more posttranslational modifications. Thioflavine S positive cored plaques in AD were found to contain predominantly Abeta 42, whereas thioflavine S positive compact plaques and vascular amyloid consist mostly of Abeta 40. Diffuse plaques from AD and PA, as well as from PS2APP mice are composed predominantly of Abeta 1-42. Despite biochemical similarities in human and PS2APP mice, immuno-electron microscopy revealed an extensive extracellular matrix associated with Abeta fibrils in AD, specifically in diffuse plaques. Amino-terminal truncations of Abeta, especially pyroglutamate 3-40/42, are more frequently found in human plaques. In cored plaques we measured an increase of N-terminal truncations of approximately 20% between Braak stages IV to VI. In contrast, diffuse plaques of AD and PA cases, show consistently only low levels of amino-terminal truncations. Our data support the concept that diffuse plaques represent initial Abeta deposits but indicate a structural difference for Abeta depositions in human AD compared with PS2APP mice already at the stage of diffuse plaque formation.

Aged, 80 and over↗
PubMed2004

Oligopeptide-mediated acceleration of amyloid fibril formation of amyloid beta(Abeta) and alpha-synuclein fragment peptide (NAC).

The effects of oligopeptides on the secondary structures of Abeta and NAC, a fragment of alpha-synuclein protein, were studied by circular dichroism (CD) spectra. The effects of oligopeptides on the amyloid fibril formation were also studied by fluorescence spectra due to thioflavine-T. The oligopeptides were composed of a fragment of Abeta or NAC and were interposed by acidic or basic amino acid residues. The peptide, Ac-ELVFFAKK-NH2, which involved a fragment Leu-Val-Phe-Phe-Ala at Abeta(17-21), had no effect on the secondary structures of Abeta(1-28) in 60% or 90% trifluoroethanol (TFE) solutions at both pH 3.2 and pH 7.2. However, it showed pronounced effects on the secondary structure of Abeta(1-28) at pH 5.4. The Ac-ELVFFAKK-NH2 reduced the alpha-helical content, while it increased the beta-sheet content of Abeta(1-28). In phosphate buffer solutions at pH 7.0, Ac-ELVFFAKK-NH2 had little effect on the secondary structures of Abeta(1-28). However, it accelerated amyloid fibril formation when monitored by fluorescence spectra due to thioflavine-T. On the other hand, LPFFD, a peptide known as a beta-sheet breaker, caused neither an appreciable extent of change in the secondary structure nor amyloid fibril formation in the same buffer solution. The peptide, Ac-ETVK-NH2, which involved a fragment Thr-Val at NAC(21-22), had no effect on the secondary structure of NAC in 90% TFE and in isotonic phosphate buffer. However, Ac-ETVK-NH2 in water with small amounts of NaN3 and hexafluoroisopropanol greatly increased the beta-sheet content of NAC after standing the solution for more than 1 week. Interestingly, in this solution. Ac-ETVK-NH2, accelerated the fibril formation of NAC. It was concluded that an oligopeptide that involves a fragment of amyloidogenic proteins could be a trigger for the formation of amyloid plaques of the proteins even when it had little effect on the secondary structures of the proteins as monitored by CD spectra for a short incubation time.

Amino Acid Sequence↗
PubMed1998

Amyloid enhancing factor and dietary transmission in accelerated amyloid A amyloidosis.

The etiology and pathogenesis of amyloid A (AA) amyloidosis that may occur as an occasional complication of chronic inflammatory and infectious diseases are poorly understood. The preamyloid phase of experimentally induced AA amyloidosis can be greatly shortened in recipient animals by intravenous or intraperitoneal transfer of amyloid enhancing factor (AEF) when there is a concomitant inflammatory episode. AEF is an operational term applied to poorly characterized tissue extracts and increased AEF activity that precedes amyloid deposition. We now report that AA is rapidly formed in mice following oral administration of an AEF preparation that does not contain AA peptides. This finding indicates that a transmissible agent present in diet may be a contributory factor in amyloid fibril formation.

Administration, Oral↗
PubMed2003

Early pathogenesis of cardiac amyloid deposition in senile systemic amyloidosis: close relationship between amyloid deposits and the basement membranes of myocardial cells.

Despite a number of in vitro studies of transthyretin (TTR) amyloidogenesis the early stage of in vivo amyloidogenesis in the human heart is largely unknown. A heart with a mild degree of cardiac amyloidosis removed from a 90-year old woman at autopsy was selected for analysis. The genotype of the TTR was the wild type. An immunohistochemical study with anti-TTR antibody was performed on serial paraffin sections, and 17 TTR-positive lesions less than 50 micro m in diameter consisting of 13 interstitial and 4 vascular lesions were identified. The early interstitial lesions start as thick membranous deposits between interfacing myocardial cells. They are Congophilic with green birefringence and positive for apolipoprotein E but negative for amyloid P component. The TTR-positive amyloid extends along intercellular spaces and becomes larger, involving several myocardial fibers. The media is the initial site of arteriolar involvement. According to the in vitro studies of amyloid fibrillogenesis, the most critical step is formation of the nucleus under supersaturated conditions. The supersaturated conditions are speculated to be achieved by binding to proteoglycans or lipid membranes. Our results indicate that the basement membrane of myocardial cells is the initial site of amyloid deposition, providing a suitable place for concentration of TTR.

Aged↗
PubMed1991

Peptides homologous to the amyloid protein of Alzheimer's disease containing a glutamine for glutamic acid substitution have accelerated amyloid fibril formation.

beta-Amyloid (A beta) deposition in fibril form is the central event in a number of diseases, including Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis - Dutch type (HCHWA-D). A beta is produced by degradation of a larger amyloid precursor protein (APP). Recently a mutation in the APP gene has been found in HCHWA-D causing a glutamine for glutamic acid substitution at residue 22 of A beta. The influence of this mutation on fibrillogenesis is not known, although it is clear that affected patients have accelerated cerebrovascular amyloid deposition, with disease symptoms early in life. We report the in vitro demonstration of accelerated fibril formation in a 28 residue synthetic peptide homologous to the Dutch variant A beta. Furthermore, in eight residue peptides homologous to A beta the presence of the mutation is necessary for fibril formation. These findings provide a mechanism for accelerated amyloid formation in the Dutch variant of APP.

Alzheimer Disease↗
PubMed1995

Characterization of amyloid A protein in human secondary amyloidosis: the predominant deposition of serum amyloid A1.

Serum amyloid A protein (SAA) is the plasma precursor for amyloid A protein (AA), the subunit protein in amyloid deposits of secondary or reactive amyloidosis. Several forms of acute phase SAA have been identified in human plasma. To elucidate whether one of these forms of SAA predominates in the formation of AA amyloid deposits, the amino acid sequence of the subunit protein in six cases of reactive amyloidosis was investigated. Minimal heterogeneity was present at the N-terminus as all samples started with residue 1, 2, or 3 of SAA. The C-terminus, however, was more heterogeneous with the AA protein in each case terminating at multiple sites from residue 58 to 84 of SAA. Since less than 20% of the AA protein in each case contained sequence past residue 67 of SAA, the sequence and recovery of tryptic peptides containing residues 52, 57, and 60 where human SAA1 and 2 differ was used to determine the relative amounts of SAA1 and 2 present. One sample contained only SAA1 sequence, four contained approx. 11% or less of SAA2 sequence, and the sixth contained 24-33% of SAA2 sequence. Thus, while five of the six AA samples contained both SAA1 and 2, the predominant form in all cases was SAA1. In three of the six cases, the protein defensin was isolated along with the AA protein from the fibrils. This may suggest neutrophil involvement in SAA processing to AA fibrils.

Amino Acid Sequence↗
PubMed2004

Zinc binding agonist effect on the recognition of the beta-amyloid (4-10) epitope by anti-beta-amyloid antibodies.

Amyloid plaques associated to Alzheimer's disease present a high content of zinc ions. We previously showed that the N-terminal region of the amyloid peptide Abeta constitutes an autonomous zinc-binding domain. This region encompasses the previously identified epitope Abeta(4-10) targeted by antibodies capable to reduce amyloid deposition, but the influence of Abeta/Zn binding on the epitope recognition remains unknown. We demonstrate here the effect of Zn2+ ions on the recognition of peptides sharing the sequence of the Abeta N-terminal domain, by two monoclonal antibodies recognizing the beta-amyloid(4-10) epitope. The presence of Zn2+, but not of other cations, increased the recognition of the (1-16) peptide, while it was without effect on the recognition of the (1-10) peptide. These findings show a zinc-induced conformational change of the (1-16)-N-terminal region of AP3, which results in a better accessibility of the Abeta(4-10) epitope to the anti-Abeta antibodies, and suggest a role of zinc in epitope-based vaccination approaches.

Amyloid beta-Peptides↗
PubMed2005

Inhibition of hIAPP amyloid-fibril formation and apoptotic cell death by a designed hIAPP amyloid- core-containing hexapeptide.

The pathogenesis of type II diabetes is associated with the aggregation of the 37-residue human islet amyloid polypeptide (hIAPP) into cytotoxic beta sheet aggregates and fibrils. We have recently shown that introduction of two N-methyl rests in the beta sheet- and amyloid-core-containing sequence hIAPP(22-27), or NFGAIL converted this amyloidogenic and cytotoxic sequence into nonamyloidogenic and noncytotoxic NF(N-Me)GA(N-Me)IL. Here, we show that NF(N-Me)GA(N-Me)IL is able to bind with high-affinity full-length hIAPP and to inhibit its fibrillogenesis. NF(N-Me)GA(N-Me)IL also inhibits hIAPP-mediated apoptotic beta cell death. By contrast, unmodified NFGAIL does not inhibit hIAPP amyloidogenesis and cytotoxicity, suggesting that N-methylation conferred on NFGAIL the properties of NF(N-Me)GA(N-Me)IL. These results support the concept that rational N-methylation of hIAPP amyloid-core sequences may be a valuable strategy to design pancreatic-amyloid diagnostics and therapeutics for type II diabetes.

Amyloid↗
PubMed2002

Expression of alpha-synuclein, the precursor of non-amyloid beta component of Alzheimer's disease amyloid, in human cerebral blood vessels.

The non-amyloid beta component of Alzheimer's disease amyloid (NAC) is detected in cerebral amyloid angiopathy; and the precursor of NAC is now known to be identical to alpha-synuclein (alpha-S), a major component of Lewy bodies in Parkinson's disease. We studied if cerebral vascular cells express alpha-S. Immunohistochemical studies of human cerebral tissues from control and cerebral amyloid angiopathy patients revealed the expression of alpha-S in vascular endothelial and smooth muscle cells. Then we studied the expression of alpha-S in vitro using cultures of vascular cells. Cultures of human umbilical vein endothelial cells and umbilical artery smooth muscle cells were found to constitutively express alpha-S messenger RNA and protein. alpha-S is normally expressed in vascular cells and may play some physiological role in the vascular wall.

Aged↗
PubMed1992

Alzheimer's disease and control brain contain soluble derivatives of the amyloid protein precursor that end within the beta amyloid protein region.

The 39-43 amino acid beta amyloid protein (A beta) that deposits as amyloid in the brains of patients with Alzheimer's disease (AD) is encoded as an internal sequence within a larger membrane-associated protein known as the amyloid protein precursor (APP). In cultured cells, the APP is normally cleaved within the A beta to generate a large secreted derivative and a small membrane-associated fragment. Neither of these derivatives can produce amyloid because neither contains the entire A beta. Our study was designed to determine whether the soluble APP derivatives in human brain end within the A beta as described in cell culture or whether AD brain produces potentially amyloidogenic soluble derivatives that contain the entire A beta. We find that both AD and control brain contain nonamyloidogenic soluble derivatives that end at position 15 of the A beta. We have been unable to detect any soluble derivatives that contain the entire A beta in either the AD or control brain.

Alzheimer Disease↗
PubMed2002

Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid.

GM1 ganglioside-bound amyloid beta-protein (GM1-Abeta), found in brains exhibiting early pathological changes of Alzheimer's disease (AD) plaques, has been suggested to accelerate amyloid fibril formation by acting as a seed. We have previously found using dye-labeled Abeta that Abeta recognizes a GM1 cluster, the formation of which is facilitated by cholesterol [Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y., and Matsuzaki, K. (2001) J. Biol. Chem. 276, 24985-24990]. In this study, we investigated the ganglioside species-specificity in its potency to induce a conformational change of Abeta, by which ganglioside-bound Abeta acts as a seed for Abeta fibrillogenesis, using a major ganglioside occurring in brains (GM1, GD1a, GD1b, and GT1b) in raft-like membranes composed of cholesterol and sphingomyelin. Abeta recognized ganglioside clusters, the density of which increased with the number of sialic acid residues. Interestingly, however, mixing of gangliosides inhibited cluster formation. In contrast, the affinities of the protein for the clusters were similar irrespective of lipid composition and of the order of 10(6) M(-)(1) at 37 degrees C. Abeta underwent a conformational transition from an alpha-helix-rich structure to a beta-sheet-rich structure with the increase in protein density on the membrane. Ganglioside-bound Abeta proteins exhibited seeding abilities for amyloid formation. GM1-Abeta exhibited the strongest seeding potential, especially under beta-sheet-forming conditions. This study suggested that lipid composition including gangliosides and cholesterol strictly controls amyloid formation.

Alzheimer Disease↗