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PubMed2004

2-deoxyglucose induces beta-APP overexpression, tau hyperphosphorylation and expansion of the trans-part of the Golgi complex in rat cerebral cortex.

The effects of a single intraperitoneal injection of a non-metabolizable glucose analog 2-deoxyglucose (2-DG, 500 mg/kg) on the levels of beta-APP expression, and phosphorylated and unphosphorylated tau protein in the rat cerebral cortex were investigated. The effects of 2-DG on the ultrastructure of cortical neurons with particular emphasis on the morphology of the Golgi apparatus, and on brain bioenergetics assessed by in vivo 31P-MRS technique were also evaluated. Seven and a half hours after injection of 2-deoxyglucose a significant increase in brain cortex beta-APP expression, increased tau phosphorylation, and a marked relative expansion of the trans- part of the Golgi intracellular secretory pathway in cortical neurons has been found. The changes of beta-APP expression and tau phosphorylation appeared within 1 h after 2-DG application and continued for at least 24 h. However, brain 31P resonance spectra remained unchanged for up to 7.5 h after 2-DG. It is suggested that the increase of beta-APP expression represents a response of brain tissues to 2-DG-evoked biochemical stress, while tau hyperphosphorylation and the change in Golgi morphology may be secondary phenomena.

Amyloid beta-Protein Precursor↗
PubMed2000

Differential effects of zinc on amyloid precursor protein (APP) processing in copper-resistant variants of cultured Chinese hamster ovary cells.

Previous studies have demonstrated that adding copper to Chinese-hamster ovary (CHO) cells greatly reduced the levels of beta-amyloid (Abeta) peptide in parental CHO-K1 and in copper resistant CHO-CUR3 cells which have lower intracellular copper levels. In the current study, zinc, the zinc chelator 1,10-phenanthroline or copper chelators bathocuproine and D-penicillamine were added to the culture media of stably transfected CHO cells. The data show that zinc up to concentrations of 50 microM or the presence of 1,10-phenanthroline specifically increased the level of secreted APP in CHO-K1 cells. By contrast, the level of secreted APP in CHO-CUR3 cells remained unaffected. APP holoprotein increased dramatically in CHO-CUR3 cells compared with CHO-K1 cells. The large decrease of Abeta release seen in both cell lines at elevated extracellular zinc levels was due to specific inhibition of secretion. These results indicate that a disturbed zinc-homeostasis may be an important factor influencing APP production, transport and processing.

Amino Acid Sequence↗
PubMed2001

Excitotoxicity-induced expression of amyloid precursor protein (beta-APP) in the hippocampus and cortex of rat brain. an electron-microscopy and biochemical study.

After stereotaxic microinjection of N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA) to CA1 of rat hippocampus, the animals were sacrificed: 0 h, 2 h, 12 h, 24 h and 3 days after the insult. Other groups of animals before microinjection of the excitotoxins received intraperitoneal injection of dizocilpine (MK-801). Expression of beta-APP was assessed by immunohistochemical and immunobiochemical methods, and the results were correlated with changes in tissue ultrastructure observed in the electron microscopy. The results of the immunochemical analyses study demonstrated that application of NMDA and AMPA resulted in the increase of the expression of beta-APP in the CA1 of hippocampus and to a less extent in the cortex. Pretreatment with MK-801 strongly suppressed this effect. Beta-amyloid release was not detected. Morphological and cytochemical study revealed that NMDA injection induced massive damage of hippocampal and cortical neurones, associated with mitochondrial calcium sequestration and unusual accumulation of neurofilaments. Ultrastructural changes after AMPA application were limited to the brain cortex. These data indicate that although excitotoxic insult induces hyperexpression of beta3-APP, there is no relation between this effect and neurodegeneration, and excitotoxicity does not induce amyloidogenic processing of beta-APP.

Amyloid beta-Protein Precursor↗
PubMed2002

[Construction and expression of APP(SWE) transgenic mice model].

OBJECTIVE: To prepare transgenic mice model of human Swedish mutation of amyloid precursor protein(APP(SWE)) gene. METHODS: By pronuclear microinjection, human APP (SWE) genes were microinjected into pronuclei of zygotes of C57 and Kunming white mice. Integral zygotes were implanted into the oviducts of pseudopregnant female mice. The integration and expression of exogeneous genes in offsprings were detected by polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH) and reverse transcription-ploymerase chain reaction (RT-PCR) analysis. RESULTS: The success rate of microinjection and the birth rate were 76.62% and 10.38%, respectively. There were 6 founders and the integration rate was 35.29%. The exogeneous gene was transferred to the third generation. Expression of human APP(SWE) gene was detected in the brain, heart and muscle but not detected in the liver and kidney of transgenic mice. CONCLUSION: The transgenic mice model of human APP(SWE) gene has been prepared successfully.

Amyloid beta-Protein Precursor↗
PubMed2002

Immunohistochemical and biochemical studies in 4-aminopyrazolopyrimidine (4-APP)-induced fatty liver.

Four-aminopyrazolopyrimidine (4-APP)-induced fatty livers were studied immunohistochemically and biochemically. Immunohistochemical localization of glutathione-peroxidase (GSH-PO) in control rat liver was predominantly observed in the hepatocytes of portal zones of the hepatic lobules. After 3 days of 4-APP administration, the intensity of GSH-PO staining was weaker than that of control. Especially, this tendency was predominantly observed in portal zones of the hepatic lobules. Biochemcally, lipid peroxide levels measured by thiobarbituric acid method in the liver homogenates were markedly increased following 4-APP administration. However, glutathione-peroxidase (GSH-PO) activity in the same homogenates was decreased. Based on our data, we strongly suggested that pathogenesis of 4-APP induced-fatty liver may be due to uncontrolled free radical formation, peroxidation of lipids, and an associated lipid accumulation in the liver.

Animals↗
PubMed1991

Conversion of the Alzheimer's beta-amyloid precursor protein (APP) Kunitz domain into a potent human neutrophil elastase inhibitor.

Site-specific mutagenesis techniques have been used to construct active site variants of the Kunitz-type protease inhibitor domain present in the Alzheimer's beta-amyloid precursor protein (APP-KD). Striking alteration of its protease inhibitory properties were obtained when the putative P1 residue, arginine, was replaced with the small hydrophobic residue valine. The altered protein was no longer inhibitory toward bovine pancreatic trypsin, human Factor XIa, mouse epidermal growth factor-binding protein, or bovine chymotrypsin, all of which are strongly inhibited by the unaltered APP-KD (Sinha, S., Dovey, H. F., Seubert, P., Ward, P. J., Blacher, R. W., Blaber, M., Bradshaw, R. A., Arici, M., Mobley, W. C., and Lieberburg, I. (1990) J. Biol. Chem. 265, 8983-8985). Instead, the P1-Val-APP-KD was a potent inhibitor of human neutrophil elastase, with a Ki = 0.8 nM, as estimated by the inhibition of the activity of human neutrophil elastase measured using a chromogenic substrate. It also inhibited the degradation of insoluble elastin by the enzyme virtually stoichiometrically. Replacement of the P1' (Ala) and P2' (Met) residues of P1-Val-MKD with the corresponding residues (Ser, Ile) from alpha 1-proteinase inhibitor resulted in an inactive protein, underscoring the mechanistic differences between the serpins from the Kunitz-type protease inhibitor family. These results confirm the importance of the P1 arginine residue of APP-KD in determining inhibitory specificity, and are also the first time that a single amino acid replacement has been shown to generate a specific potent human neutrophil elastase inhibitor from a human KD sequence.

Amino Acid Sequence↗
PubMed2005

Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease.

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Interleukin-1alpha stimulates non-amyloidogenic pathway by alpha-secretase (ADAM-10 and ADAM-17) cleavage of APP in human astrocytic cells involving p38 MAP kinase.

Interleukin-1alpha (IL-1alpha) stimulates a disintegrin and metalloproteinase, ADAM-17 synthesis, consistent with activation of the soluble fragment of Amyloid Precursor Protein, APP, (sAPPalpha) in human primary astrocytes. To characterize the mechanism by which IL-1alpha promotes the non-amyloidogenic pathway of APP metabolism, we used U373 MG astrocytoma cells. IL-1alpha significantly increased levels of ADAM-10 and ADAM-17 mRNA in 16 hr. Upregulation of ADAM-17 mRNA by IL-1alpha was more pronounced despite higher basal levels of ADAM-10 mRNA. This pattern was also observed at the protein level with the upregulation of alpha-secretase. RNA interference (RNAi) of ADAM-10 and ADAM-17 inhibited IL-1alpha-stimulated sAPPalpha release and the effect was more pronounced with ADAM-17 RNAi. Concomitantly, the level of sAPPalpha was significantly increased by IL-1alpha in 48 hr; however, IL-1alpha stimulated cell-associated APP levels maximally at 6 h but the induction declined at 48 hr. IL-1alpha treatment of cells for 48 h reduced both intracellular and secreted levels of amyloid-beta, Abeta-40, and Abeta-42 peptides. Multiple MAP kinases (MAPK), including MEK/ERK, p38 kinase, PI3 kinase (PI3K) but not JNK were involved in the regulation of IL-1alpha-stimulated alpha-secretase activity and sAPPalpha release. p38 MAPK seems to be the most proximal of these MAPKs, as it was the earliest to be activated by IL-1alpha and blocking this pathway attenuated activation of IL-1alpha-induced MEK and PI3K pathways. Our data show a complex mechanism of sAPPalpha regulation by IL-1alpha that involves ADAM-10, ADAM-17 and p38 MAPK upstream of MEK and PI3K.

ADAM Proteins↗
PubMed1995

Parametric sensitivity analysis of avian pancreatic polypeptide (APP).

Computer simulations utilizing a classical force field have been widely used to study biomolecular properties. It is important to identify the key force field parameters or structural groups controlling the molecular properties. In the present paper the sensitivity analysis method is applied to study how various partial charges and solvation parameters affect the equilibrium structure and free energy of avian pancreatic polypeptide (APP). The general shape of APP is characterized by its three principal moments of inertia. A molecular dynamics simulation of APP was carried out with the OPLS/Amber force field and a continuum model of solvation energy. The analysis pinpoints the parameters which have the largest (or smallest) impact on the protein equilibrium structure (i.e., the moments of inertia) or free energy. A display of the protein with its atoms colored according to their sensitivities illustrates the patterns of the interactions responsible for the protein stability. The results suggest that the electrostatic interactions play a more dominant role in protein stability than the part of the solvation effect modeled by the atomic solvation parameters.

Animals↗
PubMed1998

Additive effects of PS1 and APP mutations on secretion of the 42-residue amyloid beta-protein.

Humans harboring missense mutations in the presenilin 1 (PS1) gene undergo progressive cerebral deposition of the 42-residue amyloid beta-protein (A beta 42) at an early age and develop severe Alzheimer's disease. A beta 42 is selectively elevated in the conditioned media of cells expressing mutant but not wild-type PS1, indicating that presenilin mutations alter APP processing. Here we analyze the effects of various PS1 mutant constructs on the cellular production of A beta 42. A construct expressing only the PS1 N-terminal endoproteolytic fragment with the mutation Y115H causes no significant increase in A beta 42, whereas a full-length PS1 construct with the same mutation does. This result suggests that the pathogenic effect of mutant presenilins is produced by the full-length molecule even though only a minor proportion of total PS1 occurs as holoprotein in tissues and cell lines. We demonstrate that the effects of two different PS1 mutations are additive when engineered into the same PS1 molecule. Therefore, two mutations alter gamma-secretase processing of APP more than one and the PS1 mutations described to date do not cause the maximum possible PS1-mediated rise in A beta 42. When a PS1 mutation was expressed in cells carrying the APPV717I mutation, A beta 42 rose dramatically to become the predominant secreted A beta species, an observation of interest for transgenic modeling of AD. Our results are consistent with the hypothesis that presenilin is a major regulator of the proteolytic processing of APP by gamma-secretases.

Age of Onset↗
PubMed1995

Characterization of muscarinic acetylcholine receptors in cultured adult skin fibroblasts: effects of the Swedish Alzheimer's disease APP 670/671 mutation on binding levels.

We have characterised the muscarinic receptor subtypes found in human skin fibroblasts and compared binding levels in cell lines from members of the Alzheimer's disease family with the Swedish amyloid precursor protein (APP) 670/671 mutation. Binding studies with [3H] quinuclidinyl benzilate ([3H]QNB) and the M2/M4 selective antagonist [3H] (+/-)-5,11-dihydro-11-([(2-[(di-propylamino)methyl]-1- piperidinyl]ethyl)amino]carbonyl)-6H-pyrido(2,3-b)(1,4)benzodiazepine-6- one ([3H]AF-DX 384) revealed the presence of a single population of muscarinic receptors on lysed fibroblast membranes. [3H]QNB binding was displaced by a number of selective muscarinic ligands with a rank order of potency: atropine > himbacine > methoctramine > (+/-)-p-fluoro-hexahydro-sila-difenidol hydrochloride > pirenzepine > muscarinic-toxin-3. APP 670/671 mutation carrying cell lines showed 25-35% lower levels of muscarinic receptors labelled with [3H]QNB, [3H]N-methyl scopolamine and [3H]AF-DX 384, compared to controls. This difference was not statistically significant due to large individual variation. It is concluded that muscarinic receptors on adult skin fibroblasts are predominantly of the M2 subtype. Since these cells do not possess M1 and M3 receptor subtypes, they are unlikely to provide a good model for studying muscarinic receptor regulation of APP processing.

Aged↗
PubMed1998

Monogenetic determinants of Alzheimer's disease: APP mutations.

Mutations within exons 16 and 17 of the beta-amyloid precursor protein (APP) gene were the first known cause of familial Alzheimer's disease. These mutations are rare and have been reported in a handful of families exhibiting autosomal dominant inheritance of Alzheimer's disease with age of onset around 50 years. In vitro and in vivo studies have demonstrated that each of these mutations alters proteolytic processing of APP, resulting in an increase in the production of A beta 42, a highly fibrillogenic peptide, that spontaneously aggregates and deposits in the brain. Transgenic mice carrying a mutant human APP gene also show age-dependent beta-amyloid (A beta) deposition in the brain. The rate of deposition in these mice can be modified by apolipoprotein E expression.

Age of Onset↗
PubMed2001

Distinct expression patterns of two zebrafish homologues of the human APP gene during embryonic development.

The human amyloid protein precursor (APP) gene correlates with early onset of Alzheimer's disease in humans. We have identified two APP homologues in zebrafish, which we call appa and appb. They show a high degree of identity to human APP particularly in the beta APP42 and the transmembrane domain. Widespread expression of both appa and appb was detected from mid-gastrulation until the bud stage. During segmentation, the two genes diverged in their pattern of expression: at 14 h post-fertilisation (hpf) and 18 hpf both genes were expressed rostrally in the prospective CNS, but only appa was found caudally in the paraxial segmental plate and presomitic mesoderm, excluding the midline. In contrast, appb was found caudally in the neural rod at 14 hpf and the developing spinal cord at 18 hpf. Later, at 24 hpf both genes shared common expression domains, namely the telencephalon, the ventral diencephalon, the trigeminal ganglia, and the posterior lateral line ganglia. Unique expression domains for appa were the lens, the otic vesicles and the somites, while appb was expressed in a serially repeated set of nuclei within the hindbrain, the ventral mesencephalon and the motoneurones of the developing spinal cord.

Amyloid beta-Protein Precursor↗
PubMed2006

Gender dependent APP processing in a transgenic mouse model of Alzheimer's disease.

Epidemiological studies have reported a higher prevalence and incidence of Alzheimer's disease (AD) in women. The biochemical basis for this gender-disparate susceptibility is unknown. A gender effect on AD-typical plaque pathology has been shown in APP transgenic mouse models of AD. Female mice elicit higher plaque load than male mice. In an effort to analyze gender-dependent APP processing during postnatal development, we examined APP transgenic mice at time points prior to plaque deposition. At 14 weeks of age there was a significant elevation of C99 and Abeta in female mice compared to males. Furthermore we observed a slight decrease of BACE-activity in male mice as well as higher cerebral manganese levels in females. Although the decline in estrogen levels due to menopause in female patients is still discussed to be a risk factor for AD our results implicates that additional factors like modified BACE-activity or metal levels may contribute to the higher prevalence and incidence of AD in females.

Alzheimer Disease↗
PubMedDate not supplied

Brain prolyl endopeptidase expression in aging, APP transgenic mice and Alzheimer's disease.

Prolyl endopeptidase (PEP) is believed to inactivate neuropeptides that are present in the extracellular space. However, the intracellular localization of PEP suggests additional, yet unidentified physiological functions for this enzyme. Here we studied the expression, enzymatic activity and subcellular localization of PEP in adult and aged mouse brain as well as in brains of age-matched APP transgenic Tg2576 mice and in brains of Alzheimer's disease patients. In mouse brain PEP was exclusively expressed by neurons and displayed region- and age-specific differences in expression levels, with the highest PEP activity being present in cerebellum and a significant increase in hippocampal but not cortical or cerebellar PEP activity in aged mouse brain. In brains of young APP transgenic Tg2576 mice, hippocampal PEP activity was increased compared to wild-type littermates in the pre-plaque phase but not in aged mice with beta-amyloid plaque pathology. This "accelerated aging" with regard to hippocampal PEP expression in young APP transgenic mice might be one factor contributing to the observed cognitive deficits in these mice in the pre-plaque phase and could also explain in part the cognition-enhancing effects of PEP inhibitors in several experimental paradigms.

Aging↗
PubMedDate not supplied

Novel tricyclic pyrone compounds prevent intracellular APP C99-induced cell death.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the progressive and global loss of cognitive functions. Pathological features include a loss of neurons in vulnerable brain regions and the extracellular deposition of abnormal protein aggregates known as amyloid plaques. Amyloid-beta protein (A beta is the major component of amyloid plaques and is derived from a larger transmembrane glycoprotein, termed amyloid beta protein precursor (APP), by proteolysis. The AD research has focused on A beta production and metabolism, its extracellular deposition, and its cellular toxicity. Recent evidence, however, suggests that A beta as well as the C-terminal fragments (CTF) of APP can accumulate intraneuronally. The neuronal loss and synaptic transmission deficit in AD may therefore depend on intraneuronal accumulation of A beta/CTF rather than on extracellular plaque formation. Accordingly, we propose that one of the primary targets of therapeutic intervention should be intracellular A beta/CTF and its toxic cellular effect. We have established a cell-culture model in which the neurons degenerate on induction of endogenous expression of A beta/CTF of APP. These cultures have been used to test whether tricyclic pyrone (TP) compounds may prevent A beta/CTF-mediated neuronal death. The results to date have been encouraging. Lead compounds will now be selected for their abilities to ameliorate A beta/CTF-mediated pathology in transgenic mice. Our hope is that these compounds may eventually prove beneficial for the prevention and treatment of AD.

Alzheimer Disease↗
PubMed1992

APP RNA splicing is not affected by differentiation of neurons and glia in culture.

Amyloid precursor protein (APP) gene expression was investigated in primary cultures of neurons, astrocytes, microglial cells and oligodendrocytes. Neurons from various rat brain regions, as well as oligodendrocytes, contained RNA encoding APP695, while astrocytes and microglial cells expressed high levels of RNAs for APP770 and APP751. It was studied whether the cell type-specific regulation of APP gene expression could be modified by induction of cellular differentiation in vitro. While neuronal differentiation of PC12 cells has been shown to correspond with an altered pattern of APP splicing, in the primary cultures neither the time in culture nor a treatment of the cells with appropriate differentiation factors affected this pattern.

Amyloid beta-Protein Precursor↗
PubMed1994

Increased beta-amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the Swedish Alzheimer's disease APP670/671 mutation.

Cell lines transfected with the Swedish Alzheimer's disease amyloid precursor protein APP670/671 mutation release significantly more beta-amyloid than wild-type cells. Citron et al. [Proc. Natl. Acad. Sci. USA (1994) in press] have recently shown that fibroblasts carrying the APP670/671 mutation also release more beta-amyloid than control cells [1]. The present study confirms a ca. threefold increase in beta-amyloid release from mutation-bearing fibroblasts. APP mRNA levels did not differ between mutation-bearing and control cells, although mutation-bearing fibroblasts contained significantly more APP751/770 than controls. Mild stress decreased beta-amyloid secretion and increased APP751/770 levels in all cell lines. In conclusion, the proportion of APP committed to amyloidogenic processing is increased in fibroblasts from family members with the APP670/671 mutation, and this mutation may also compromise the APP stress response.

Alzheimer Disease↗