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At least 541 records · Page 30Linked to original sources
PubMed2003

Negative association between amyloid plaques and cerebral amyloid angiopathy in Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is an important, though still relatively neglected, aspect of the pathology of Alzheimer's disease (AD), and both the source of amyloid beta protein (Abeta) in CAA, and its relationship to senile plaque (SP) Abeta, remain unclear. We have investigated the relationship between Abeta deposition in SP and CAA in four regions of brain from 69 patients with AD in order to gain insight into the pathogenetic mechanism(s) underlying these pathologies. CAA was present to some degree in all 69 patients, with the occipital cortex being affected more often and more severely than frontal, temporal and parietal cortices. By definition, SPs were present in all brain areas in all 69 patients, with greater uniformity of distribution than CAA, though the occipital cortex was less severely affected than the other brain regions. There was no significant (positive) correlation between CAA rating and that of SP for any one cortical region, but on combining data from all four regions there was a significant inverse correlation (P=0.037) between CAA and SP ratings. Such data suggest that the cellular sources and mechanisms leading to Abeta deposition as SP or CAA are likely to differ and may proceed independently of each other.

Aged↗
PubMed2004

Huperzine A enhances the level of secretory amyloid precursor protein and protein kinase C-alpha in intracerebroventricular beta-amyloid-(1-40) infused rats and human embryonic kidney 293 Swedish mutant cells.

We examined whether huperzine A (HupA), a promising therapeutic agent for Alzheimer's disease, could alter the processing of amyloid precursor protein (APP) in rats with beta-amyloid protein-(1-40) (Abeta(1-40)) infusion into the cerebral ventricle and in human embryonic kidney 293 (HEK293sw) cells. Daily intraperitoneal administration of HupA for 12 consecutive days produced significant reversals of the Abeta(1-40)-induced down-regulation of secretory APP (APPs) and protein kinase C (PKC) in rats. In the HEK293sw cells, the level of APPs was increased significantly with HupA treatment, and there was a similar change in PKCalpha level under the same condition. However, no significant alternations in the levels of PKCdelta and PKC were found after HupA treatment. These findings suggest that HupA may affect the processing of APP by up-regulating PKC, especially PKCalpha.

Alkaloids↗
PubMed2004

Immunization of Alzheimer model mice with adenovirus vectors encoding amyloid beta-protein and GM-CSF reduces amyloid load in the brain.

Induction of anti-amyloid beta-protein (Abeta) antibodies in transgenic mouse models of Alzheimer disease (AD) by repeated injection of synthetic Abeta was shown to be effective in preventing and removing deposition of Abeta aggregates in the brain. Here, we have tested a non-invasive modality whereby a replication-defective adenovirus vector encoding Abeta was intranasally administered to mice to elicit immune responses against Abeta. Intranasal immunization only with the adenovirus vector failed to induce significant immune responses. When an adenovirus vector encoding granulocyte/macrophage-colony stimulating factor (GM-CSF) was used as an adjuvant in conjunction with the adenovirus encoding Abeta, a marked immune response was elicited against Abeta. Immunoglobulin isotyping revealed that the induced anti-Abeta antibodies are predominantly of the IgG2b and IgG1 isotypes, suggesting a Th-2 anti-inflammatory type. Furthermore, amyloid load in the brain of AD model mice (Tg2576) vaccinated with adenovirus vectors encoding Abeta and GM-CSF was much smaller than that in control Tg2576 mice. Thus, intranasal administration of adenovirus vectors encoding Abeta and GM-CSF may be effective in prevention and treatment of AD.

Adenoviridae↗
PubMed2006

Evidence for an extended interacting surface between beta-amyloid and serum amyloid P component.

Studying the interaction between serum amyloid P component (SAP) and beta-amyloid (Abeta) a new Abeta binding site was identified on the SAP near the known binding site at the two bound calcium ions. SAP stabilizes deposits in neurodegenerative diseases, which is manifested via Abeta-binding. Because the inhibition of this interaction is a potential therapeutic target in neurodegeneration, the structural basis of SAP-Abeta binding was studied. The chymotryptic digestion of SAP resulted in a 18,223Da product identified by mass spectrometry. This cleavage was inhibited by Abeta revealing that this cleaving site between Tyr-140 and Gly-141 is involved in the interaction between SAP and Abeta These results suggest that the Abeta-binding site on SAP is larger than it was recently assumed.

Amyloid beta-Peptides↗
PubMed2004

Peptide sequence and amyloid formation; molecular simulations and experimental study of a human islet amyloid polypeptide fragment and its analogs.

We present a combined experimental and theoretical investigation of the tendencies to form amyloid fibrils by a hexapeptide derivative of the human islet amyloid polypeptide, the NFGAIL (22-27) fragment and its mutants. We performed a complete alanine scan of this fragment and studied the capability of the wild-type and its mutant analogs to form ordered fibrils by ultrastructural and biophysical analyses. In parallel, we conducted a meticulous characterization of each sequence-complex at an atomistic level by performing nine independent molecular dynamics simulations for a total of 36 ns. These allowed us to rationalize the experimental observations and to establish the role of every residue in the fibrillogenesis. The main factor that determines the formation of regular fibrils is a coherent organization of the intersheet space. In particular, phenylalanine side chains cement the macromolecular assemblies due to their aromatic chemical character and restricted conformational flexibility when interacting with aliphatic residues.

Alanine↗
PubMed1997

Echocardiographic assessment of cardiac involvement in systemic AL amyloidosis in relation to whole body amyloid load measured by serum amyloid P component (SAP) clearance.

The severity of cardiac infiltration in AL amyloidosis is unrelated to whole body amyloid load as measured by serum amyloid P (SAP) tracer studies. Radiolabeled SAP and echocardiography permit identification of patients with severe cardiac disease with a low whole body load who may be the best candidates for transplantation.

Adult↗
PubMed1998

Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein.

Although brain trauma is a risk factor for Alzheimer's disease, no experimental model has been generated to explore this relationship. We developed a model of brain trauma in transgenic mice that overexpress mutant human amyloid precursor protein (PDAPP) leading to the appearance of Alzheimer's disease-like beta-amyloid (Abeta) plaques beginning at 6 months of age. We induced cortical impact brain injury in the PDAPP animals and their wild-type littermates at 4 months of age, ie, before Abeta plaque formation, and evaluated changes in posttraumatic memory function, histopathology, and regional tissue levels of the Abeta peptides Abeta1-40 and Abeta1-42. We found that noninjured PDAPP mice had impaired memory function compared to noninjured wild-type littermates (P < 0.01) and that brain-injured PDAPP mice had more profound memory dysfunction than brain-injured wild-type littermates (P < 0.001). Although no augmentation of Abeta plaque formation was observed in brain-injured PDAPP mice, a substantial exacerbation of neuron death was found in the hippocampus (P < 0.001) in association with an acute threefold increase in Abeta1-40 and sevenfold increase in Abeta1-42 levels selectively in the hippocampus (P < 0.01). These data suggest a mechanistic link between brain trauma and Abeta levels and the death of neurons.

Amyloid beta-Peptides↗
PubMed2003

Serum amyloid P component induces neuronal apoptosis and beta-amyloid immunoreactivity.

Previously we have reported serum amyloid P component (SAP) induced cell death in cerebro-cortical cultures of rat brain. In this paper we studied the types of target cells and the molecular mechanism of SAP-induced cell death. Immuno-electron and light microscopy revealed that SAP penetrates the plasma membrane and translocates selectively into the nuclei of neurons. Neuronal cells with SAP immunoreactivity exhibit the morphological hallmarks of apoptosis in vitro. The apoptotic mechanism of cell death is also supported by the increased Bax/Bcl-2 ratio. In addition to neurotoxic effects, we detected elevated beta-amyloid (Abeta) immunoreactivity following SAP treatment. This study supports the thesis that SAP plays an important role in the pathomechanism of neurodegenerative diseases, including Alzheimer's disease by inducing neuronal apoptosis.

Amyloid beta-Peptides↗
PubMed1997

Characterization of amyloid beta protein species in cerebral amyloid angiopathy of a squirrel monkey by immunocytochemistry and enzyme-linked immunosorbent assay.

We analyzed the composition of amyloid beta protein (A beta) species in cerebral amyloid angiopathy (CAA) of an aged squirrel monkey. Immunocytochemistry demonstrated that the cerebral cortex contained no lesions other than widespread CAA with A beta40 as its apparent major component. However, enzyme-linked immunosorbent assay revealed that A beta42(43) predominated over A beta40 in a formic acid-extracted cortical fraction. These findings suggest possible underestimation of A beta42(43) levels in some previous immunocytochemical investigations.

Aging↗
PubMed2000

Effects of sodium azide on the secretion of soluble amyloid-beta precursor protein and the accumulation of beta-amyloid(1-40) in cultured chick neurons.

Sodium azide has been reported in the literature to reduce the release of secreted amyloid beta-precursor protein (AbetaPPs) and to produce a large increase in the cellular level of an 11.5 kDa C-terminal AbetaPP derivative containing the beta-amyloid (Abeta) sequence. Here we report that 1 mM of sodium azide, reduced the constitutive AbetaPPs secretion from cultured embryonic chick neurons after 12 h of incubation. After 24 h of incubation there was a modest increase in lactate dehydrogenase (LDH) release and no change in MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction, suggesting that the reduced AbetaPPs secretion was not due to the cell toxic effects of NaN(3). However, NaN(3) reduced the accumulation of Abeta(1-40) in the cell lysates and decreased the acetylcholine esterase activity both in cell culture media and in cell lysates. It is concluded that the effect of NaN(3) upon AbetaPP metabolism in the chick cultured neurons may be a rather non-specific effect.

Amyloid beta-Peptides↗
PubMed2001

Tau, beta-amyloid and beta-amyloid precursor protein distribution in the entorhinal-hippocampal alvear and perforant pathways in the Alzheimer's brain.

It has been suggested that the pathological lesions of Alzheimer's disease (AD) spread along neuronal connections. This study was designed to examine this hypothesis in the alvear and perforant pathways, two well-defined neuroanatomical pathways that project from the entorhinal cortex to the hippocampus. Paraffin-sections of hippocampal-entorhinal cortex from 25 AD cases were immunolabelled for tau, beta-amyloid (Abeta) and beta-amyloid precursor protein (betaAPP). We used image-analysis to quantify immunolabelling at both ends of the alvear and perforant pathways. At the beginning and the end of the alvear pathway, area of immunolabelling in microm2 per area of field (72000 microm2) were as follows: tau 349 and 821 (P<0.01), Abeta 349 and 61 (P<0.05) and betaAPP 18 and 73 (P<0.01). Corresponding values for the perforant pathway were tau 421 and 387, Abeta 382 and 115 (P<0.05) and betaAPP 55 and 83. Tau was significantly greater at the end than at the beginning of the alvear pathway, but similar at both ends of the perforant pathway. There was significantly more Abeta at the beginning than at the end of the alvear and perforant pathway. These results at least in part reinforce previous work [19] that tau-rich areas may be neuronally connected to Abeta-rich areas.

Aged↗
PubMed2003

Importance of IgG2c isotype in the immune response to beta-amyloid in amyloid precursor protein/transgenic mice.

A careful analysis of the immune response to immunization of amyloid precursor protein/transgenic (APP/Tg) mice with beta-amyloid (Abeta) may provide insights into why a subset of the patients in a clinical trial receiving Abeta-immunotherapy developed encephalomyelitis. Characterization of isotypic immune responses have been reported in different APP/Tg models. In these studies the relative ratios of IgG1 to IgG2a anti-Abeta antibodies has been used as an indirect measure of T helper 1 (Th1) and Th2 types immune responses. However, it has previously been shown that certain strains of mice, C57Bl/6, C57Bl/10, SJL, and NOD, have an IgG2c rather than an IgG2a gene. Since a substantial number of Abeta-immunization studies rely on APP/Tg mice that have at least one parental C57Bl/6 strain, we have investigated whether antibodies specific for IgG2a can be used for characterization of antibody isotypes in APP/Tg2576 mice. Our results suggest that APP/Tg2576 and major histocompatibilty complex-matched parental strains are not expressing IgG2a, producing instead IgG2c anti-Abeta antibodies.

Amyloid beta-Peptides↗
PubMed2003

Identification of neuronal plasma membrane microdomains that colocalize beta-amyloid and presenilin: implications for beta-amyloid precursor protein processing.

Alzheimer's disease (AD) is associated with the accumulation of extracellular deposits of the beta-amyloid protein (Abeta). Abeta is a result of misprocessing of the beta-amyloid precursor protein (APP). Gamma-secretase is involved in APP misprocessing and one hypothesis holds that this secretase is identical to PS1. We tested this hypothesis by determining whether PS is co-localised with Abeta in situ. Using confocal analyses and a sensitive immunogold procedure we show that PS and Abeta are co-localised within discrete microdomains of neuronal plasma membranes in AD patients and in aged dogs, an established model of human brain aging. Our data indicate that APP misprocessing occurs in discrete plasma membrane domains of neurons and provide evidence that PS1 is critically involved in Abeta formation.

Aged↗
PubMed2003

Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice.

The present study was designed to examine whether brain inflammation caused by systemic administration of lipopolysaccharides (LPS) alters the expression/processing of amyloid precursor protein (APP) and increases the generation of amyloid beta peptide (Abeta). APPswe transgenic (Tg) mice were treated with either LPS or phosphate-buffered saline (PBS). In LPS-treated APPswe mice, Abeta1-40/42 was 3-fold and APP was 1.8-fold higher than those in PBS-treated mice (P < 0.05) by ELISA, Western blots and immunoprecipitation-mass spectrometry (IP-MS) ProteinChip analysis. Numbers of Abeta- and APP-immunoreactive neurons (Abeta(+) and APP(+) neurons) increased significantly in LPS-treated APPswe mice; APP(+) and Abeta(+) neurons in neocortex were associated with an increased number of F4/80-immunoreactive microglia (F4/80(+) microglia) in their anatomical environment. Our findings demonstrate that experimental neuroinflammation increases APP expression/processing and causes intracellular accumulation of Abeta. It remains to be seen whether such events can cause neuronal dysfunction/degeneration and, with time, lead to extracellular Abeta deposits, as they occur in Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Spontaneous in vitro formation of supramolecular beta-amyloid structures, "betaamy balls", by beta-amyloid 1-40 peptide.

The concentration of beta-amyloid peptide (Abeta), x-42 or x-40 amino acids long, increases in brain with the progression Alzheimer's disease (AD). These peptides are deposited extracellularly as highly insoluble fibrils that form densities of amyloid plaques. Abeta fibrillization is a complex polymerization process preceded by the formation of oligomeric and prefibrillar Abeta intermediates. In some of our in vitro studies, in which the kinetics of intermediate steps of fibril formation were examined, we used concentrations of synthetic Abeta that exceed what is normally employed in fibrillization studies, 300-600 microM. At these concentrations, in a cell free system and under physiological conditions, Abeta 1-40 peptide (Abeta40) forms fibrils that spontaneously assemble into clearly defined spheres, "betaamy balls", with diameters of approximately 20-200 microm. These supramolecular structures show weak birefringence with Congo red staining and high stability with prolonged incubation times (at least 2 weeks) at 30 degrees C, freezing, and dilution in H(2)O. At 600 microM, they are detected after incubation for approximately 20 h. Abeta peptide 1-42 (Abeta42) lacks the ability to form betaamy balls but accelerates Abeta40 betaamy ball formation at low stoichiometric levels (1:20 Abeta42:Abeta40 ratio). Abeta42 levels above this (=10-50% w/w) impede Abeta40 betaamy ball formation. Using light (LM) and electron microscopy (EM), this study examines the gross morphology and ultrastructure of Abeta40 betaamy balls and their time course of formation, in the absence and presence of Abeta42, along with some stability measures. As spheres of a misfolded protein, betaamy balls resemble both AD Abeta senile plaques and neuronal inclusion bodies associated with other neurodegenerative diseases.

Alzheimer Disease↗
PubMed2005

The role of His-18 in amyloid formation by human islet amyloid polypeptide.

The 37-residue islet amyloid polypeptide (IAPP) is the major protein component of the amyloid deposits found in type-II diabetes. IAPP is stored in a relatively low pH environment in the pancreatic secretory granules prior to its release to the extracellular environment. Human IAPP contains a single histidine at position 18. Aggregation of IAPP is considerably faster at a lower pH (4.0 +/- 0.3) than at high pH (8.8 +/- 0.3), as judged by turbidity and thioflavine-T fluorescence studies. The rate of aggregation at low pH increases drastically in the presence of salt. CD experiments show that the conversion of largely unstructured monomers to beta-sheet-rich structures is faster at high pH. TEM studies show that fibrils are formed at both pH values but are more prevalent at pH 8.8 (+/-0.3). Both the free N terminus of IAPP and His-18 will titrate over the pH range studied. An N-terminal acetylated fragment consisting of residues 8-37 of human IAPP was also studied to isolate contributions from the protonation of His-18. Previous studies have shown that this fragment forms protofibrils that are very similar to those formed by intact IAPP. The effects of varying the protonation state of His-18 in the 8-37 analogue indicate that the rate of aggregation and fibril formation is noticeably faster when His-18 is deprotonated, similar to the wild type. However, the pH-dependent effects are larger for full-length IAPP than for the disulfide-truncated, acetylated analogue. TEM studies indicate differences in the morphology of the deposits formed at high and low pH. These results are discussed in light of recent structural models of IAPP fibrils.

Amino Acid Sequence↗
PubMed1998

Presenilin 1 regulates the processing of beta-amyloid precursor protein C-terminal fragments and the generation of amyloid beta-protein in endoplasmic reticulum and Golgi.

Progressive cerebral deposition of the amyloid beta-protein (Abeta) is believed to play a pivotal role in the pathogenesis of Alzheimer's disease (AD). The highly amyloidogenic 42-residue form of Abeta (Abeta42) is the first species to be deposited in both sporadic and familial AD. Mutations in two familial AD-linked genes, presenilins 1 (PS1) and 2 (PS2), selectively increase the production of Abeta42 in cultured cells and the brains of transgenic mice, and gene deletion of PS1 shows that it is required for normal gamma-secretase cleavage of the beta-amyloid precursor protein (APP) to generate Abeta. To establish the subcellular localization of the PS1 regulation of APP processing to Abeta, fibroblasts from PS1 wild-type (wt) or knockout (KO) embryos as well as Chinese hamster ovary (CHO) cells stably transfected with wt or mutant PS1 were subjected to subcellular fractionation on discontinuous Iodixanol gradients. APP C-terminal fragments (CTF) were markedly increased in both endoplasmic reticulum- (ER-) and Golgi-rich fractions of fibroblasts from KO mice; moreover, similar increases were documented directly in KO brain tissue. No change in the subcellular distribution of full-length APP was detectable in fibroblasts lacking PS1. In CHO cells, a small portion of APP, principally the N-glycosylated isoform, formed complexes with PS1 in both ER- and Golgi-rich fractions, as detected by coimmunoprecipitation. When the same fractions were analyzed by enzyme-linked immunosorbent assays for Abetatotal and Abeta42, Abeta42 was the major Abeta species in the ER fraction (Abeta42:Abetatotal ratio 0.5-1.0), whereas absolute levels of both Abeta42 and Abeta40 were higher in the Golgi fraction and the Abeta42:Abetatoal ratio was 0.05-0.16 there. Mutant PS1 significantly increased Abeta42 levels in the Golgi fraction. Our results indicate PS1 and APP can interact in the ER and Golgi, where PS1 is required for proper gamma-secretase processing of APP CTFs, and that PS1 mutations augment Abeta42 levels principally in Golgi-like vesicles.

Alzheimer Disease↗