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PubMed1999

Can serum amyloid A or macrophage colony stimulating factor serve as marker of amyloid formation process?

Amyloid formation depends on amyloid precursor production and is influenced by the activity of the underlying disorder and mediated by some proinflammatory cytokines. In this pilot study we tried to find some specific markers that could establish the activity of the disease. We investigated 45 samples of sera and 38 samples of urine from patients (pts) with secondary amyloidosis (AA), primary amyloidosis (AL), systemic autoimmune diseases with renal impairment (Vasc) and healthy controls (Co). Pts with AA had increased plasma levels of TNF alpha (9.97 +/- 4.22 vs. 2.63 +/- 1.34 pg/mL, p < 0.001) and SAA (43.14 +/- 16.0 vs. 3.42 +/- 0.7 ng/mL, p < 0.05) in comparison with Co. Plasma levels of M-CSF in the AA group were significantly increased in comparison with Co (1077.34 +/- 238.6 vs. 137.71 +/- 19.6, pg/mL, p < 0.001) and also in comparison with Vasc (482.24 +/- 86.7 pg/mL, p < 0.05). Urinary excretions of TNF alpha (8.92 +/- 8.1 vs. 0.17 +/- 0.11 microgram/mol creatinine, p < 0.01), sIL-6R (1.39 +/- 1.14 vs. 0.07 +/- 0.05 g/mol creatinine, p < 0.01) and M-CSF (650.2 +/- 153.7 vs. 33.3 +/- 8.6 micrograms/mol creatinine, p < 0.01) in AA were significantly increased in comparison with Co. Pts with AL had increased plasma levels of M-CSF (819.83 +/- 264.2 vs. 137.71 +/- 19.6 pg/mL, p < 0.05) and urinary excretion of M-CSF (865.0 +/- 188.4 vs. 33.3 +/- 8.6 micrograms/mol creatinine, p < 0.01) in comparison with Co. SAA has a low specificity for amyloidosis but is a sensitive acute phase reactant. TNF alpha, a proinflammatory cytokine, may reflect the activity of the underlying diseases in secondary amyloidosis. M-CSF was increased both in plasma and urine in amyloidosis groups and seems to be the most promising (possibly specific) marker of amyloidosis.

Amyloid↗
PubMed2003

Genetic background regulates beta-amyloid precursor protein processing and beta-amyloid deposition in the mouse.

Alzheimer's disease (AD) is a multigenic neurodegenerative disorder characterized by distinct neuropathological hallmarks including deposits of the beta-amyloid (A beta) peptide. A beta is a 39- to 43-amino acid peptide derived from the proteolytic processing of the amyloid precursor protein (APP). While increasing evidence suggests that altered APP processing and A beta metabolism is a common feature of AD, the relationship between the levels of A beta and various APP products and the onset of AD remains unclear. We have undertaken a screen to characterize genetic factors that modify APP processing, A beta metabolism and A beta deposition in a genomic-based yeast artificial chromosome (YAC) transgenic mouse model of AD. A mutant human APP YAC transgene was transferred to three inbred mouse strains. Despite similar levels of holo-APP expression in the congenic strains, the levels of APP C-terminal fragments as well as brain and plasma A beta in young animals varied by genetic background. Furthermore, we demonstrate that age-dependent A beta deposition in the APP YAC transgenic model is dramatically altered depending on the congenic strain examined. These studies demonstrate that APP processing, A beta metabolism and A beta deposition are regulated by genetic background and that analysis of these phenotypes in mice should provide new insights into the factors that regulate AD pathogenesis.

Alzheimer Disease↗
PubMed2002

Long-term accumulation of amyloid-beta in axons following brain trauma without persistent upregulation of amyloid precursor protein genes.

Brain trauma has been shown to be a risk factor for developing Alzheimer disease (AD), and AD-like plaques containing amyloid-beta (Abeta) peptides have been found in the brain shortly following trauma. Here, we evaluated the effects of brain trauma on the accumulation of Abeta and expression of amyloid precursor protein (APP) genes (APP695 and APP751/ 770) over 1 yr in a non-transgenic rodent model. Anesthetized male Sprague-Dawley rats were subjected to parasagittal fluid percussion brain injury of moderate severity (2.5-2.9 atm) or sham treatment and their brains were evaluated at 2, 4, 7, 14 days, and 1, 2, 6, 12 months following injury. Immunohistochemical analysis detected only weak Abeta staining by 2 wk following injury. However, by 1 month to 1 yr following injury, strong immunoreactivity for Abeta was found in damaged axons throughout the thalamus and white matter. Western blot analysis confirmed the accumulation of Abeta peptides in tissue from injured brains. Although in situ hybridization demonstrated an increased gene expression of APP751/770 surrounding the cortical lesion at 2 to 7 days following injury, this expression returned to baseline levels at all subsequent time points and no increase in the expression of APP695 was detected at any time point. These results demonstrate that long-termAbeta accumulation in damaged axons can be induced in a non-transgenic rodent model of brain trauma. Surprisingly, the extent of this Abeta production appeared to be dependent on the maturity of the injury, but uncoupled from the gene expression of APP. Together, these data suggest a mechanism that may contribute to long-term neurodegeneration following brain trauma.

Amyloid beta-Peptides↗
PubMed2000

Amyloid beta-protein length and cerebral amyloid angiopathy-related haemorrhage.

The relationship between amyloid beta-protein (A beta) length and the apolipoprotein E (APOE) epsilon 2 allele, which is over-represented in cerebral amyloid angiopathy-related haemorrhage (CAAH), has not previously been examined. Of 57 CAA patients studied, 37 had CAAH. All patients, particularly those with CAAH had more blood vessels immunoreactive for A beta 40 than A beta 42 in both the leptomeninges and cerebral cortex. CAAH patients had more A beta 40-immunoreactive blood vessels in the leptomeninges (p < 0.001) and cortex (p = 0.027) than had non-haemorrhage patients. Cortical blood vessels, the usual source of haemorrhage in CAAH, were more frequently A beta 42 immunoreactive in APOE epsilon 2 carriers than in non-epsilon 2 carriers (p = 0.022). The APOE epsilon 2 allele may predispose to CAAH by increasing the seeding of cortical blood vessels by A beta 42.

Aged↗
PubMed2004

Involvement of CD14 and toll-like receptor 4 in the acute phase response of serum amyloid A proteins and serum amyloid P component in the liver after burn injury.

Acute phase proteins such as serum amyloid A proteins (SAAs) and serum amyloid P component (SAP) are induced in the liver after various insults (e.g., infection, injury). The cellular and molecular mechanisms controlling the expression of these acute phase proteins may be specifically designed for different insults. The roles of two central molecules of the lipopolysaccharide (LPS)-mediated inflammation pathway (CD14 and toll-like receptor 4 [Tlr4]) were investigated for the regulation of SAAs and SAP in the liver of mice after an 18% total body surface area burn injury. RT-PCR analysis revealed a subtype- and time-dependent induction of SAA mRNAs between 3 h and 3 days, while there was a peak induction of SAP mRNA at day 1. Marked elevations of SAA and SAP protein levels at day 1 supported the mRNA data. Furthermore, a differential regulation of SAAs and SAP mRNAs was noted between CD14 knockout (KO) and their control mice after injury. SAA protein was induced to a lesser degree after injury in C3H/HeJ (Tlr4-defective) mice than in their control mice. In addition, in both CD14 KO and C3H/HeJ mice, the induction of SAP protein was significantly reduced compared with respective controls. These data provide evidence that CD14 and Tlr4 participate, at least in part, in a cascade of signaling events that control the immediate-early and differential induction of SAAs and SAP in the liver after injury. They also suggest that LPS may be one of the initial inducing agents associated with these acute phase responses in the liver after injury.

Acute-Phase Reaction↗
PubMed1984

Degradation of amyloid A and serum amyloid A by red blood cell haemolysate in patients with familial mediterranean fever.

Enzymatic activity for the degradation of serum amyloid A (SAA) and amyloid A (AA) was detected in erythrolysates of normal subjects and patients with familial mediterranean fever. A significant difference between the activity of normal subjects and patients was not found. Serum inhibited the SAA (but not the AA) haemolysate proteolytic activity. Interindividual variation in the susceptibility of SAA to degradation by RBC haemolysates was shown. The original digestible fraction of SAA became gradually resistant to proteolytic cleavage over a 9 month period while the susceptibility of AA to degradation remained unchanged in this time period. These findings suggest that enzymatic degradation of SAA depends on the source of SAA, as well as inhibitory activity in serum.

Amyloid↗
PubMed1981

Purification of amyloid fibrils and protein AA from mouse amyloid deposits induced by caseinate and M. butyricum.

Amyloidosis was induced in mice by the simultaneous injection of sodium caseinate and heat-killed M. butyricum. Amyloid fibrils were isolated by collagenase digestion, 1 M NaCl extraction and repeated washing with 0.15 M NaCl. The amyloid fibril fraction was practically free of contaminations such as collagen, chromatin and membranes as judged by electron microscopic morphometry. The protein AA was purified from the isolated fibrils to an apparent homogeneity as judged by sodium dodecyl sulphate polyacrylamide gel electrophoresis using one step gel filtration from Sephacryl S-200 in the presence of 6 M guanidine-HCl and 50 mM dithiothreitol. The molecular weight of the peptides of the protein AA were 8,500 and 10,000.

Amyloid↗
PubMed2005

Expression of human FE65 in amyloid precursor protein transgenic mice is associated with a reduction in beta-amyloid load.

FE65 is an adaptor protein that interacts with the cytoplasmic tail of the amyloid precursor protein (APP). In cultured non-neuronal cells, the formation of the FE65-APP complex is a key element for the modulation of APP processing, signalling and beta-amyloid (Abeta) production. The functions of FE65 in vivo, including its role in the metabolism of neuronal APP, remain to be investigated. In this study, transgenic mice expressing human FE65 were generated and crossbred with APP transgenic mice, known to develop Abeta deposits at 6 months of age. Compared with APP mice, APP/FE65 double transgenic mice exhibited a lower Abeta accumulation in the cerebral cortex as demonstrated by immunohistochemistry and immunoassay, and a lower level of APP-CTFs. The reduced accumulation of Abeta in APP/FE65 double transgenics, compared with APP mice, could be linked to the low Abeta42 level observed at 4 months of age and to the lower APP-CTFs levels. The present work provides evidence that FE65 plays a role in the regulation of APP processing in an in vivo model.

Amyloid beta-Peptides↗
PubMed2006

Reduction of iron-regulated amyloid precursor protein and beta-amyloid peptide by (-)-epigallocatechin-3-gallate in cell cultures: implications for iron chelation in Alzheimer's disease.

Brain iron dysregulation and its association with amyloid precursor protein (APP) plaque formation are implicated in Alzheimer's disease (AD) pathology and so iron chelation could be considered a rational therapeutic strategy for AD. Here we analyzed the effect of the main polyphenol constituent of green tea, (-)-epigallocatechin-3-gallate (EGCG), which possesses metal-chelating and radical-scavenging properties, on the regulation of the iron metabolism-related proteins APP and transferrin receptor (TfR). EGCG exhibited potent iron-chelating activity comparable to that of the prototype iron chelator desferrioxamine, and dose dependently (1-10 microm) increased TfR protein and mRNA levels in human SH-SY5Y neuroblastoma cells. Both the immature and full-length cellular holo-APP were significantly reduced by EGCG, as shown by two-dimensional gel electrophoresis, without altering APP mRNA levels, suggesting a post-transcriptional action. Indeed, EGCG suppressed the translation of a luciferase reporter gene fused to the APP mRNA 5'-untranslated region, encompassing the APP iron-responsive element. The finding that Fe(2)SO(4) reversed the action of EGCG on APP and TfR proteins reinforces the likelihood that these effects are mediated through modulation of the intracellular iron pool. Furthermore, EGCG reduced toxic beta-amyloid peptide generation in Chinese hamster ovary cells overexpressing the APP 'Swedish' mutation. Thus, the natural non-toxic brain-permeable EGCG may provide a potential therapeutic approach for AD and other iron-associated disorders.

Amyloid beta-Peptides↗
PubMed1993

Normal cellular processing of the beta-amyloid precursor protein results in the secretion of the amyloid beta peptide and related molecules.

Alzheimer's disease is characterized by the extracellular deposition in the brain and its blood vessels of insoluble aggregates of the amyloid beta peptide (A beta). This peptide is derived from a large integral membrane protein, the beta-amyloid precursor protein (beta APP), by proteolytic processing. The A beta has previously been found only in the brains of patients with Alzheimer's disease or advanced aging. We describe here the finding that A beta is produced continuously by normal processing in tissue culture cells. A beta and closely related peptides were identified in the media of cells transfected with cDNAs coding for beta APP in a variety of cell lines and primary tissue cultured cells. The identity of these peptides was confirmed by epitope mapping and radiosequencing. Peptides of a molecular weight of approximately 3 and approximately 4 kDa are described. The 4 kDa range contains mostly the A beta and two related peptides starting N-terminal to the beginning of A beta. In the 3 kDa range, the majority of peptides start at the secretase site; in addition, two longer peptides were found starting at amino acid F(4) and E(11) of the A beta sequence. To identify the processing pathways which lead to the secretion of these peptides, we used a variety of drugs known to interfere with certain cell biological pathways. We conclude that lysosomes may not play a predominant role in the formation of 3 and 4 kDa peptides. We show that an acidic environment is necessary to create the N-terminus of the A beta and postulate that alternative secretory cleavage might result in the formation of the N-terminus of A beta and related peptides. This cleavage takes place either in the late Golgi, at the cell-surface or in early endosomes, but not in lysosomes. The N-terminus of most of the 3 kDa peptides is created by secretory cleavage on the cell surface or within late Golgi.

Amino Acid Sequence↗
PubMed1996

Participation of gene expression in the protection against amyloid beta-peptide toxicity by the beta-amyloid precursor protein.

The amyloid beta-peptide (A beta) is a toxic derivative of the beta-amyloid precursor protein. Alternative processing of this precursor also yields large soluble forms (APPSs) which are secreted from many cell types. These APPSs have neuritogenic and neuroprotective activities; indeed, APPSs can protect primary neurons from the toxicity of A beta itself. To begin to explore the regulation of gene expression by APPS, we have focused on the NF-kappa B transcription factor family. NF-kappa B is induced by conditions of stress, including cellular oxidation. We report that NF-kappa B can also be induced by APPS. Furthermore, we effected direct activation of NF-kappa B through disinhibition using antisense oligonucleotide technology. This means of activating NF-kappa B resulted in protection of neuroblastoma cells from the toxicity of a calcium ionophore and protection of primary hippocampal neurons from the toxicity of A beta. Together, these data suggest that NF-kappa B may exist as a common agent inducing a neuroprotective pattern of gene expression in response to either trophic cytokines or stress itself.

Amyloid beta-Peptides↗
PubMed2000

Regulation of cytokine secretion and amyloid precursor protein processing by proinflammatory amyloid beta (A beta).

Neurodegenerative processes in Alzheimer's disease (AD) are thought to be driven, in part, by the deposition of amyloid beta (A beta), a 39-43-aminoacid peptide product resulting from an alternative cleavage of amyloid precursor protein (APP). In addition to its neurotoxic properties, A beta may influence neuropathology by stimulating glial cell cytokine and acute phase protein secretion in affected areas of the brain (e.g., cortex, hippocampus). Using an in vitro human astrocyte model (U-373 MG astrocytoma cells), the effects of A beta treatment on acute phase protein (APP and alpha-1-antichymotrypsin [alpha 1-ACT]) and interleukin-8 (IL-8) were examined. U-373 MG cells secreted increased levels of alpha 1-ACT and neurotrophic/neuroprotective alpha-cleaved APP (alpha APP) after exposure to interleukin-1 beta (IL-1 beta) for 24 hours. A beta treatment resulted in a similar, but modest increase in alpha 1-ACT secretion, a two- to threefold stimulation of IL-8 production, and, conversely, a profound reduction in the levels of secreted alpha APPs. A beta inhibited alpha APP secretion by U-373 MG cells in a concentration- and conformation-dependent manner. Moreover, the reduction in alpha APP secretion was accompanied by an increase in cell-associated APP. Another proinflammatory amyloidogenic peptide, human amylin, similarly affected APP processing in U-373 astrocytoma cells. These data suggest that A beta may contribute to Alzheimer's-associated neuropathology by lowering the production of neuroprotective/neurotrophic alpha APPs. Moreover, the concomitant increase in cell-associated APP may provide increased substrate for the generation of amyloidogenic peptides within astrocytes.

Alzheimer Disease↗
PubMed2006

Physiological and biophysical factors that influence Alzheimer's disease amyloid plaque targeting of native and putrescine modified human amyloid beta40.

Amyloid beta40 (Abeta40) and its derivatives are being developed as probes for the ante-mortem diagnosis of Alzheimer's disease. Putrescine-Abeta40 (PUT-Abeta40) showed better plaque targeting than the native Abeta40, which was not solely explained by the differences in their blood-brain-barrier (BBB) permeabilities. The objective of this study was to elucidate the physiological and biophysical factors influencing the differential targeting of Abeta40 and PUT-Abeta40. Despite better plaque-targeting ability 125I-PUT-Abeta40 was more rapidly cleared from the systemic circulation than amyloid beta40 labeled with 125I (125I-Abeta40) after i.v. administration in mice. The BBB permeability of both compounds was inhibited by circulating peripheral Abeta40 levels. 125I-Abeta40 but not 125I-PUT-Abeta40 was actively taken up by the mouse brain slices in vitro. Only fluorescein-Abeta40, not fluorescein-PUT-Abeta40, was localized in the brain parenchymal cells in vitro. The metabolism of 125I-Abeta40 in the brain slices was twice as great as 125I-PUT-Abeta40. 125I-Abeta40 efflux from the brain slices was saturable and found to be 5 times greater than that of 125I-PUT-Abeta40. Thioflavin-T fibrillogenesis assay demonstrated that PUT-Abeta40 has a greater propensity to form insoluble fibrils compared with Abeta40, most likely due to the ability of PUT-Abeta40 to form beta sheet structure more readily than Abeta40. These results demonstrate that the inadequate plaque targeting of Abeta40 is due to cellular uptake, metabolism, and efflux from the brain parenchyma. Despite better plaque targeting of PUTAbeta40, its propensity to form fibrils may render it less suitable for human use and thus allow increased focus on the development of novel derivatives of Abeta with improved characteristics.

Alzheimer Disease↗
PubMed2006

Identification of novel small molecule inhibitors of amyloid precursor protein synthesis as a route to lower Alzheimer's disease amyloid-beta peptide.

A wealth of independent research with transgenic mice, antibodies, and vaccines has pointed to a causative role of the amyloid-beta peptide (A beta) in Alzheimer's disease (AD). Based on these and earlier associative studies, A beta represents a promising target for development of therapeutics focused on AD disease progression. Interestingly, a cholinesterase inhibitor currently in clinical trials, phenserine, has been shown to inhibit production of both amyloid precursor protein (APP) and A beta. We have shown that this inhibition occurs at the post-transcriptional level with a specific blocking of the synthesis of APP relative to total protein synthesis (Shaw et al., 2001). However, the dose of phenserine necessary to block APP production is far higher than that needed to elicit its anticholinesterase activity, and it is these latter actions that are dose limiting in vivo. The focus of this study was to screen 144 analogs of phenserine to identify additional small molecules that inhibit APP protein synthesis, and thereby A beta production, without possessing potent acetylcholinesterase (AChE) inhibitory activity. An enzyme-linked immunosorbent assay was used to identify analogs capable of suppressing APP production following treatment of human neuroblastoma cells with 20 muM of compound. Eight analogs were capable of dose dependently reducing APP and A beta production without causing cell toxicity in further studies. Several of these analogs had little to no AChE activities. Translation of APP and A beta actions to mice was demonstrated with one agent. They thus represent interesting lead molecules for assessment in animal models, to define their tolerance and utility as potential AD therapeutics.

Alzheimer Disease↗
PubMed2007

Dominance of amyloid precursor protein sequence over host cell secretases in determining beta-amyloid profiles studies of interspecies variation and drug action by internally standardized immunoprecipitation/mass spectrometry.

beta-Amyloid peptides, tentatively regarded as the principal neurotoxins responsible for Alzheimer's Disease, make up a set of products that varies significantly among different biological systems. The full implications of this complexity and its variations have yet to be defined. In this work, Abeta peptide populations were extracted from animal brain tissue or cell-conditioned media, immunoprecipitated with specific antibodies, and analyzed by matrix-assisted laser desorption time-of-flight mass spectrometry. (15)N-Substituted Abeta internal standards were added to gauge variations in the profile of captured peptides. Results from a range of species, including guinea pig, dog, rabbit, and wild-type and transgenic mice, showed that the Abeta peptide population in each system was mainly determined by the species of origin of the amyloid precursor protein (APP) and not by the host tissue or cell line. The same method was used to gauge the effect on the Abeta peptide profile of an inhibitor of gamma-secretase, one of the two proteinases that excises Abeta peptides from the precursor protein with different effects on specific peptides. Overall, the results demonstrate that the species of origin of the APP substrate dictates the outcome of APP processing to a greater extent than the origin of the processing enzymes, an important consideration in rationalizing the properties of different model systems.

Alanine↗
PubMed1993

Release of excess amyloid beta protein from a mutant amyloid beta protein precursor.

The 4-kilodalton amyloid beta protein (A beta), which forms fibrillar deposits in Alzheimer's disease (AD), is derived from a large protein referred to as the amyloid beta protein precursor (beta APP). Human neuroblastoma (M17) cells transfected with constructs expressing wild-type beta APP or a mutant, beta APP delta NL, recently linked to familial AD were compared. After continuous metabolic labeling for 8 hours, cells expressing beta APP delta NL had five times more of an A beta-bearing, carboxyl terminal, beta APP derivative than cells expressing wild-type beta APP and they released six times more A beta into the medium. Thus this mutant beta APP may cause AD because its processing is altered in a way that releases increased amounts of A beta.

Alzheimer Disease↗
PubMed2003

Unaltered plasma levels of beta-amyloid(1-40) and beta-amyloid(1-42) upon stimulation of human platelets.

Accumulation of beta-amyloid (Abeta) in the brain is one of the central lesions in Alzheimer's disease (AD). Alternative cleavage of the amyloid precursor protein (APP), occurring in both normal and AD subjects, results in the generation and secretion of soluble APP, Abeta(40) and Abeta(42). Platelets have been regarded as the primary source of circulating APP and Abeta. Plasma levels of Abeta may therefore be dependent on platelet activation. We analysed Abeta(40/42) in plasma in the presence of physiological agonists of platelet activation such as adenosine diphosphate, collagen, thrombin, and a synthetic agonist, thrombin receptor activator peptide 6. We found that the levels of Abeta(40/42) in plasma were not related to platelet activation, suggesting that sampling techniques affecting platelet activation do not confound measurement of Abeta(40/42 )in plasma.

Alzheimer Disease↗
PubMed2006

Role of amyloid precursor protein, amyloid-beta and gamma-secretase in cholesterol maintenance.

Lipids play an important part as risk factors for Alzheimer's disease. This article summarizes the current understanding of the molecular mechanism by which amyloid-beta (Abeta) peptides regulate cholesterol and sphingomyelin metabolism, and how in return cholesterol and sphingomyelin regulate Abeta peptide production. An understanding of the physiological function of amyloid precursor protein processing and Abeta function is critical for the development of future therapeutic approaches, e.g. statin treatment.

Alzheimer Disease↗