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At least 415 records · Page 23Linked to original sources
PubMed2003

High cholesterol affects platelet APP processing in controls and in AD patients.

Alzheimer disease (AD) is characterised by a decrease of platelet Amyloid Precursor Protein forms ratio (APPr), which parallels symptoms' severity. Recent studies have suggested that cholesterol might play a role in the pathophysiology of AD by modulating Abeta production. Aim of this study was to evaluate the relationship between serum cholesterol levels and platelet APP processing in controls and AD. Sixty AD patients and 45 age-matched controls (CTRL) were investigated. Neuropsychological assessment, cholesterol dosage and APP forms' evaluation were performed on each subject. CTRL showed lower serum cholesterol levels compared to AD (P<0.01) and higher mean APPr scores (P<0.0001). Hypercholesterolaemic AD patients showed lower APPr scores compared to normocholesterolaemic AD patients matched for disease severity (0.31+/-0.16 versus 0.45+/-0.28; P<0.05), since the early stage of the disease. In AD, cholesterol levels influence APPr independently of disease severity. These findings confirm the association between cholesterol and AD, and suggest that in vivo cholesterol affects APP processing by interfering with its maturation.

Aged↗
PubMed1998

Expressing mRNAs for presenilin-1 and amyloid precursor protein (APP-695) from same neuronal populations in rat hippocampus.

Presenilin-1 gene (PS1, s182) encoding a protein that contains seven transmembrane domains was recently identified as a risk factor for Alzheimer's disease (AD). Mutations on this gene may contribute to pathogenesis of AD. In this study, we used in situ hybridization histochemistry to detect the expression of PS1 in neurons in the hippocampal formation and cerebral cortex of the rat brain. Specifically, mRNAs of PS1 were predominantly found in pyramidal neurons in CA1, CA3, and granule cells in the hilar region of the dentate gyrus of the hippocampus and in the external and internal pyramidal layers of the cerebral cortex. The same neuronal populations express the amyloid protein precursor (APP-695). Transgenic mice expressing a mutated APP-695 produced increased levels of beta-amyloid (A beta) and exhibited behavioral deficits. These results lead us to suggest that when PS1 and APP-695 colocalize in neurons in the brain, PS1 may play a regulatory role in production of (A beta) protein of AD.

Amyloid beta-Protein Precursor↗
PubMed2002

Possible mechanisms of APP-mediated oxidative stress in Alzheimer's disease.

Oxidative stress was presented to play an important role in the pathogenesis of Alzheimer's disease (AD), especially in the early evolution of AD amyloidogenesis and not only as a consequence thereof. The effect of oxidative stress catalysed by transition metals appears to have a critical relevance in AD. Metal-ion homeostasis is severely dysregulated in AD and it was found that experimentally induced disturbances in the homeostasis of Zn(II) and Cu(II) affect the amyloid precursor protein (APP) metabolism. APP itself binds Zn(II) and Cu(II) at nanomolar concentrations and an altered APP metabolism or expression level is believed to result in neurotoxic processes.

Alzheimer Disease↗
PubMed2002

ApoE genotype influences the biological effect of donepezil on APP metabolism in Alzheimer disease: evidence from a peripheral model.

Three major amyloid precursor protein (APP) forms with apparent molecular weight ranging from 106 to 130 kDa are present in human platelets. Alzheimer disease (AD) is associated with a decreased APP forms ratio (APPr) between the three major forms. A total of 25 mild to moderate AD patients were investigated. Platelet APPr was studied before and after 30 days of acetylcholinesterase-inhibitor treatment (donepezil, 5 mg daily). Patients were grouped into non-epsilon4 carriers and epsilon4 carriers according to apolipoprotein E (ApoE) genotype. At baseline, all patients showed low APPr levels and no significant difference was found between the two ApoE subgroups. After treatment, although a marked improvement in APPr was observed in most patients, non-epsilon4 carriers displayed a higher increase compared to epsilon4 carriers (P<0.0001). The present study provides evidence that donepezil influences APP metabolism in platelets, and suggests that ApoE genotype might be an important modulating factor for drug responsiveness in AD.

Aged↗
PubMed2003

Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease.

The processing of amyloid precursor protein (APP) generates amyloid-beta (Abeta) peptides 1-40 and 1-42. The latter is neurotoxic and its accumulation results in amyloid fibril formation and the generation of senile plaques, the hallmark of Alzheimer's disease (AD). Whilst there has been considerable progress made in understanding the generation of Abeta by alpha-, beta- and gamma-secretase activity on APP, recently enzymes involved in the degradation of Abeta have been identified including neprilysin and insulin-degrading enzyme (IDE). We review the pathways involved in proteolytic processing of APP and discuss the potential implications of aberrant proteolysis on neurodegeneration. It is conceivable that single nucleotide polymorphisms (SNPs) in the regulatory regions of genes in these proteolytic cascades, which alter their expression, could contribute to some of the age-related changes seen in AD.

Alzheimer Disease↗
PubMed2005

An inhibitor binding pocket distinct from the catalytic active site on human beta-APP cleaving enzyme.

Beta-APP cleaving enzyme (BACE) is responsible for the first of two proteolytic cleavages of the APP protein that together lead to the generation of the Alzheimer's disease-associated Abeta peptide. It is widely believed that halting the production of Abeta peptide, by inhibition of BACE, is an attractive therapeutic modality for the treatment of Alzheimer's disease. BACE is an aspartyl protease, and there is significant effort in the pharmaceutical community to apply traditional design methods to the development of active site-directed inhibitors of this enzyme. We report here the discovery of a ligand binding pocket within the catalytic domain of BACE that is distinct from the enzymatic active site (i.e., an exosite). Peptides, initially identified from combinatorial phage peptide libraries, contain the sequence YPYF(I/L)P(L/I) and bind specifically to this exosite, even in the presence of saturating concentrations of active site-directed inhibitors. Binding of peptides to the BACE exosite leads to a concentration-dependent inhibition of proteolysis for APP-related, protein-based substrates of BACE. The discovery of this exosite opens new opportunities for the identification and development of novel and potentially selective small molecule inhibitors of BACE that act through exosite, rather than active site, binding interactions.

Amino Acid Sequence↗
PubMed1997

Mutations in the transmembrane domain of APP altering gamma-secretase specificity.

Alzheimer's disease (AD) beta-amyloid peptide (Abeta and betaA4) is derived from the amyloid precursor protein (APP) by the subsequent action of the so-far unidentified beta- and gamma-secretases. gamma-secretase, which generates the C-terminus of Abeta, cleaves within the transmembrane domain of APP, preferentially after Abeta-residue 40 (Abeta 40) but also after residue 42 (Abeta 42). This Abeta 42 represents the major subunit of the plaques in AD. Since the position of gamma-secretase cleavage is crucial for understanding the pathogenic pathway, we investigated the effect of different point mutations at Thr43 on gamma-secretase specificity in SPA4CT (SPC99)-expressing COS7 cells. These constructs only require gamma-cleavage for Abeta release. We observed that all Thr43 mutations altered the specificity of gamma-secretase. Small hydrophobic residues favored the generation of Abeta 42, leading to an increase in the 42/40 ratio of Abeta (1.6-2.8-fold). The increase was even stronger (5.6-5.8-fold) when combined with the familial mutation Val46Phe. Thus, these constructs might be highly valuable for the generation of animal models for AD. Processing of full-length APP or SPA4CT yielded the same 42/40 ratio of Abeta (4. 7%). Both constructs, bearing the familial AD mutation Val46Phe, led to a similar increase in the 42/40 ratio (3.3- versus 3.6-fold). The p3 fragment, produced by alpha- and gamma-secretase, showed 42/40 ratios similar to Abeta when derived from wild-type and mutant proteins. These results suggest that the different Abeta- and p3-species are generated by gamma-cleavage activities with a similar enzymatic mechanism.

Amyloid Precursor Protein Secretases↗
PubMed2000

A distinct ER/IC gamma-secretase competes with the proteasome for cleavage of APP.

The deposition of amyloid-beta peptides (Abeta) in senile plaques (SPs) is a central pathological feature of Alzheimer's disease (AD). Since SPs are composed predominantly of Abeta1-42, which is more amyloidogenic in vitro, the enzymes involved in generating Abeta1-42 may be particularly important to the pathogenesis of AD. In contrast to Abeta1-40, which is generated in the trans-Golgi network and other cytoplasmic organelles, intracellular Abeta1-42 is produced in the endoplasmic reticulum/intermediate compartment (ER/IC), where it accumulates in a stable insoluble pool. Since this pool of insoluble Abeta1-42 may play a critical role in AD amyloidogenesis, we sought to determine how the production of intracellular Abeta is regulated. Surprisingly, the production of insoluble intracellular Abeta1-42 was increased by a putative gamma-secretase inhibitor as well as by an inhibitor of the proteasome. We further demonstrate that this increased generation of Abeta1-42 in the ER/IC is due to a reduction in the turnover of Abeta-containing APP C-terminal fragments. We conclude that the proteasome is a novel site for degradation of ER/IC-generated APP fragments. Proteasome inhibitors may augment the availability of APP C-terminal fragments for gamma-secretase cleavage and thereby increase production of Abeta1-42 in the ER/IC. Based on the organelle-specific differences in the generation of Abeta by gamma-secretase, we conclude that intracellular ER/IC-generated Abeta1-42 and secreted Abeta1-40 are produced by different gamma-secretases. Further, the fact that a putative gamma-secretase inhibitor had opposite effects on the production of secreted and intracellular Abeta may have important implications for AD drug design.

Acetylcysteine↗
PubMed1998

Xylosylation of alternatively spliced isoforms of Alzheimer APP by xylosyltransferase.

Acceptor affinities of UDP-D-xylose:proteoglycan core protein beta-D-xylosyltransferase (XT) recognition signals in synthetic L-APP and L-APLP2 homologous peptides were determined. The Michaelis-Menten constants (KM) of the L-APP peptide TENEGSGLTNIK and the L-APLP2 peptide SENEGSGMAEQK were 20.1 and 18.9 microM, respectively. Therefore, the peptides proved to be as good acceptors for XT as the bikunin aminoterminus homologous peptide (KM = 22 microM). Due to the occurrence of L-APP and L-APLP2 transcripts in human brain tissue, XT activity was measured in human liquor cerebrospinalis. Mean values were calculated as 0.22 mU/L in males and 0.47 mU/L in females without disturbance of blood brain barrier. In addition, in homogenized rat brain tissue a mean XT activity of 0.75 mU/L was determined. Furthermore, XT activity was investigated in 21 different human cell lines. In 7 cell lines an enzyme activity was not detected in either extracellular space or cytoplasma. Our findings indicate that XT is not ubiquitously expressed in human cell types.

Alternative Splicing↗
PubMed2005

APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.

We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA). Among these families, the duplicated segments had a minimal size ranging from 0.58 to 6.37 Mb. Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides. Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.

Age of Onset↗
PubMed2006

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development.

beta-Amyloid precursor protein binding protein 1 (APP-BP1) was previously identified based on its binding to the carboxyl terminal of beta-amyloid precursor protein. In this report, we have discovered that a mutation of dAPP-BP1 (Drosophila ortholog of APP-BP1) hinders tissue development, causes apoptosis in imaginal disc cells, and blocks the NEDD8 conjugation pathway. We show that dAPP-BP1 specifically binds the intracellular domain of APP-like protein (APPL). The dAPP-BP1 mutation partially suppresses the abnormal macrochaete phenotype of Appl(d), while overexpression of dAPP-BP1 causes abnormal macrochaetes. When APPL is overexpressed, the normal bristle pattern in the fly thorax is disturbed and apoptosis is induced in wing imaginal discs. APPL overexpression phenotypes are enhanced by reducing the level of dAPP-BP1. APPL overexpression is shown to inhibit the NEDD8 conjugation pathway. APPL-induced apoptosis is rescued by overexpression of dAPP-BP1. Our data suggest that APPL and dAPP-BP1 interact antagonistically during Drosophila development.

Amino Acid Sequence↗
PubMed2006

The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Abeta generation in vivo.

The cholesterol-synthesizing enzyme seladin-1, encoded by the Dhcr24 gene, is a flavin adenine dinucleotide-dependent oxidoreductase and regulates responses to oncogenic and oxidative stimuli. It has a role in neuroprotection and is downregulated in affected neurons in Alzheimer's disease (AD). Here we show that seladin-1-deficient mouse brains had reduced levels of cholesterol and disorganized cholesterol-rich detergent-resistant membrane domains (DRMs). This was associated with inefficient plasminogen binding and plasmin activation, the displacement of beta-secretase (BACE) from DRMs to APP-containing membrane fractions, increased beta-cleavage of APP and high levels of Abeta peptides. In contrast, overexpression of seladin-1 increased both cholesterol and the recruitment of DRM components into DRM fractions, induced plasmin activation and reduced both BACE processing of APP and Abeta formation. These results establish a role of seladin-1 in the formation of DRMs and suggest that seladin-1-dependent cholesterol synthesis is involved in lowering Abeta levels. Pharmacological enhancement of seladin-1 activity may be a novel Abeta-lowering approach for the treatment of AD.

Alzheimer Disease↗
PubMed2003

Identification of a novel high affinity copper binding site in the APP(145-155) fragment of amyloid precursor protein.

The copper(II) binding features of the APP(145-155) and APP(145-157) fragments of the amyloid precursor protein, Ac-Glu-Thr-His-Leu-His-Trp-His-Thr-Val-Ala-Lys-NH2 and Ac-Glu-Thr-His-Leu-His-Trp-His-Thr-Val-Ala-Lys-Glu-Thr-NH2 were studied by NMR spectroscopy and NMR findings were supported by UV-vis, CD and EPR spectra. Potentiometric measurements were performed only for the more soluble Ac-Glu-Thr-His-Leu-His-Trp-His-Thr-Val-Ala-Lys-Glu-Thr-NH2 peptide fragment. The following was shown: (i) the imidazole rings of all the three His residues are involved in metal coordination; (ii) metal binding induces ionisation of Leu-148 and His-149 amide nitrogens that complete the donor set to copper(II) in the species dominant at neutral pH; (iii) the unusual coordination scheme of the His-Xxx-His-Xxx-His consensus sequence justifies the high specificity for Cu(II) when compared to SOD-like or albumin-like peptides or even in amyloid Abeta fragments. The present findings may represent the key for interpreting the observed requirement of His residues conservation for the redox cycling between Cu(II) and Cu(I) by soluble APP.

Amyloid beta-Protein Precursor↗
PubMed2002

Positive and negative regulation of APP amyloidogenesis by sumoylation.

Amyloid beta peptide (Abeta) generated from amyloid precursor protein (APP) is central to Alzheimer's disease (AD). Signaling pathways affecting APP amyloidogenesis play critical roles in AD pathogenesis and can be exploited for therapeutic intervention. Here, we show that sumoylation, covalent modification of cellular proteins by small ubiquitin-like modifier (SUMO) proteins, regulates Abeta generation. Increased protein sumoylation resulting from overexpression of SUMO-3 dramatically reduces Abeta production. Conversely, reducing endogenous protein sumoylation with dominant-negative SUMO-3 mutants significantly increases Abeta production. We also show that mutant SUMO-3, K11R, which can only be monomerically conjugated to target proteins, has an opposite effect on Abeta generation to that by SUMO-3, which can form polymeric chains on target proteins. In addition, SUMO-3 immunoreactivity is predominantly detected in neurons in brains from AD, Down's syndrome, and nondemented humans. Therefore, polysumoylation reduces whereas monosumoylation or undersumoylation enhances Abeta generation. These findings provide a regulatory mechanism in APP amyloidogenesis and suggest that components in the sumoylation pathway may be critical in AD onset or progression.

Amyloid beta-Peptides↗
PubMed2001

The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate.

Release of Abeta peptides from beta-amyloid precursor protein (APP) requires sequential cleavage by two endopeptidases, beta- and gamma-secretases. beta-Secretase was recently identified as a novel membrane-bound aspartyl protease, named BACE1, Asp2, or memapsin 2. Employing confocal microscopy and subcellular fractionation, we have found that BACE1 is largely situated in the distal Golgi membrane with a minor presence in the endoplasmic reticulum, endosomes, and plasma membrane in human neuroblastoma SHEP cells and in mouse Neuro-2a cell lines expressing either endogenous mouse BACE1 or additional exogenous human BACE1. The major cellular beta-secretase activity is located in the late Golgi apparatus, consistent with its cellular localization. Furthermore, we demonstrate that the single transmembrane domain of BACE1 alone determines the retention of BACE1 to the Golgi compartments, through examination of recombinant proteins of various BACE1 fragments fused to a reporter green fluorescence protein. In addition, we show that the transmembrane domain of BACE1 is required for the access of BACE1 enzymatic activity to the cellular APP substrate and hence for the optimal generation of the C-terminal fragment of APP (CTF99). The results suggest a molecular and cell biological mechanism for the regulation of beta-secretase activity in vivo.

Alzheimer Disease↗
PubMed1999

Toxic neuronal apoptosis and modifications of tau and APP gene and protein expressions.

The causes and the mechanisms of neuronal death in Alzheimer's disease are not elucidated, although some new insights have been proposed over the past years, including free-radical toxicity, beta-amyloid toxicity, excitotoxicity, and disturbed cellular calcium metabolism. Some authors have also pointed out that apoptosis could play a role in neuronal degeneration, but it is still largely debated. Here, we review some recent data linking the induction of experimental neuronal apoptosis in vitro and the molecular pathology of the tau protein and amyloid precursor protein (APP). In cultures exposed to mild glutamate toxicity, tau mRNA expression, not beta-actin, is enhanced in stressed neurons. The Guam cycad toxin metabolite methylazoxymethanol also produces an increase of tau gene transcription that exacerbates changes induced by glutamate. In serum-deprived cultures or glutamate-exposed cultures, neurons committed to apoptosis have a reduced tau gene expression, whereas resistant neurons display a stable or even augmented tau mRNA expression accompanied by a persistent tau phosphorylation near serine 202. In the same conditions, stressed neurons produce membrane blebbings strongly immunopositive for APP and putative amyloidogenic fragments that are subsequently released in the extracellular space. Experimental apoptosis in neurons can recapitulate tau and APP modifications that could be associated with a selective vulnerability and a progression of cellular degeneration along the neuronal network.

Amyloid beta-Protein Precursor↗
PubMed2002

Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress.

We studied the effect of microtubule-associated tau protein on trafficking of vesicles and organelles in primary cortical neurons, retinal ganglion cells, and neuroblastoma cells. Tau inhibits kinesin-dependent transport of peroxisomes, neurofilaments, and Golgi-derived vesicles into neurites. Loss of peroxisomes makes cells vulnerable to oxidative stress and leads to degeneration. In particular, tau inhibits transport of amyloid precursor protein (APP) into axons and dendrites, causing its accumulation in the cell body. APP tagged with yellow fluorescent protein and transfected by adenovirus associates with vesicles moving rapidly forward in the axon (approximately 80%) and slowly back (approximately 20%). Both movements are strongly inhibited by cotransfection with fluorescently tagged tau (cyan fluorescent protein-tau) as seen by two-color confocal microscopy. The data suggests a linkage between tau and APP trafficking, which may be significant in Alzheimer's disease.

Alzheimer Disease↗
PubMed2005

Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain.

Amyloid precursor protein (APP), implicated in Alzheimer's disease, is a trans-membrane protein of undetermined function. APP is cleaved by gamma-secretase that releases the APP intracellular domain (AICD) in the cytoplasm. In vitro studies have implicated AICD in cell signaling and transcriptional regulation, but its biologic relevance has been uncertain and its in vivo function has not been examined. To investigate its functional role, we generated AICD transgenic mice, and found that AICD causes significant biologic changes in vivo. AICD transgenic mice show activation of glycogen synthase kinase-3beta (GSK-3beta) and phosphorylation of CRMP2 protein, a GSK-3beta substrate that plays a crucial role in Semaphorin3a-mediated axonal guidance. Our data suggest that AICD is biologically relevant, causes significant alterations in cell signaling, and may play a role in axonal elongation or pathfinding.

Amyloid beta-Protein Precursor↗