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At least 523 records · Page 29Linked to original sources
PubMed2001

The severity of cortical Alzheimer's type changes is positively correlated with increased amyloid-beta Levels: Resolubilization of amyloid-beta with transition metal ion chelators.

The most consistent diagnostic neuropathological lesion in Alzheimer's disease (AD) is the senile plaque of which the 4 kD amyloid-beta (Abeta) peptide is the major proteinaceous component. In this study cortical Abeta levels were immunochemically measured in 70 post-mortem human brains and compared against their neuropathological grading as determined by the densities of amyloid plaques and neurofibrillary tangles. The mean concentration of cortical Abeta/mg protein increased with the severity of the cortical degenerative changes (AD0 < AD1 < AD2 < AD3). Brains with the severe degenerative changes (AD3), corresponded to definite AD cases and exhibited significantly increased concentrations of Abeta (11.1+/-3.08 ng/mg total protein, n=17) when compared with control brains without any degenerative changes (AD0; 0.06+/-0.06 ng/mg total protein, n=14,P=0.003). The extraction of Abeta from the cortex of AD3 brains was significantly enhanced in a dose dependent manner by the presence of the metal ion chelator N,N,N',N'-tetrakis(2-pyridylmethyl) ethylenediamine (5 mM TPEN, P < 0.0001). The chelator/antioxidant 1,2-dithiolane-3-pentanoic acid (lipoic acid), also resolubilized Abetain a dose-dependant manner. Both chelators also enhanced the extraction of Abeta from the frontal cortex of AbetaPP-transgenic mice suggesting this animal model of amyloidosis may be useful for evaluating the biochemical and therapeutic effects of chelators/antioxidants on Abeta deposition. In summary our results indicate that increased Abeta load is correlated with the severity of the cortical AD-type changes and that chelators/antioxidants may be useful in reducing neuronal amyloid burden.

Journal Article↗
PubMed2000

Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis.

A novel missense mutation, Leu723Pro, in the amyloid precursor protein (APP) gene was discovered in an early-onset Alzheimer's disease family. Expression of L723P mutant APP complementary DNA in CHO cells resulted in a 1.4- to 1.9-fold increased production of the 42(43)-amino acid length amyloid beta peptide compared with the wild-type sequence and was capable of causing apoptosis. The mutation is predicted to alter the luminal transmembrane length and helical arrangement of the APP molecule and thus affect the gamma-secretase cleavage site.

Amino Acid Sequence↗
PubMed2003

Proteasome-mediated degradation of the C-terminus of the Alzheimer's disease beta-amyloid protein precursor: effect of C-terminal truncation on production of beta-amyloid protein.

The beta-amyloid protein (Abeta) is derived by proteolytic processing of the amyloid protein precursor (APP). Cleavage of APP by beta-secretase generates a C-terminal fragment (APP-CTFbeta), which is subsequently cleaved by gamma-secretase to produce Abeta. Our previous studies have shown that the proteasome can cleave the C-terminal cytoplasmic domain of APP. To identify proteasome cleavage sites in APP, two peptides homologous to the C-terminus of APP were incubated with recombinant 20S proteasome. Cleavage of the peptides was monitored by reversed phase high-performance liquid chromatography and mass spectrometry. Proteasome cleaved the APP C-terminal peptides at several sites, including a region around the sequence YENPTY that interacts with several APP-binding proteins. To examine the effect of this cleavage on Abeta production, APP-CTFbeta and mutant forms of APP-CTFbeta terminating on either side of the YENPTY sequence were expressed in CHO cells. Truncation of APP-CTFbeta on the N-terminal side of the YENPTY sequence at residue 677 significantly decreased the amount of Abeta produced, whereas truncation on the C-terminal side of residue 690 had little effect. The results suggest that proteasomal cleavage of the cytosolic domain of APP at the YENPTY sequence decreases gamma-secretase processing, and consequently inhibits Abeta production. Therefore, the proteasome-dependent trafficking pathway of APP may be a valid therapeutic target for altering Abeta production in the Alzheimer's disease brain.

Alzheimer Disease↗
PubMed2002

Intraneuronal amyloid precursor protein (APP) and appearance of extracellular beta-amyloid peptide (abeta) in the brain of aging kokanee salmon.

Antibodies to human amyloid precursor protein (APP(695)) and beta-amyloid peptide (A beta(1-42)) were used to determine timing of amyloidosis in the brain of kokanee salmon (Oncorhynchus nerka kennerlyi) in one of four reproductive stages: immature (IM), maturing (MA), sexually mature (SM), and spawning (SP), representing a range of aging from somatically mature but sexually immature to spawning and somatic senescence. In IM fish, immunoreactive (ir) intracellular APP occurred in 18 of 23 brain regions. During sexual maturation and aging, the number of neurons expressing APP increased in 11 of these APP-ir regions. A beta-ir was absent in IM fish, present in seven regions in MA fish, moderately abundant in 15 regions in SM fish, and was most abundant in all brain regions of SP fish exhibiting A beta-ir. Intracellular APP-ir was observed in brain regions involved in sensory integration, olfaction, vision, stress responses, reproduction, and coordination. Intra- and extracellular A beta(1-42) immunoreactivity (A beta-ir) was present in all APP-ir regions except the nucleus lateralis tuberis (hypothalamus) and Purkinje cells (cerebellum). APP-ir and A beta deposition increase during aging. APP-ir is present in IM fish; A beta-ir usually appears first in MA or SM fish and increases in SM fish as does APP-ir. Extracellular A beta deposition dramatically increases between SM and SP stages (1-2 weeks) in all fish, indicating an extremely rapid and synchronized process. Rapid senescence observed in pacific salmon could make them a useful model to investigate timing of amyloidosis and neurodegeneration during brain aging.

Aging↗
PubMed1993

Secretory form of Alzheimer amyloid precursor protein 695 in human brain lacks beta/A4 amyloid immunoreactivity.

It is not clear how Alzheimer amyloid precursor proteins (APP) are metabolized in the brain itself. Secretory forms of APP in a phosphate buffer-soluble fraction were purified from post-mortem human brain by heparin-affinity and ion-exchange chromatography and analyzed by N-terminal amino acid sequencing and SDS polyacrylamide gel electrophoresis/immunoblotting. We found apparently similar multi-isoforms of secretory APP (at 93-97, 105-112 and 123 KDa) to those that we have described recently in cerebrospinal fluid. Antisera to the initial part of the beta/A4 sequence labelled only those bands that were found to react with antiserum to the Kunitz-type inhibitor insert of APP, suggesting that beta/A4 amyloid may be generated specifically from APP-695.

Adult↗
PubMed1995

An age-related correlation between levels of beta-amyloid precursor protein and beta-amyloid in human cerebrospinal fluid.

We investigated the levels of amyloid precursor protein (APP) and beta-amyloid peptide (A beta) in the cerebrospinal fluid (CSF) from 110 individuals ranging in age from newborn to 82-years old to analyze their regulation with age. These samples were segregated into two groups; one group contained CSF samples from patients with diagnosed CNS abnormalities and the second group contained CSF samples from patients with no known CNS disorders. The presence of APP and A beta was detected in all ages and from both CSF groups. No significant difference in the average level of A beta or APP was noted from either group with a change in age. However, a positive correlation was found to exist between levels of APP and A beta in individuals 25 years and older, suggesting that APP and A beta processing in the CSF is developmentally regulated. This observation was observed for both CSF groups.

Adolescent↗
PubMed1994

Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury.

Alternative processing of the beta-amyloid precursor protein (beta APP) can result in liberation of either secreted forms of beta APP (APPSs), which may play roles in neuronal plasticity and survival, or amyloid beta-peptide (A beta), which can be neurotoxic. In rat hippocampal cell cultures A beta 1-40 caused a time- and concentration-dependent reduction in neuronal survival. APPS695 and APPS751 significantly reduced A beta-induced injury in a concentration-dependent manner. A beta caused an elevation of intracellular calcium levels ([Ca2+]i) which was significantly attenuated by APPSs. A beta also caused induction of reactive oxygen species (measured using the oxidation-sensitive fluorescent dye 2,7-dichlorofluorescein) which was also attenuated by APPSs. A beta-induced neurotoxicity and elevations of [Ca2+]i were attenuated by vitamin E, suggesting the involvement of free radicals in A beta-induced loss of calcium homeostasis and neuronal injury. The APPSs protected neurons against oxidative injury caused by exposure to iron. Taken together, the data indicate that A beta kills neurons by causing free radical production and increased [Ca2+]i. APPSs can protect neurons against such free radical- and Ca(2+)-mediated injury. These findings support the hypothesis that altered processing of beta APP contributes to neuronal injury in Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1990

Topographic heterogeneity of amyloid B-protein epitopes in brains with various forms of neuronal ceroid lipofuscinoses suggesting defective processing of amyloid precursor protein.

To verify our hypothesis of defective protease inhibitor domains that are encoded by abnormal processing of amyloid precursor protein (APP) in brains of patients with neuronal ceroid lipofuscinoses (NCL), immunohistochemical and cytochemical studies were performed with monoclonal antibodies (mAbs) directed against various domains of APP. For the studies, 22 autopsy brains were used: 12 with different forms of NCL, and 10 control brains. The staining procedure for the avidin-biotin complex (ABC) technique and the postembedding gold-labelled procedure for electron microscopy (EM) were employed. Of all mAbs used for the study, only mAbs generated against amyloid B-protein bound to neural tissue were affected with NCL. The strongest immunostaining of neurons and of some reactive glial cells was found in brains with the juvenile form of NCL. Only in the infantile form of the disease were some neurons overloaded with storage material weakly immunoreactive. In brains of patients with the adult form of NCL, immunoreactivity was found in affected neurons and in extracellularly deposited material of senile plaques. The results of EM study showed that the immunoreactivity was restricted to lysosomal cytosomes in neural tissue with any form of NCL selectively localized on the curvilinear and fingerprint proteinaceous component of ceroid lipofuscin. Studies performed on control aging brains and Alzheimer's disease (AD) brains confirmed previous observations of immunoreactivity being found diffusely in the protein component of some neurons containing lipopigment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1997

Differential pattern of beta-amyloid, amyloid precursor protein and apolipoprotein E expression in cortical senile plaques.

Regional differences in senile plaques immunostained by antibodies against beta-amyloid A4 (beta-A4), amyloid precursor protein 695 (APP) and apolipoprotein E (apo E) were studied in the hippocampus and the entorhinal, temporal and occipital cortices both quantitatively and semiquantitatively with respect to the laminar cortical distribution of the plaques. These patterns were related to the staging of Alzheimer's disease in regard to the distribution of neurofibrillary tangles (Braak and Braak (1991) Acta Neuropathol 82: 239-259). In the hippocampus and especially in sector CA 1, no significant differences in the number of plaques visualized by the different antibodies were found. In contrast, there was a striking difference in neocortical regions. Here, significantly higher numbers of plaques positive for beta-A4 than that for APP and apo E were present in all stages, except in the stages I and VI, and for apo E in stage II. The highest densities of beta-A4-positive plaques were found in the isocortical layers III and V and in the entorhinal pre-alpha, pre-gamma, pri-alpha and pri-beta layers. The preferentially affected area, showing plaques positive for all three antibodies, was the entorhinal-hippocampal circuit with early affection of CA 1, which represents the direct and indirect target of the entorhinal neurons of the upper layers. Therefore, we suggest that plaques with dystrophic neurites, positive for APP, seem to be generated secondarily in afferent areas such as the hippocampus, which is the main afferent target of the entorhinal region. Diffuse plaques, negative for APP and apo E, are virtually absent in the CA 1 and seem to originate independently of afferent neuronal dysfunction, as indicated by neurofibrillary tangles.

Alzheimer Disease↗
PubMed1984

A variant prealbumin-related low molecular weight amyloid fibril protein in familial amyloid polyneuropathy of Japanese origin.

Amyloid fibril protein with a molecular weight of 8K daltons, in addition to one of 16K daltons, has been isolated and characterized from an autopsy sample of a patient with familial amyloid polyneuropathy in a Japanese family from Ogawa Village, Nagano Prefecture. The component was shown to react with an antiserum to normal plasma prealbumin, as did the other. Following the purification by reverse phase liquid chromatography, it was digested with trypsin and the peptides, after the purification by HPLC were sequenced. The data showed that the component was a distinct fragment whose sequence was identical with that of the residues from Gly-6 to Tyr-78 of the prealbumin, except that it had a methionine for a valine at position 25. This corresponded with the position 30 where a valine residues has been reported for the sequence of the normal plasma prealbumin.

Amino Acid Sequence↗
PubMed1993

The expression of amyloid beta protein precursor protects nerve cells from beta-amyloid and glutamate toxicity and alters their interaction with the extracellular matrix.

The biological function of amyloid beta protein precursor (ABPP) in nerve cells is examined by transfecting it into the B103 clonal nerve cell line which makes no ABPP and asking if a variety of biological activities are altered. Although ABPP is expressed by the transfected cells at high levels, there are no detectable differences between the ABPP negative clones and the clones expressing ABPP with respect to growth rate in high serum medium, dibutyryl-cyclic AMP-induced differentiation, or morphology on plastic culture dishes. There are, however, significant differences in a number of properties between the two groups of cell lines. Cells expressing ABPP adhere more rapidly and have an enhanced rate of neurite outgrowth on collagen substrata. They also grow more rapidly in low serum medium. Finally, the expression of ABPP weakly but significantly protects the nerve cells from amyloid beta protein and glutamate toxicity.

Amyloid beta-Peptides↗
PubMed1994

Interleukin-1 beta dissociates beta-amyloid precursor protein and beta-amyloid peptide secretion.

A heightened production of interleukin 1 beta (IL-1 beta) has been reported in microglial-associated amyloid deposits in Alzheimer's disease (AD) brains. These plaques are composed predominantly of beta/A4 peptide derived from beta-amyloid precursor protein (beta APP). We demonstrate that short-term (1 h) IL-1 beta-treatment increases beta APPs secretion and concomitantly decreases cell-associated beta APP in human H4 neuroglioma cells. Long-term (5 h) IL-1 beta treatment did not alter secreted or cell-associated beta APP content. In contrast, the secretion of beta/A4-containing epitope was not affected by short-term IL-1 beta stimulation; however, long-term IL-1 beta treatment decreased the amount of beta/A4-containing epitope secreted from the cells. These results show that IL-1 beta modifies the processing and secretion of beta APP to exacerbate perhaps the neuropathology of AD.

Amyloid beta-Peptides↗
PubMed1991

An antibody to beta amyloid and the amyloid precursor protein inhibits cell-substratum adhesion in many mammalian cell types.

An epitope-specific antibody directed against the first 16 amino acids of the beta amyloid protein (anti-BP16) immunoprecipitated the secreted form of the amyloid precursor protein (APP) from the conditioned medium of PC12 cells. This antibody caused neurite retraction in differentiated PC12 cells and inhibited cell-substratum adhesion in many neuronal and non-neuronal cell types. The inhibitory effect of anti-BP16 was abolished by preabsorption of the antibody with BP16 peptide. Antibodies directed against other domains of APP did not inhibit cell adhesion. The secreted form of APP may be important for cell adhesion in many different mammalian cell types.

Adrenal Gland Neoplasms↗
PubMed1995

Amyloid beta peptide induces cytoplasmic accumulation of amyloid protein precursor via tau protein kinase I/glycogen synthase kinase-3 beta in rat hippocampal neurons.

Exogenous application of synthetic amyloid beta protein (A beta) is known to induce neurotoxic effects in rat hippocampal culture. We report here that A beta (25-35) induces accumulation of amyloid precursor protein (APP) derivatives in the cytoplasm of neurons. At the same time, the level of the secreted form of APP released into the culture medium decreases. Tau protein kinase I/glycogen synthase kinase-3 beta (TPK I/GSK-3 beta) antisense oligonucleotide blocked APP accumulation and prevented neuronal death. These results provide evidence that APP accumulation after A beta treatment is regulated by TPK I/GSK-3 beta. A beta neurotoxicity is probably mediated via phosphorylation of tau by TPK I/GSK-3 beta, resulting in an impairment of axonal transport, and cytoplasmic accumulation of APP.

Amyloid beta-Peptides↗
PubMed1995

Carboxyl end-specific monoclonal antibodies to amyloid beta protein (A beta) subtypes (A beta 40 and A beta 42(43)) differentiate A beta in senile plaques and amyloid angiopathy in brains of aged cynomolgus monkeys.

Senile plaques (SPs) and cerebral amyloid angiopathy (CAA) in the brains of five aged (20-26 years old) cynomolgus monkeys were investigated immunohistochemically using two monoclonal antibodies (anti-A beta 40 (BA27) and anti-A beta 42(43) (BC05)) that can differentiate the carboxyl termini of amyloid beta protein (A beta) subtypes. In four of five animals, all types of SPs (i.e. diffuse, primitive, and classical plaques; DPs, PPs, and CPs, respectively) were identified by BC05. However, BA27 did not label DPs and stained only about one third of PPs and CPs, mainly labeling granular structures and cored portions, respectively. In CAA, lesions of cortical capillaries reacted to BC05 in four of five cases, but rarely and weakly to BA27 in two of five cases. On the other hand, lesions of parenchymal and meningeal arterioles were stained by both BA27 and BC05. These staining profiles of SPs in cynomolgus monkeys correspond well to those in humans, although there are two remarkable features in cynomolgus monkeys. First, BA27 stained PPs associated with granular structures. Secondly, capillary A beta reacted intensely to BC05 but only slightly to BA27. Despite these unique features, the results suggest that aged cynomolgus monkeys can be used to investigate the pathogenesis of A beta deposition in SPs and CAA.

Amyloid beta-Peptides↗
PubMed1995

Amyloid beta protein in rat soleus muscle in chloroquine-induced myopathy using end-specific antibodies for A beta 40 and A beta 42: immunohistochemical evidence for amyloid beta protein.

Previous immunohistochemical studies from this laboratory demonstrated that monoclonal antibodies raised against various regions of amyloid precursor protein (APP) (i.e., N-terminus, amyloid beta protein (A beta), and C-terminus) strongly labeled vacuoles in chloroquine-induced myopathy-affected muscle in rats. In this study, we used antibodies end specific for the A beta 40 and A beta 42 species, and a monoclonal antibody to A beta 1-9 which reacts with APP and A beta. Most vacuoles clearly reacted with anti-A beta 1-9, while about half reacted with anti-A beta 42, and only a few reacted with anti-A beta 40. These results demonstrate that vacuoles in chloroquine-induced myopathy-affected muscle contain cleaved A beta, and that distribution of the two major A beta species is similar to what is observed in A beta deposition in Alzheimer's disease (AD)-affected brain. This provides further evidence that chloroquine-induced myopathy in rats provides a suitable model to understand APP processing into A beta, and the role of APP in terms of the pathogenesis of AD.

Amyloid beta-Peptides↗
PubMed1991

Amyloid in the pancreatic islets of the cougar (Felis concolor) is derived from islet amyloid polypeptide (IAPP).

1. Islet amyloid isolated from the pancreas of a 20-year-old cougar (Felis concolor) was dissolved and purified by gel permeation and reversed phase HPLC for amino acid sequence analysis. 2. N-Terminal amino acid sequence analysis of the purified protein revealed a primary structure (positions 1-28) identical to islet amyloid polypeptide (IAPP) from domesticated cats. 3. IAPP from the cougar, like IAPP from the human and domesticated cat, incorporates an inherently amyloidogenic AILS sequence at positions 25-28.

Amino Acid Sequence↗