Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “AMYLOID”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 685 records · Page 38Linked to original sources
PubMed2002

Caspase-3-mediated cleavage of amyloid precursor protein and formation of amyloid Beta peptide in traumatic axonal injury.

Immunohistochemical studies demonstrate accumulation of the beta-amyloid precursor protein (APP) within injured axons following traumatic brain injury (TBI). Despite such descriptions, little is known about the ultimate fate of accumulating APP at sites of traumatic axonal injury (TAI). Recently, caspase-3-mediated cleavage of APP and subsequent Abeta deposition was linked to apoptotic neuronal death pathways in hippocampal neurons following ischemic and excitotoxic brain injury. Given that (1) APP is known to accumulate within traumatically injured axons, (2) caspase-3 activation has been demonstrated in traumatic axonal injury (TAI), and (3) recent studies have identified a caspase-3 cleavage site within APP, we initiated the current investigation to determine whether caspase-3-mediated cleavage of APP occurs in TAI. We further assessed whether these events were found in relation to Abeta peptide formation. To this end, we employed antibodies targeting APP, the caspase-3-mediated breakdown product of APP proteolysis, and the Abeta peptide. Rats were subjected to impact acceleration TBI (6 h to 10 days survival), and their brains were processed for single-label bright field and multiple double-label immunofluorescent paradigms using the above antibodies. By 12 h postinjury, caspase-3-mediated APP proteolysis (CMAP) was demonstrated within the medial lemniscus (ML) and medial longitudinal fasciculus (MLF) in axons undergoing TAI, identified by their concomitant APP accumulation. Immunoreactivity for CMAP persisted up to 48 h postinjury in the ML and MLF, but was notably reduced by 10 days following injury. Further, CMAP was colocalized with Abeta formation in foci of TAI. The current study demonstrates that caspase-3 cleavage of APP occurs in TAI and is associated with formation of Abeta peptide. These findings are of interest given recent epidemiological studies supporting an association between TBI and later risk for AD development.

Alzheimer Disease↗
PubMed1993

A new hypothesis for the mechanism of amyloid toxicity, based on the calcium channel activity of amyloid beta protein (A beta P) in phospholipid bilayer membranes.

Amyloid beta protein (A beta P) is the 40-42 residue polypeptide implicated in the pathogenesis of Alzheimer's disease (AD). We have reconstituted this peptide into phosphatidylserine liposomes and then fused the liposomes with a planar lipid bilayer. When incorporated into this bilayer, the A beta P forms cation selective channels capable of transporting calcium and some monovalent cations including cesium, lithium, potassium, and sodium. The channels behave in an ohmic fashion and single channels can be shown to exhibit multiple subconductance states. Hitherto, A beta P has been presumed to be neurotoxic, although direct demonstration of toxicity has proved elusive. On the basis of the present data we suggest that the ion channel activity of the polypeptide may be the basis of its neurotoxic effects.

Alum Compounds↗
PubMed2002

Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor.

Cerebral amyloid beta-protein angiopathy (CAA) is a key pathological feature of patients with Alzheimer's disease and certain related disorders. Several mutations have been identified within the Abeta region of the Abeta protein precursor (AbetaPP) gene that appear to enhance the severity of CAA. A new mutation has been identified within the Abeta region (D23N) of AbetaPP that is associated with severe CAA in an Iowa kindred. Recently, we showed that E22Q Dutch, D23N Iowa, and E22Q/D23N Dutch/Iowa double-mutant Abeta40 peptides rapidly assemble in solution to form fibrils compared to wild-type Abeta40. Similarly, the E22Q Dutch and D23N Iowa Abeta40 peptides were found to induce robust pathologic responses in cultured human cerebrovascular smooth muscle (HCSM) cells, including elevated levels of cell-associated AbetaPP, proteolytic breakdown of actin, and cell death. Double-mutant E22Q/D23N Dutch/Iowa Abeta40 was more potent than either single-mutant form of Abeta in causing pathologic responses in HCSM cells. These in vitro data suggested that the E22Q Dutch and D23N Iowa substitutions promote fibrillogenesis and the pathogenicity of Abeta towards HCSM cells. Moreover, the presence of both CAA substitutions in the same Abeta peptide further enhances the fibrillogenic and pathogenic properties of Abeta. We also have generated transgenic mouse models to examine the effects of single and double CAA mutations in AbetaPP in vivo. Preliminary analysis of transgenic mouse brains indicates that expression of double-mutant E22Q/D23N Dutch/Iowa AbetaPP leads to robust deposition of Abeta in a vascular-weighted manner.

Amino Acid Sequence↗
PubMed2004

The amyloid paradox: amyloid-beta-metal complexes can be neurotoxic and neuroprotective.

Senile plaques in the brains of people with Alzheimer disease (AD) are primarily composed of the amyloid-beta (Abeta) peptide and contain substantially elevated levels of iron, copper and zinc. These metals bind to Abeta and have been reported to increase the toxicity of Abeta to cultured neurones. Other reports have demonstrated that Abeta can reduce the neurotoxicity of metal ions, suggesting that the interaction can, under some circumstances, be protective. To investigate these apparently conflicting results, human Abeta1-42 was co-injected with iron, copper or zinc (at the concentrations found in plaques) into rat cerebral cortex, and the resulting numbers of dying neurones were compared. It was found that Abeta complexed with either iron or zinc was more toxic than Abeta alone. In contrast, Abeta-copper complexes were not neurotoxic. Surprisingly, we observed that when iron or copper were combined with Abeta, the neurotoxicity of these metals was substantially reduced, suggesting that Abeta may help to limit the toxicity of redox-active metal ions, thereby assisting the antioxidant defence of the brain. Thus paradoxical effects occur when Abeta complexes with metal ions, where Abeta-metal complexes are capable of being neurotoxic and neuroprotective.

Amyloid beta-Peptides↗
PubMed1979

Lymphoid cells in endotoxin-induced production of the amyloid-related serum amyloid A protein.

Endotoxin-treated mice exhibit a rapid rise in the level of the serum amyloid A (SAA) protein, but this effect is not observed in endotoxin-resistant C3H/HeJ mice. To evaluate the role of lymphoid cells in the production of SAA protein, C3H/HeJ mice were adoptively transfused with endotoxin-sensitive (C3H/HeN) bone marrow cells. After such adoptive transfer, endotoxin treatment of C3H/HeJ mice resulted in high serum levels of SAA protein. The ability of chimeric mice to make SAA protein correlated with the presence of endotoxin-sensitive B lymphocytes and macrophages. These findings suggest that lymphocytes and/or macrophages play an important role in initiating SAA protein synthesis after endotoxin treatment and suggest a possible mechanism by which chronic infection or inflammation leads to amyloidosis.

Amyloid↗
PubMed2005

Beta-amyloid and oxidative stress jointly induce neuronal death, amyloid deposits, gliosis, and memory impairment in the rat brain.

Infusion of Fe2+, Abeta42, and buthionine-sulfoximine (FAB), but not Abeta42 alone or in combination with Fe2+, into the left cerebral ventricle of Long-Evans rats for 4 weeks induced memory impairment that was accompanied by increased hyperphosphorylated Tau protein levels in the CSF. FAB-infused animals displayed thioflavin-S-positive amyloid deposits, hyperphosphorylated Tau protein, neuronal loss, and gliosis. Animals treated with Abeta42, Fe2+, or buthionine-sulfoximine alone or in combination failed to show the histological modifications seen with FAB. This data suggests that Abeta42 is not sufficient to induce an Alzheimer's disease-like symptomatology, and it supports a model whereby a decrease in the brain's antioxidant defense system leads to the Abeta42-independent oxidative stress necessary for the peptide to induce histopathological changes and memory loss.

Amyloid↗
PubMed2001

Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome.

CONTEXT: Down syndrome patients who live to middle age invariably develop the neuropathologic features of Alzheimer disease, providing a unique situation in which to study the early and sequential development of these changes. OBJECTIVE: To study the development of amyloid deposits, senile plaques, astrocytic and microglial reactions, and neurofibrillary tangles in the brains of young individuals (<30 years of age) with Down syndrome. METHODS: Histologic and immunocytochemical study of a series of autopsy brains (n = 14, from subjects aged 11 months to 56 years, with 9 subjects <30 years) examined at the Office of the Chief Medical Examiner of the State of Maryland and The Johns Hopkins Hospital. RESULTS: The principal observations included the presence of intraneuronal Abeta immunostaining in the hippocampus and cerebral cortex of very young Down syndrome patients (preceding the extracellular deposition of Abeta) and the formation of senile plaques and neurofibrillary tangles. CONCLUSIONS: We propose the following sequence of events in the development of neuropathologic changes of Alzheimer disease in Down syndrome: (1) intracellular accumulation of Abeta in neurons and astrocytes, (2) deposition of extracellular Abeta and formation of diffuse plaques, and (3) development of neuritic plaques and neurofibrillary tangles with activation of microglial cells.

Adolescent↗
PubMed2000

Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease.

Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect the neuropathological findings. To test this hypothesis, we treated PDAPP mice, a transgenic line displaying numerous neuropathological features of AD, between the ages of approximately 5 and approximately 12 months with human Abeta synthetic peptide mucosally each week. We found significant decreases in the cerebral Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti-Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD.

Administration, Intranasal↗
PubMed2003

[Deletion mutation of beta-amyloid precursor protein decreases the secretion of beta-amyloid in SH-SY5Y neuroblastoma cells].

OBJECTIVE: To explore the effect of A beta secretion lacking exons 2 and 3 of APP695 (delta APP695) on SH-SY5Y neuroblastoma cells. METHODS: APP695 cDNA and delta APP695 cDNA eukaryotic expression vectors were constructed by gene recombination. Immunoprecipitation Western blotting was used to analyse the A beta secretion and MTT assay to observe the cell viability's change after being stably transfected with the plasmids by lipofectamine method. RESULTS: Stable transfectants were selected in 0.6 g.L-1 G418. delta APP695 cDNA construct transfection decreased significantly the production of beta amyloid in the SH-SY5Y compared with APP695 cDNA construct. It did not affect the cell viability by MTT method. CONCLUSION: This result suggests that the alternative splicing of APP exons 2 and 3 modulates the secretion of A beta by influencing the processing of APP.

Amyloid beta-Peptides↗
PubMed1985

Human serum amyloid P component. cDNA isolation, complete sequence of pre-serum amyloid P component, and localization of the gene to chromosome 1.

Complementary DNA clones corresponding to the human serum amyloid P component (SAP) were isolated, and the complete nucleotide and derived amino acid sequence of preSAP was determined. PreSAP biosynthesis is directed by a 1.1-kilobase mRNA. Synthesis and postsynthetic processing of preSAP in Xenopus oocytes result in secretion of a protein with mobility similar to native purified SAP when analyzed by sodium dodecyl sulfate gel electrophoresis. The human SAP gene is on chromosome 1, probably closely linked to the gene for C-reactive protein which encodes the related acute phase reactant found in human plasma.

Amino Acid Sequence↗
PubMed1982

Secretion of serum amyloid protein and assembly of serum amyloid protein-rich high density lipoprotein in primary mouse hepatocyte culture.

The serum amyloid protein (apo-SAA) is a unique high density lipoprotein apoprotein exhibiting dramatic increases in plasma concentration following host injury. The events involved in the secretion of apo-SAA and assembly of apo-SAA-rich lipoprotein particles were studied in primary, serum-free culture of adult BALB/c mouse hepatocytes harvested 3 h following administration of the potent apo-SAA inducer, bacterial endotoxin (50 micrograms of intraperitoneally administered Salmonella typhosa lipopolysaccharide). An approximately 3.5-fold increase in the initial rate of apo-SAA secretion was observed over that of hepatocytes isolated from control mice, whereas the rate of apo-A-I secretion was unchanged by endotoxin administration. Sodium dodecyl sulfate-gel electrophoresis and autoradiography of [35S]methionine-labeled cell products indicated the synthesis of both major mouse apo-SAA isotypes by hepatocytes. Essentially all of the secreted apo-SAA chromatographed in Sephadex G-150 with an elution volume corresponding to a molecular weight of approximately 12,000. Approximately 90% of the secreted apo-SAA was recovered in fractions (d greater than 1.21 g/ml) following ultracentrifugal fractionation. In media supplemented with human lipoproteins (100 micrograms/ml), approximately 50% of the secreted apo-SAA was recovered in the high density lipoprotein fraction. These results suggest that mouse apo-SAA is secreted in monomeric form and becomes associated with lipoproteins in the intravascular compartment.

Amyloid↗
PubMed1997

Characterization of new polyclonal antibodies specific for 40 and 42 amino acid-long amyloid beta peptides: their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases.

BACKGROUND: In Alzheimer's disease (AD), the main histological lesion is a proteinaceous deposit, the senile plaque, which is mainly composed of a peptide called A beta. The aggregation process is thought to occur through enhanced concentration of A beta 40 or increased production of the more readily aggregating 42 amino acid-long A beta 42 species. MATERIALS AND METHODS: Specificity of the antibodies was assessed by dot blot, Western blot, ELISA, and immunoprecipitation procedures on synthetic and endogenous A beta produced by secreted HK293 cells. A beta and p3 production by wild-type and mutated presenilin 1-expressing cells transiently transfected with beta APP751 was monitored after metabolic labeling and immunoprecipitation procedures. Immunohistochemical analysis was performed on brains of sporadic and typical cerebrovascular amyloid angiopathy (CAA) cases. RESULTS: Dot and Western blot analyses indicate that IgG-purified fractions of antisera recognize native and denaturated A beta s. FCA3340 and FCA 3542 display full specificity for A beta 40 and A beta 42, respectively. Antibodies immunoprecipitate their respective synthetic A beta species but also A beta s and their related p3 counterparts endogenously secreted by transfected human kidney 293 cells. This allowed us to show that mutations on presenilin 1 triggered similar increased ratios of A beta 42 and its p 342 counterpart over total A beta and p3. ELISA assays allow detection of about 25-50 pg/ml of A beta s and remain linear up to 750 to 1500 pg/ml without any cross-reactivity. FCA18 and FCA3542 label diffuse and mature plaques of a sporadic AD case whereas FCA3340 only reveals the mature lesions and particularly labels their central dense core. In a CAA case, FCA18 and FCA3340 reveal leptomeningeal and cortical arterioles whereas FCA3542 only faintly labels such structures. CONCLUSIONS: Polyclonal antibodies exclusively recognizing A beta 40 (FCA 3340) or A beta 42 (FCA3542) were obtained. These demonstrated that FAD-linked presenilins similarly affect both p342 and A beta 42, suggesting that these mutations misroute the beta APP to a compartment where gamma-secretase, but not alpha-secretase, cleavages are modified. Overall, these antibodies should prove useful for fundamental and diagnostic approaches, as suggested by their usefulness for biochemical, cell biological, and immunohistochemical techniques.

Alzheimer Disease↗
PubMed2000

Effect of apolipoprotein AII on the interaction of apolipoprotein E with beta-amyloid: some apo(E-AII) complexes inhibit the internalization of beta-amyloid in cultures of neuroblastoma cells.

Apolipoprotein (apo) E and its polymorphism are linked to the pathogenesis of late-onset and sporadic Alzheimer's disease (AD). ApoE facilitates the deposition and fibrillogenesis of beta-amyloid (Abeta), and may participate in Abeta clearance. We recently found that apo(E-AII) complex binds to Abeta much more strongly than does monomeric apoE. Here, we investigated the effect of apoAII on the interaction between apoE and Abeta. Addition of apoAII to apoE monomers increased the binding of apoE2 and apoE3 to Abeta(1-42), presumably following the formation of apo(E3-AII), apo(E2-AII), and apo(AII-E2-AII) complexes. This increased binding was not seen in the case of apoE4. When neuroblastoma cells were cultured in media containing Abeta(1-42) and a mixture of apoE3 and apoAII, intracellular Abeta was significantly reduced and cell viability was maintained at a higher level than in cells cultured without apoAII. ApoE2 itself seemed to act as an inhibitor of the endocytosis of Abeta, and we did not observe a significant effect of apoAII on the movement of Abeta in apoE2-containing medium. However, cell viability could be maintained at a higher level (as with apoE3) by adding apoAII to apoE2, despite the reduced viability of cells incubated without apoAII. In medium containing apoE4, both the amount of Abeta accumulated into cells and the cell viability were unchanged by the presence of apoAII in the medium. In addition, apoE4 itself was toxic, as previously suggested. These findings demonstrate that the type of apo(E-AII) complex present could underlie the isoform-specific role of apoE in the pathogenesis of AD.

Alzheimer Disease↗
PubMed2004

Cerebrospinal fluid amyloid beta peptide patterns in Alzheimer's disease patients and nondemented controls depend on sample pretreatment: indication of carrier-mediated epitope masking of amyloid beta peptides.

A quantitative urea-based amyloid beta (Abeta)-sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western immunoblot (Abeta-SDS-PAGE/immunoblot) reveals highly conserved and disease-specific Abeta peptide patterns (Abeta 1-37, 1-38, 1-39, 1-40, 1-42) in Alzheimer's disease (AD) patients and nondemented controls. For further standardization of this method, we analyzed cerebrospinal fluid (CSF) of eight probable AD patients and seven nondemented controls using different preanalytical procedures for Abeta-SDS-PAGE/immunoblot and Abeta1-42-enzyme linked immunosorbent assay (ELISA). Both diagnostic groups were discriminated significantly by absolute levels of Abeta1-42 and ratios of Abeta1-42/40, 1-42/38, 1-42/39. Preanalytical freezing of CSF led to a highly significant loss of all Abeta peptide species. This effect was most pronounced for Abeta1-42 and completely prevented by SDS-heat denaturation prior to freezing. Prolonged storage of SDS-heat denatured CSF led to a selective loss of Abeta1-42 and impaired the discrimination of diagnostic groups as measured by Abeta-SDS-PAGE/immunoblot. Neither freezing nor storage significantly affected absolute Abeta1-42 levels as determined by Abeta1-42-ELISA, but both impaired the discrimination of diagnostic groups. Hence, we suggest immediate analysis of samples for Abeta1-42-ELISA, analysis after a short freezing interval for Abeta-SDS-PAGE/immunoblot, and avoidance of prolonged storage intervals. Remarkably, Abeta-SDS-PAGE/immunoblot measured threefold higher levels of Abeta1-42 in CSF than Abeta1-42-ELISA. In summary, our results indicate carrier-mediated epitope masking of Abeta1-42.

Adult↗
PubMed2006

Amyloid beta up-regulates brain-derived neurotrophic factor production from astrocytes: rescue from amyloid beta-related neuritic degeneration.

Astrocytes, the most abundant type of glia in the brain, are considered to play a key role in Alzheimer's disease (AD) pathologies. In a cell culture study, we have previously shown that astroglial responses against amyloid beta (Abeta) occur before obvious neuronal damage could be detected, suggesting the possibility that astrocytes might be an attractive therapeutic target for treating AD. In the present study, we investigated astroglial gene expression changes in response to Abeta to elucidate further the role of astrocytes in Abeta toxicity. By using real-time PCR and ELISA analyses, we found that Abeta rapidly induced astrocytes to produce brain-derived neurotrophic factor (BDNF). Abeta42 was more effective than Abeta40 in increasing astroglial BDNF production. Moreover, BDNF treatment rescued the neuronally differentiated human neuroblastoma cells from neuritic degeneration caused by Abeta toxicity. This is the first study to demonstrate that astrocytes are capable of increasing the production of a particular neurotrophic factor in response to Abeta. Our findings also identify BDNF as a potential therapeutic agent for preventing Abeta-related neuritic degeneration.

Amyloid↗
PubMed1993

A constitutively expressed serum amyloid A protein gene (SAA4) is closely linked to, and shares structural similarities with, an acute-phase serum amyloid A protein gene (SAA2).

The acute-phase reactant serum amyloid A (SAA) is a polymorphic apolipoprotein encoded by a family of highly homologous and closely linked genes: SAA1, SAA2, and SAA3. We have isolated a human genomic cosmid clone containing the gene encoding a fourth, constitutively expressed member of the human SAA superfamily, C-SAA, together with an SAA2*2 (SAA2 beta) gene. The gene encoding C-SAA shares the same 5' to 3' orientation as SAA2*2 and has the characteristic four-exon structure of the other members of the SAA superfamily. The exons of the gene encoding C-SAA share only limited sequence identity with those of SAA1, SAA2, and SAA3; they specify an mRNA, represented by the CS-1 cDNA reported previously by us, which is expressed at low levels (relative to the acute-phase SAAs) in normal and acute-phase liver. The gene encoding C-SAA is located 9 kb downstream of SAA2*2 and therefore occupies the locus that has been identified as containing the SAA4 gene.

Acute-Phase Proteins↗
PubMed2001

Intracellular apolipoprotein E affects Amyloid Precursor Protein processing and amyloid Abeta production in COS-1 cells.

The apoE gene has been identified as a major susceptibility locus for late-onset Alzheimer's disease (LOAD). The epsilon4 allele greatly reduces age of onset of LOAD as compared to the wild-type 3 allele. The molecular mechanism(s) underlying the association has not yet been fully elucidated. The apoE protein has been shown to physically interact with the Abeta region of the Amyloid Precursor Protein (APP), but also with the ectodomain of the APP holoprotein itself. In this study we have used apoE fusion proteins containing either the ER retention sequence KDEL or trans-Golgi network (TGN) signal sequence in order to define potential apoE-mediated alterations in APP protein processing. Co-expression and pulse-chase experiments showed that a functional apoE:APP interaction occurs intracellularly which directly affects maturation and subsequently the secretion kinetics of APP. In addition, an epsilon4 allele-specific induction of Abeta production has been demonstrated. apoE3 resulted in increased Abeta production only when targeted to the ER, as observed in cells transfected with an apoE3KDEL fusion protein as well as following treatment with brefeldin A. The findings suggest that in cells that express both apoE and APP, such as astrocytes and microglia, a functional apoE:APP interaction may occur which modulates APP processing and Abeta production.

Alleles↗