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At least 19 recordsLinked to original sources

PubMed2006

Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice.

Accumulation of amyloid beta protein (Abeta) aggregates is hypothesized to trigger a pathological cascade that causes Alzheimer's disease (AD). Active or passive immunizations targeting Abeta are therefore of great interest as potential therapeutic strategies. We have evaluated the use of recombinant anti-Abeta single-chain variable fragments (scFvs) as a potentially safer form of anti-Abeta immunotherapy. We have generated and characterized three anti-Abeta scFvs that recognize Abeta 1-16, Abeta x-40, or Abeta x-42. To achieve widespread brain delivery, constructs expressing these anti-Abeta scFvs were packaged into adeno-associated virus (AAV) vectors and injected into the ventricles of postnatal day 0 (P0) amyloid precursor protein CRND8-transgenic mice. Intracranial delivery of AAV to neonatal mice resulted in widespread neuronal delivery. In situ expression of each of the anti-Abeta scFvs after intracerebroventricular AAV serotype 1 delivery to P0 pups decreased Abeta deposition by 25-50%. These data suggest that intracranial anti-Abeta scFv expression is an effective strategy to attenuate amyloid deposition. As opposed to transgenic approaches, these studies also establish a "somatic brain transgenic" paradigm to rapidly and cost-effectively evaluate potential modifiers of AD-like pathology in AD mouse models.

Alzheimer Disease↗

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↗

PubMed2006

Fermented papaya preparation attenuates beta-amyloid precursor protein: beta-amyloid-mediated copper neurotoxicity in beta-amyloid precursor protein and beta-amyloid precursor protein Swedish mutation overexpressing SH-SY5Y cells.

Recent studies indicate that the deposition of beta-amyloid (Abeta) is related in the pathogenesis of Alzheimer's disease (AD), but the underlying mechanism is still not clear. The abnormal interactions of Abeta with metal ions such as copper are implicated in the process of Abeta deposition and oxidative stress in AD brains. In the present study, we established a new AD model, using which we found that copper triggered the Abeta neurotoxicity in SH-SY5Y cells overexpressing the Swedish mutant form of human APP (APPsw) in a concentration dependent manner. Fermented papaya preparation (FPP) has shown high free radical scavenging ability in vivo and in vitro. FPP post-treatment increased cell viability and decreased the intracellular [Ca2+]i, reactive oxygen species (ROS) generation such as hydroxyl free radical and superoxide anion and nitric oxide (NO) accumulation in the cell. Our results also show that FPP prevents the cell apoptosis through bax/bcl-2 sensitive pathway.

Amyloid beta-Peptides↗

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↗

PubMed2005

Proteolysis of serum amyloid A and AA amyloid proteins by cysteine proteases: cathepsin B generates AA amyloid proteins and cathepsin L may prevent their formation.

BACKGROUND: AA amyloidosis develops in patients with chronic inflammatory diseases. The AA amyloid proteins are proteolytic fragments obtained from serum amyloid A (SAA). Previous studies have provided evidence that endosomes or lysosomes might be involved in the processing of SAA, and contribute to the pathology of AA amyloidosis. OBJECTIVE: To investigate the anatomical distribution of cathepsin (Cath) B and CathL in AA amyloidosis and their ability to process SAA and AA amyloid proteins. METHODS: and results: CathB and CathL were found immunohistochemically in every patient with AA amyloidosis and displayed a spatial relationship with amyloid in all the cases studied. Both degraded SAA and AA amyloid proteins in vitro. With the help of mass spectrometry 27 fragments were identified after incubation of SAA with CathB, nine of which resembled AA amyloid proteins, and seven fragments after incubation with CathL. CathL did not generate AA amyloid-like peptides. When native human AA amyloid proteins were used as a substrate 26 fragments were identified after incubation with CathB and 18 after incubation with CathL. CONCLUSION: The two most abundant and ubiquitously expressed lysosomal proteases can cleave SAA and AA amyloid proteins. CathB generates nine AA amyloid-like proteins by its carboxypeptidase activity, whereas CathL may prevent the formation of AA amyloid proteins by endoproteolytic activity within the N-terminal region of SAA. This is particularly interesting, because AA amyloidosis is a systemic disease affecting many organs and tissue types, almost all of which express CathB and CathL.

Adult↗

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↗

PubMed2004

beta-site amyloid precursor protein cleaving enzyme 1 increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACE x APP[V717I] double-transgenic mice.

The generation of amyloid peptides (Abeta) from the amyloid precursor protein (APP) is initiated by beta-secretase (BACE), whereas subsequent gamma-secretase cleavage mediated by presenilin-1, produces Abeta peptides mainly of 40 or 42 amino acids long. In addition, alternative beta'-cleavage of APP at position 11 of the amyloid sequence results in N-truncated Abeta(11-40/42) peptides, but the functional significance or pathological impact is unknown. Here we demonstrate that in the brain of BACE x APP[V717I] double-transgenic mice, amyloidogenic processing at both Asp1 and Glu11 is increased resulting in more and different Abeta species and APP C-terminal fragments. Pathologically, BACE significantly increased the number of diffuse and senile amyloid plaques in old double-transgenic mice. Unexpectedly, vascular amyloid deposition was dramatically lower in the same BACE x APP[V717I] double-transgenic mice, relative to sex- and age-matched APP[V717I] single-transgenic mice in the same genetic background. The tight inverse relation of vascular amyloid to the levels of the less soluble N-terminally truncated Abeta peptides is consistent with the hypothesis that vascular amyloid deposition depends on drainage of excess tissue Abeta. This provides biochemical evidence in vivo for the preferential contribution of N-truncated Abeta to parenchymal amyloid deposition in contrast to vascular amyloid pathology.

Age Factors↗

PubMed2006

Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid.

Vaccination with Abeta(1-42) and treatment with NCX-2216, a novel nitric oxide releasing flurbiprofen derivative, have each been shown separately to reduce amyloid deposition in transgenic mice and have been suggested as potential therapies for Alzheimer's disease. In the current study we treated doubly transgenic amyloid precursor protein and presenilin-1 (APP+PS1) mice with Abeta(1-42) vaccination, NCX-2216 or both drugs simultaneously for 9 months. We found that all treatments reduced amyloid deposition, both compact and diffuse, to the same extent while only vaccinated animals, with or without nonsteroidal anti-inflammatory drug (NSAID) treatment, showed increased microglial activation associated with the remaining amyloid deposits. We also found that active Abeta vaccination resulted in significantly increased cerebral amyloid angiopathy and associated microhemorrhages, while NCX-2216 did not, in spite of similar reductions in parenchymal amyloid. Co-administration of NCX-2216 did not attenuate this effect of the vaccine. This is the first report showing that active immunization can result in increased vascular amyloid and microhemorrhage, as has been observed with passive immunization. Co-administration of an NSAID agent with Abeta vaccination does not substantially modify the effects of Abeta immunotherapy. The difference between these treatments with respect to vascular amyloid development may reflect the clearance-promoting actions of the vaccine as opposed to the production-modifying effects proposed for flurbiprofen.

Alzheimer Disease↗

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↗

PubMed2006

Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice.

Systemic administration of anti-amyloid-beta (Abeta) antibodies results in reduced parenchymal amyloid but increased vascular amyloid and microhemorrhage in amyloid precursor protein (APP) transgenic mice. Here, we evaluate the effects of reducing effector interactions of the antibody via deglycosylation. Mice aged 20 months were treated weekly for 4 months and tested behaviorally before they were killed. APP transgenic mice receiving either anti-Abeta (2H6) or deglycosylated anti-Abeta (de-2H6) showed significant improvement in radial arm water maze performance compared with mice receiving a control antibody. Both groups receiving anti-Abeta antibodies showed significant reductions in total Abeta immunochemistry and Congo red. Significantly fewer vascular amyloid deposits and microhemorrhages were observed in mice administered the de-2H6 antibody compared with those receiving unmodified 2H6 antibody. Deglycosylated anti-Abeta antibodies may be preferable to unmodified IgG because they retain the cognition-enhancing and amyloid-reducing properties of anti-Abeta immunotherapy, while greatly attenuating the increased vascular amyloid deposition and microhemorrhage observed with unmodified IgG.

Aging↗

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↗

PubMed2004

Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition.

The role of microglia in the removal of amyloid deposits after systemically administered anti-Abeta antibodies remains unclear. In the current study, we injected Tg2576 APP transgenic mice weekly with an anti-Abeta antibody for 1, 2, or 3 months such that all mice were 22 months at the end of the study. In mice immunized for 3 months, we found an improvement in alternation performance in the Y maze. Histologically, we were able to detect mouse IgG bound to congophilic amyloid deposits in those mice treated with the anti-Abeta antibody but not in those treated with a control antibody. We found that Fcgamma receptor expression on microglia was increased after 1 month of treatment, whereas CD45 was increased after 2 months of treatment. Associated with these microglial changes was a reduction in both diffuse and compact amyloid deposits after 2 months of treatment. Interestingly, the microglia markers were reduced to control levels after 3 months of treatment, whereas amyloid levels remained reduced. Serum Abeta levels and anti-Abeta antibody levels were elevated to similar levels at all three survival times in mice given anti-Abeta injections rather than control antibody injections. These data show that the antibody is able to enter the brain and bind to the amyloid deposits, likely opsonizing the Abeta and resulting in Fcgamma receptor-mediated phagocytosis. Together with our earlier work, our data argue that all proposed mechanisms of anti-Abeta antibody-mediated amyloid removal can be simultaneously active.

Amyloid↗