Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “app”

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

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

At least 217 records · Page 12Linked to original sources
PubMed1994

beta-Amyloid precursor protein (APP)-like immunoreactivity in the human sympathetic ganglia.

The localization of the beta/A4 amyloid precursor protein (APP) was studied in the human lumbar paravertebral sympathetic ganglia of subjects of different ages, free of neurologic disease, using combined immunohistochemistry and image analysis techniques (optic microdensitometry). To ascertain which cells displayed APP-like immunoreactivity (APP-LI), S-100 and neurofilament proteins were studied in parallel to label the supporting glial cells and the neuron perikarya, respectively. Specific APP-LI was observed labelling both neuron cell bodies and supporting glial cells independently of age. In all cases, the intensity of immunostaining was stronger in glial cells than in neurons. Moreover, the intensity of APP-LI was independent of both age and neuron size. Present results provide evidence for the presence of APP-LI in the human sympathetic ganglia, and for the absence of changes in the expression of this protein, or proteins, with aging. The functional and clinical relevance of these findings remains to be clarified.

Adult↗
PubMed1991

The promoter activity of the gene encoding Alzheimer beta-amyloid precursor protein (APP) is regulated by two blocks of upstream sequences.

Transcriptional regulation of the gene encoding the amyloid precursor protein (APP) may play an important role in the formation of the amyloid depositions observed in Alzheimer disease and Down syndrome patients. To determine the promoter sequence requirements for the expression of the APP gene, we constructed plasmids containing different parts of the APP gene promoter fused to the bacterial chloramphenicol acetyl transferase (CAT) gene. Transfection of these constructs into Hela and PC12 cells revealed the presence of two blocks of regulatory sequences in the APP promoter. One block extending from about -600 to -460 bp acts as a positive regulator as its removal results in a substantial decrease in promoter activity. A second block of sequences extending from -450 to -150 bp acts like a negative regulator. We have also observed that a 38 mer synthetic oligonucleotide encompassing the region -489 to -452 of the APP promoter stimulated the activity of the heterologous TK promoter, suggesting that this region may be part of an enhancer-like element. In addition, our results suggest that the effects of various APP promoter domains on its activity may be cell specific.

Alzheimer Disease↗
PubMed1993

Regional distribution of the alternatively spliced isoforms of beta APP RNA transcript in the brain of normal, heterozygous and homozygous weaver mutant mice as revealed by in situ hybridization histochemistry.

The cellular localization of amyloid beta-protein precursor (beta APP) RNA transcripts was studied by in situ hybridization histochemistry in normal, heterozygous and homozygous weaver (wv) mutant mice, which lose midbrain dopamine (DA) neurons, cerebellar granule cells, and Purkinje cells. The beta APP gene is located at the distal end of mouse chromosome (MMU) 16, on which the wv locus has been assigned as well. Transcripts encoding isoforms beta APP695, beta APP714 and beta APP751 were present in several different brain areas of normal (+/+) mice, including hippocampus, substantia nigra (SN) pars compacta and cerebellum. The same transcripts were progressively reduced in homozygous weaver (wv/wv) SN, in correlation with DA neuron loss. The beta APP770 species--normally seen in striatum and not SN--was present in the mutant striatum. There were not any obvious changes in beta APP expression in the nigrostriatal system of weaver heterozygotes (wv/+). In normal cerebellum, Purkinje cells showed very high levels of hybridization signal for beta APP695, beta APP714 and beta APP751 RNA transcripts, and a moderate signal for the beta APP770 species. In weaver heterozygotes and homozygotes, Purkinje cells, which are typically not arranged in a monolayer, showed strong hybridization signal. No changes in beta APP mRNAs were observed in brain areas other than the cerebellum and ventral midbrain of weaver mutants. These findings suggest that the decreased beta APP gene expression seen in the cerebellum and SN of weaver mutants most likely represents an epiphenomenon of the regional nerve cell loss and, therefore, the wv gene defect on MMU 16 does not seem to influence the expression of the closely linked beta APP gene in brain areas outside the nigrostriatal pathway and cerebellar cortex.

Alternative Splicing↗
PubMed1993

Beta-amyloid precursor protein (beta APP) as a marker for axonal injury after head injury.

It has been demonstrated recently that beta-amyloid protein (beta AP), generally associated with the plaques of Alzheimer's disease, can also be found in the brains of survivors of head injury. In this study the distribution of the beta AP precursor protein (beta APP) was examined immunohistochemically to determine if it is colocalized with beta AP in such cases. beta APP immunoreactivity was observed in neuronal perikarya in the neocortex and in dystrophic neurites surrounding beta AP immunoreactive plaques i.e. in a distribution similar to that seen in Alzheimer's disease. In addition, beta APP immunoreactivity was noted within white matter tracts where it marked damaged axons. However, no colocalisation of beta APP with beta AP was observed in any white matter region. These results indicate that processing of beta APP to produce beta AP occurs in the synaptic terminal field of axons and illustrate the utility of beta APP immunoreactivity as a general marker for axonal injury.

Adult↗
PubMed1994

Expression of amyloid precursor protein (APP) in rat brain and cultured neural cells.

Cell type-specific and developmental patterns of APP expression were investigated in rat brain and cultured neural cells. Nearly all astrocytes were APP-positive, whereas only selected population of neurons appeared to express APP. In these neurons, APP immunoreactivity was preferentially restricted to single processes. mRNAs encoding the major APP isoforms, APP695 and APP770, were co-expressed as 3.4-3.6 kb transcripts both in astrocytes and neurons. In addition, an unusual 2.8 kb mRNA size class was revealed in cultured cerebellar granule neurons by means of the probe recognizing APP770 mRNA. Also, for the first time, APP714 mRNA was detected in rat brain by northern blotting. The steady-state levels of these transcripts were increased from birth up to postnatal day 20, whereas no apparent changes were observed after reaching adulthood. These data hint at the involvement of APP in the major morphogenetic events taking place in rat brain during the first three postnatal weeks.

Age Factors↗
PubMed2003

Divergent roles of GSK3 and CDK5 in APP processing.

Glycogen synthase kinase-3 (GSK3) and cyclin-dependent kinase 5 (CDK5) are related serine/threonine kinases that have been well studied for their role in tau hyperphosphorylation, however, little is known about their significance in APP processing. Here we report that GSK3 and CDK5 are involved in APP processing in a divergent manner. Specific inhibition of cellular GSK3 by lithium or GSK3beta antisense elicits a reduction in Abeta. Conversely, negative modulation of cellular CDK5 activity by CDK5 inhibitor, roscovitine, or CDK5 antisense stimulates Abeta production. Neither GSK3 nor CDK5 inhibition by these means significantly affected cellular APP levels or APP maturation. Moreover, oral administration of lithium significantly reduces Abeta production whereas direct ICV administration of roscovitine augmented Abeta production in the brains of PDAPP (APP(V717F)) mice. Our data support a function for both GSK3 and CDK5 in APP processing, further implicating these two kinases in the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed2005

In the cerebral cortex of female and male mice, amyloid precursor protein (APP) promoter methylation is higher in females and differentially regulated by sex steroids.

The over-expression of amyloid precursor protein (APP) gene in certain areas of the brain indicates abnormalities in gene regulation as an important factor for the development of Alzheimer's disease (AD). We have reported recently that APP mRNA expression is lower in female as compared to male and is regulated by sex steroids. As methylation of promoter is crucial for such regulation, we have used isoschizomeric restriction enzymes MspI and HpaII to analyze the pattern of APP promoter methylation in the cerebral cortex of intact, gonadectomized, testosterone- and estradiol-treated adult and old mice of both sexes. Southern blots of DNA digested with HindIII/MspI or HindIII/HpaII from different groups of mice were probed with a 1.27-kb DIG-11-dUTP labeled APP promoter fragment. The results revealed four distinct bands of 315 bp, 596 bp, 911 bp, and 2.6 kb by MspI, a single band of 2.6 kb by HpaII in all groups and an additional 2.9 kb in intact and estradiol treated old male and testosterone-treated adult female mice. The intensity of 2.6-kb band was relatively lower in intact female as compared to male and varied with different treatments in both ages, indicating the modulation of methylation. Thus, these findings showed that APP promoter methylation is higher in female and differentially regulated by sex steroids in the mice cerebral cortex, suggesting a strong correlation between promoter methylation and transcriptional silencing of APP.

Amyloid beta-Protein Precursor↗
PubMed2006

Multiple layers of temporal and spatial control regulate accumulation of the fruiting body-specific protein APP in Sordaria macrospora and Neurospora crassa.

During fungal fruiting body development, specialized cell types differentiate from vegetative mycelium. We have isolated a protein from the ascomycete Sordaria macrospora that is not present during vegetative growth but accumulates in perithecia. The protein was sequenced by mass spectrometry and the corresponding gene was termed app (abundant perithecial protein). app transcript occurs only after the onset of sexual development; however, the formation of ascospores is not a prerequisite for APP accumulation. The transcript of the Neurospora crassa ortholog is present prior to fertilization, but the protein accumulates only after fertilization. In crosses of N. crassa Deltaapp strains with the wild type, APP accumulates when the wild type serves as female parent, but not in the reciprocal cross; thus, the presence of a functional female app allele is necessary and sufficient for APP accumulation. These findings highlight multiple layers of temporal and spatial control of gene expression during fungal development.

Alleles↗
PubMed2004

Wnt-1 expression in PC12 cells induces exon 15 deletion and expression of L-APP.

The metabolism of amyloid precursor protein (APP) is central to Alzheimer's disease pathogenesis. Recent data have linked APP and presenilin to the Wnt/wingless signaling pathway. To assess affects of Wnt stimulation on APP isoform expression, we infected PC12 cells and C57MG cells with a retrovirus containing murine Wnt-1. In PC12 cells, Wnt-1 expression is associated with induction of exon 15 deletion from APP mRNA and expression of L-APP. Our data suggest that APP isoform expression is regulated, in part, by the Wnt/wingless signaling pathway.

Alternative Splicing↗
PubMed2004

Familial Alzheimer disease associated with A713T mutation in APP.

Mutations in APP are associated with familial early-onset Alzheimer disease (FAD). Examination of the genomic sequence in one patient with FAD revealed a change located in the axon 17 of the APP gene at position 275329G>A (GenBank accession number: D87675; GI: 2429080); cDNA sequence 2137G>A (GenBank accession number: X06989; GI: 28720). This corresponds to the mutation A713T in APP. AD stage VI of neurofibrillary degeneration and stage C of Abeta-amyloid burden was found at the post-mortem neuropathological examination. Previous studies have suggested that the mutation A713T in APP is a silent mutation or polymorphism. However, we have not found this change in APP in a control population analyzed by the amplification-refractory mutation system (ARMS). It is concluded that A713T in APP is implicated in the pathogenesis of AD. Since the immunohistochemical study indicates that A713T mutation is not likely to relate with Abeta-amyloid processing, the causative role of this rare mutation remains to be warranted.

Alanine↗
PubMed2006

Spatial and temporal control of age-related APP processing in genomic-based beta-secretase transgenic mice.

Genetic mutations associated with Alzheimer's disease (AD) in the Amyloid Precursor Protein (APP) gene specifically alter the production of the APP processing product, amyloid-beta (Abeta) peptide, generated by beta- and gamma-secretases. The accumulation and deposition of Abeta is hypothesized to cause AD pathogenesis, leading to the debilitating neurological deficits observed in AD patients. However, it is unclear how processing of APP to generate Abeta corresponds with the age-dependent pattern of brain-regional neurodegeneration common in AD. We have previously shown that overexpression of BACE1, the primary beta-secretase gene, in mice expressing an AD mutant form of APP leads to significantly elevated regional Abeta levels, which coincide with the regional pattern of Abeta deposition. In the current study, we have used our genomic-based beta-secretase transgenic mice to determine how BACE1 regulates the spatial and temporal pattern of Abeta production throughout post-natal development. Specifically, we observed unique differences in the brain-regional expression pattern between neonatal and adult BACE1 transgenic mice. These alterations in the BACE1 expression profile directly corresponds with age-related differences in regional Abeta production and deposition. These studies indicate that modulation of BACE1 expression leads to dramatic alterations in APP processing and AD-like neuropathology. Furthermore, our studies provide further evidence that BACE1 plays a major role in the regulation of the APP processing pathway, influencing the age-dependent onset of AD pathogenesis.

Aging↗
PubMed2004

beta-site amyloid precursor protein cleaving enzyme 1 increases amyloid deposition in brain parenchyma but reduces cerebrovascular amyloid angiopathy in aging BACE x APP[V717I] double-transgenic mice.

The generation of amyloid peptides (Abeta) from the amyloid precursor protein (APP) is initiated by beta-secretase (BACE), whereas subsequent gamma-secretase cleavage mediated by presenilin-1, produces Abeta peptides mainly of 40 or 42 amino acids long. In addition, alternative beta'-cleavage of APP at position 11 of the amyloid sequence results in N-truncated Abeta(11-40/42) peptides, but the functional significance or pathological impact is unknown. Here we demonstrate that in the brain of BACE x APP[V717I] double-transgenic mice, amyloidogenic processing at both Asp1 and Glu11 is increased resulting in more and different Abeta species and APP C-terminal fragments. Pathologically, BACE significantly increased the number of diffuse and senile amyloid plaques in old double-transgenic mice. Unexpectedly, vascular amyloid deposition was dramatically lower in the same BACE x APP[V717I] double-transgenic mice, relative to sex- and age-matched APP[V717I] single-transgenic mice in the same genetic background. The tight inverse relation of vascular amyloid to the levels of the less soluble N-terminally truncated Abeta peptides is consistent with the hypothesis that vascular amyloid deposition depends on drainage of excess tissue Abeta. This provides biochemical evidence in vivo for the preferential contribution of N-truncated Abeta to parenchymal amyloid deposition in contrast to vascular amyloid pathology.

Age Factors↗
PubMed2001

Effects of nicotine on APP secretion and Abeta- or CT(105)-induced toxicity.

Several lines of evidence indicated that overexpression or aberrant processing of amyloid precursor protein (APP) is causally related to Alzheimer's disease (AD). Amyloid precursor protein is principally cleaved within the amyloid beta protein domain to release a large soluble ectodomain (APPs), known to have a wide range of trophic functions. The central hypothesis guiding this review is that nicotine may play an important role in APP secretion and protection against toxicity induced by APP metabolic fragments (beta-amyloid [Abeta], carboxyl terminal [CT]). Findings from our experiments have shown that nicotine enhances the release of APPs, which has neurotrophic and neuroprotective activities in concentration-dependent (>50 micromol/L) and time-dependent (>2 hours) manners. In addition, pretreatment of nicotine (>10 micromol/L for 24 hours) partially prevented Abeta or CT(105)-induced cytotoxicity in primary cultured neuron cells, and the effects of nicotine-induced protection were inhibited by the pretreatment with a nicotine alpha-bungarotoxin. Nicotine (>10 micromol/L for 24 hours) partially inhibited CT(105)-induced cytotoxicity when PC12 cells was transfected with CT(105). From these results, we proposed that nicotine or nicotinic receptor agonist treatment might improve the cognitive functions not only by supplementation of cholinergic neurotransmission, but also by protecting Abeta- or CT(105)-induced neurotoxicity probably through the increased release of APPs and the activation of nicotinic receptors.

Alzheimer Disease↗
PubMed2002

Correlation between beta-amyloid peptide production and human APP-induced neuronal death.

The production of amyloid peptide (Abeta) from its precursor (APP) plays a key role in Alzheimer's disease (AD). However, the link between Abeta production and neuronal death remains elusive. We studied the biological effects associated with human APP expression and metabolism in rat cortical neurons. Human APP expressed in neurons is processed to produce Abeta and soluble APP. Moreover, human APP expression triggers neuronal death. Pepstatin A, an inhibitor of aspartyl proteases that reduces Abeta production, protects neurons from APP-induced neurotoxicity. This suggests that Abeta production is likely to be the critical event in the neurodegenerative process of AD.

Adenoviridae↗
PubMed1987

Stereologic studies on the adrenal cortex of 4-APP (4-amino-pyrazolopyrimidine)-induced lipoprotein-deficient rats.

The effect of 4-APP (4-aminopyrazolopyrimidine), the compound reducing hepatic release of lipoproteins, on the rat adrenal cortex was studied by means of stereological methods. Within 3 days 4-APP resulted in a marked increase in the absolute and relative adrenal weights and markedly lowered plasma and adrenal total cholesterol concentration. 4-APP did not change the relative volume of individual adrenocortical zones, however significantly increased the volume in mm3 of the zona fasciculata (ZF) and reticularis (ZR) and of the entire cortex. The average volume of the ZF and ZR cells of 4-APP treated rats was markedly higher than in control rats while no difference was found in the zona glomerulosa (ZG) cell. In lipoprotein-deficient rats the number of adrenocortical cells within the entire cortex was similar to that observed in control rats. A marked increase in the number of mitoses in both, adrenocortical and endothelial cells suggests inhibitory action of 4-APP on the proliferative activity of these cells. The present study shows that 4-APP-induced changes in the rat adrenal cortex mainly depends upon the stimulatory action of that compound on ACTH secretion, however this adenine analogue also exerts a direct action on the adrenocortical cells.

Adenine↗
PubMed1998

Analysis of pufferfish homologues of the AT-rich human APP gene.

Mutations in the beta-amyloid precursor protein (APP) gene are associated with some forms of Familial Alzheimer's Disease. The human APP gene is large, the 19 exons span approximately 300 kb, and AT-rich, at 40% GC. We have examined the genomic structure and cDNA sequence of the APP gene in the pufferfish Fugu rubripes and Tetraodon fluviatilis, respectively. In contrast to human, the Fugu APP gene spans less than 10 kb of DNA, with the introns compacted 48-fold on average. Two axons, alternatively processed in humans, are absent in both pufferfish. APP is the largest, most AT-rich gene examined in Fugu and is also the most highly compressed. The genomic sequences spanning the human and the Fugu APP genes were analysed with a set of exon and gene prediction programs. Results show that these are highly reliable for the Fugu gene with lower false positive and false negative rates than are seen in the analysis of the human gene. Comparative analysis of Fugu sequences homologous to very AT-rich regions in the human genome may, therefore, be advantageous in gene-finding efforts, both for their highly reduced sizes and their reliable gene predictions.

Alzheimer Disease↗
PubMed2006

3,4-Methylenedioxymethamphetamine (MDMA), but not morphine, alters APP processing in the rat brain.

The abuse of drugs such as opioids and 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') can have detrimental effects on the cognitive functions, but the exact molecular mechanism whereby these drugs promote neurodegeneration remains to be elucidated. The major purpose of the present pilot study was to determine whether the chronic in-vivo administration of morphine (10 mg/kg) or MDMA (1 mg/kg) to rats can alter the expression and processing of amyloid precursor protein (APP), the central molecule in the proposed pathomechanism of Alzheimer's disease. MDMA treatment significantly decreased the production of APP in the cytosolic fraction of the brain cortex. A concomitant 25% increase was found both in the beta-secretase (BACE) and APP mRNA levels (108%). In contrast, in the applied single dosage chronic morphine treatment did not influence either the APP and BACE protein levels or the APP mRNA production. These results indicate that the chronic use of 'ecstasy', but not morphine, may be harmful via a novel mode of action, i.e. by altering the APP expression and processing in the brain.

Amyloid Precursor Protein Secretases↗
PubMed2001

Identification and characterization of App: an immunogenic autotransporter protein of Neisseria meningitidis.

In a search for immunogenic virulence factors in Neisseria meningitidis, we have identified a gene encoding a predicted 160 kDa protein with homology to the autotransporter family of proteins. Members of this family are secreted or surface exposed and are often associated with virulence in Gram-negative bacterial pathogens. We named the gene adhesion and penetration protein (app), because of its extensive homology to the hap gene of Haemophilus influenzae. We reconstructed the gene with reference to genomic sequence data and cloned and expressed the protein in Escherichia coli. Rabbit antiserum raised against recombinant App reacted with proteins in all meningococcal isolates examined, which represented clonal groups responsible for the majority of meningococcal invasive disease. Antibodies to the protein were detected in the sera of patients convalescing from meningococcal infection. Purified App had strong stimulating activity for T cells isolated from a number of healthy donors and from one convalescent patient. We confirmed that App is surface localized, cleaved and secreted by N. meningitidis. Importantly, the rabbit anti-App serum killed the organism in the presence of complement. Thus, App is conserved among meningococci, immunogenic in humans and potentially involved in virulence. It therefore merits further investigation as a component of a future multivalent vaccine.

Antigens, Bacterial↗