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PubMed1990

Relation of neuronal APP-751/APP-695 mRNA ratio and neuritic plaque density in Alzheimer's disease.

An ongoing controversy concerns the cellular distribution of the differentially spliced forms of the amyloid protein precursor (APP) mRNAs and changes in prevalence of these transcripts during Alzheimer's disease. In situ hybridization on serial sections was used to prove that most hippocampal pyramidal neurons contain both APP-751 and APP-695 mRNA species. The APP-751/APP-695 mRNA ratio is generally increased during Alzheimer's disease, as shown by RNA gel blot analysis. Moreover, there was a strong linear relation between the increase in APP-751/APP-695 mRNA ratio in pyramidal neurons and the density of senile plaques within the hippocampus and entorhinal cortex. Thus, the increase in APP-751/APP-695 mRNA provides a molecular marker for regional variations in plaque density between individuals diagnosed with Alzheimer's disease by the commonly used composite criteria.

Alzheimer Disease↗
PubMed2004

Role of the APP promoter in Alzheimer's disease: cell type-specific expression of the beta-amyloid precursor protein.

One of the major hallmarks in Alzheimer's disease (AD) is amyloid deposition in the brain of afflicted subjects. This tissue-specific deposition of the amyloid beta-protein (Abeta) is the major characteristic of AD. Abeta is proteolytically derived from a large Abeta precursor protein (APP). An apparent overexpression of the APP gene in certain areas of the AD brain indicates that abnormalities in gene regulation might be an important factor in AD pathology. The mechanism of expression of APP in different cell types is poorly understood. To understand the contribution of different cell types, such as neuronal, glial, and epithelial cells, APP expression was studied at the message and protein levels. Levels of APP expression, both message and protein, were greater in human neuroblastoma (NB) and PC12 cells than in glial and HeLa cells. DNA transfection experiments suggest that the relative activities of different promoter regions varied according to cell type. Although the upstream regulatory element in the promoter region is necessary for activity in PC12 and HeLa cells, this is not the case for NB cells. A 30-bp proximal promoter region was found to be important for cell type-specific APP gene expression.

Alzheimer Disease↗
PubMed2002

Cell-free generation of the notch1 intracellular domain (NICD) and APP-CTfgamma: evidence for distinct intramembranous "gamma-secretase" activities.

PSEN1 and PSEN2 encode polytopic membrane proteins, termed presenilin 1 (PS1) and presenilin 2 (PS2) that play an essential role in intramembranous ("gamma-secretase") proteolysis of selected type I membrane proteins, that include Notch1 and beta-amyloid precursor protein (APP). In order to gain insights into biochemical mechanisms underlying gamma-secretase processing of Notch1 and APP, we have developed a novel in vitro assay in which gamma-secretase-mediated generation of S3/NICD and APP-CTFgamma can be readily detected in isolated membrane fractions derived from immortalized PS1+/- mouse embryonic fibroblasts; production of the APP and Notch1 derivatives are inhibited by a highly selective and potent gamma-secretase inhibitor, L-685,458, with a IC50 of approximately 50 pM. In membranes prepared from PS1-deficient fibroblasts, we detected APP-CTFgamma, albeit at low levels. Unexpectedly, and despite the presence of endogenous PS2 in membranes prepared from PS1-deficient fibroblasts, production of the Notch derivatives, S3/NICD, was nearly undetectable in these reactions. Moreover, S3/NICD production is neither detected in detergent-solubilized membrane preparations from PS1-deficient cells, nor in reactions containing PS1-containing membranes that were co-solubilized with membranes from PS -/- cells expressing a chimeric Notch 1 species. These findings strongly suggest that the factors responsible for intramembranous, gamma-secretase proteolysis of APP and Notch1 are neither equivalent, nor exchangeable.

Amyloid Precursor Protein Secretases↗
PubMed2004

Neutralization of transthyretin reverses the neuroprotective effects of secreted amyloid precursor protein (APP) in APPSW mice resulting in tau phosphorylation and loss of hippocampal neurons: support for the amyloid hypothesis.

Alzheimer's disease (AD) may be caused by the abnormal processing of the amyloid precursor protein (APP) and the accumulation of beta-amyloid (Abeta). The amyloid precursor protein can be proteolytically cleaved into multiple fragments, many of which have distinct biological actions. Although a high level of Abeta can be toxic, the alpha-secretase cleaved APP (sAPPalpha) is neuroprotective. However, the mechanism of sAPPalpha protection is unknown. Here, we show that sAPPalpha increases the expression levels of several neuroprotective genes and protects organotypic hippocampal cultures from Abeta-induced tau phosphorylation and neuronal death. Antibody interference and small interfering RNA knock-down demonstrate that the sAPPalpha-driven expression of transthyretin and insulin-like growth factor 2 is necessary for protection against Abeta-induced neuronal death. Mice overexpressing mutant APP possess high levels of sAPPalpha and transthyretin and do not develop the tau phosphorylation or neuronal loss characteristic of human AD. Chronic infusion of an antibody against transthyretin into the hippocampus of mice overexpressing APP with the Swedish mutation (APP(Sw)) leads to increased Abeta, tau phosphorylation, and neuronal loss and apoptosis within the CA1 neuronal field. Therefore, the elevated expression of transthyretin is mediated by sAPPalpha and protects APP(Sw) mice from developing many of the neuropathologies observed in AD.

Aging↗
PubMed2005

LRP-mediated clearance of Abeta is inhibited by KPI-containing isoforms of APP.

The pathogenesis of Alzheimer's disease (AD) involves the abnormal accumulation and deposition of beta-amyloid in cerebral blood vessels and in the brain parenchyma. Critical in modulating beta-amyloid deposition in brain is the flux of Abeta across the blood brain barrier. The low-density lipoprotein receptor-related protein (LRP), is a large endocytic receptor that mediates the efflux of Abeta out of brain and into the periphery. The first step in the LRP-mediated clearance of Abeta involves the formation of a complex between Abeta and the LRP ligands apolipoprotein E (apoE) or alpha(2)-macroglobulin (alpha(2)M). The Abeta/chaperone complexes then bind to LRP via binding sites on apoE or alpha(2)M. The efflux of Abeta/chaperone complexes out of the neuropil and into the periphery may be attenuated by LRP-ligands that compete with apoE or alpha(2)M for LRP binding. LRP is also the cell surface receptor for Kunitz Protease Inhibitor (KPI) containing isoforms of Abeta's parent protein, the amyloid protein precursor (APP). Protein and mRNA levels of KPI-containing APP isoforms (APP-KPI) are elevated in AD brain and are associated with increased Abeta production. In this study we show that soluble non-amyloidogenic APP-KPI can also inhibit the uptake of Abeta/alpha(2)M in a cell culture model of LRP mediated Abeta clearance. Clearance of Abeta/apoE complexes was not inhibited by APP-KPI. Our findings are consistent with studies showing that apoE and alpha(2)M have discrete binding sites on LRP. Most significantly, our data suggests that the elevated levels of APP-KPI in AD brain may attenuate the clearance of Abeta, the proteins own amyloidogenic catabolic product.

Amyloid beta-Peptides↗
PubMed1999

Analysis of mouse intron 7 DNA sequence of the APP gene: comparison with the human homologue.

Mutations in the beta-amyloid precursor protein gene (APP) cause Alzheimer disease (AD) in certain families. The mature protein (APP) exists in several different isoforms resulting from alternative splicing of the primary transcript. Several lines of evidence indicate that particular isoform(s) of APP may contribute to the etiology of AD. One of the isoforms, APP695, lacks the Kunitz protease inhibitor (KPI) domain encoded by exon 7. APP695 is expressed predominantly in neurons, whereas the KPI domain containing isoforms, APP751 and APP770, are expressed ubiquitously. The ratio of APP751/APP695 mRNA tends to increase in the brain of AD patients. Furthermore, this ratio in mouse brain is much lower than that in human brain, and mice are resistant to the spontaneous development of beta-amyloidosis. In addition, transgenic mice that develop pathological changes similar to those of AD expressed more KPI-domain containing APP mRNA than transgenic mice without the changes. Previous studies imply that the controlling elements exist in the flanking sequences of the alternatively-spliced exons. Therefore, we have determined the DNA sequences of intron 7 and made a comparison between mouse and human DNA sequences of intron 7. Mouse intron 7 shares about 50% sequence identity with the human homologue, with higher sequence identity (approximately 85%) mainly in the 5' end (approximately 250 bp) of the intron. A palindromic sequence was found in both human and mouse intron 7 and showed subtle differences in their structure between the two species. Whether this sequence plays any roles in regulating alternative splicing of exon 7 remains to be determined. Human intron 7 contains a Alu element, which possesses potential retinoic acid and thyroid hormone responsive elements that might be involved in the regulation of alternative splicing. Mouse intron 7 sequence also contains a few repeat sequences which are specific to the genome of mice and rats. Homologies shared between human and mouse intron 7 sequences may contribute to the common characteristics of neuron-specific splicing of APP in both species. The unique features of the intron may account for differences between human and mouse brain in fine tuning of alternative splicing of the APP transcript, which may lead to their different susceptibilities to beta-amyloidosis.

Alternative Splicing↗
PubMed2006

[Expression levels of APP and PS1 genes in patients with Alzheimer's disease].

The gene expression levels of amyloid precursor protein (APP) and presenilin 1 (PS1) in the peripheral blood samples of patients with Alzheimer's disease(AD) and their association with the disease were studied. The absolute expression levels of APP and PS1 genes were quantified in 45 AD patients, 25 patients with vascular dementia (VD) and 60 healthy controls by real-time quantitative PCR using SYBR Green I. The APP expression levels in healthy controls, AD cases and VD cases are 0.026+/-0.005, 0.044+/-0.006 and 0.072+/-0.013 amol/microg cDNA, respectively; and the PS1 expression levels are 0.026+/-0.004, 0.051+/-0.011 and 0.039+/-0.005 amol/microg cDNA, respectively. Both APP and PS1 expression levels were significantly elevated in AD or in VD cases (APP, AD vs Control, t=2.639, P<0.01, VD vs Control, t=3.028P<0.01; PS1, AD vs Control, t=2.173P<0.05, VD vs Control, t=2.012P<0.05). It seems that elevated APP and PS1 gene expression is associated with dementia but not especially with AD.

Aged↗
PubMedDate not supplied

The effect of 4-aminopyrazolo (3,4-d) pyrimidine (4-APP) on some parameters of carbohydrate metabolism in the rat.

The study was designed to evaluate some parameters of carbohydrate metabolism in the rat as influenced by 4-APP, an adenine analogue. Adult female rats were injected with 1 mg 4-APP/100 g body weight/day for 3 days. 4-APP evoked a marked enlargement of the liver with lipid droplets accumulation in hepatocytes. This was accompanied by a marked lowering of the liver glycogen content. Within 3 days 4-APP did not change serum glucose, insulin and free fatty acid concentration. Serum glycogenolytic activity studied in an in vitro system showed 7 times as high glucose releasing ability in 4-APP treated rats as that of the serum of control animals. 4-APP resulted also in a marked enlargement of the adrenal medulla and lowered adrenaline and noradrenaline concentrations in the gland. The possibility of an activation of glycogenolysis in the liver of 4-APP treated rats has been discussed.

Adenine↗
PubMed1996

Expression of V642 APP mutant causes cellular apoptosis as Alzheimer trait-linked phenotype.

APP is a transmembrane precursor of beta-amyloid. In dominantly inherited familial Alzheimer's disease (FAD), point mutations V6421, V642F and V642G have been discovered in APP695. Here we show that expression of these mutants (FAD-APPs) causes a clone of COS cells to undergo apoptosis associated with DNA fragmentation. Apoptosis by the three FAD-APPs was the highest among all possible V642 mutants; normal APP695 had no effect on apoptosis, suggesting that apoptosis by APP mutants in this system is phenotypically linked to the FAD trait. FAD-APP-induced apoptosis was sensitive to bcl-2 and most probably mediated by heteromeric G proteins. This study presents a model system allowing analysis of the mechanism for FAD-APP-induced cytotoxicity.

Alzheimer Disease↗
PubMed2025

UALCAN Mobile, an app for cancer proteogenomic data analysis.

Cancer is a complex disease affecting various organs and is a major cause of death worldwide. During cancer initiation, disease progression, and tumor metastasis, various genomic and proteomic alterations are observed. Recent technological advances have led to the generation of large amounts of molecular data, including genomics and transcriptomics. These large-scale datasets can be utilized to analyze and identify sub-class-specific cancer biomarkers and targets. However, there is a need for the development of user-friendly tools for large-scale data analysis, disseminating the analyzed data in a visualizable format to cancer researchers with no programming skills. We developed UALCAN, a comprehensive platform that allows users to integrate disparate data to better understand the genes, proteins, and pathways perturbed in cancer and make discoveries of potential biomarkers and targets. In the current study, we describe the development of the UALCAN Mobile application (app) that will provide cancer transcriptomic data obtained from The Cancer Genome Atlas (TCGA) project to evaluate protein-coding gene expression based on various stratifications, including stage, grade, race, gender, and molecular-subtypes across over 30 types of cancers. In addition, the UALCAN mobile provides data analysis options for epigenetic changes due to DNA promoter methylation and Clinical Proteomic Tumor Analysis Consortium (CPTAC) cancer proteomic data. The app provides access to large cancer molecular datasets on the go. To find changes in the expression of causative genes and proteins and to identify biomarkers and therapeutic targets, UALCAN mobile app will be extremely valuable. The "UALCAN Mobile" app is free to use and can be downloaded from both the iOS/Apple and the Android Play Store and has been downloaded over 100 times in each of iOS and android app stores.

app↗
PubMed1996

Abnormal pattern of platelet APP isoforms in Alzheimer disease and Down syndrome.

OBJECTIVE: To determine if changes in levels of amyloid precursor protein (APP) isoforms in periphery are associated with Alzheimer disease and Down syndrome. DESIGN: After subjects were grouped according to diagnosis, APP isoform levels in platelets were compared. SETTING: University medical center. SUBJECTS: Ten patients who fulfilled diagnostic criteria for probable Alzheimer disease, 22 healthy volunteers, and 7 elderly (mean age, 42.7 years) and 7 young (mean age, 19.0 years) patients with Down syndrome. MAIN OUTCOME MEASURES: The levels of APP isoforms were evaluated by means of Western blot analysis and immunostaining of whole platelets. RESULTS: The ratio between the 130- and the 106- to 110-kd APP isoforms was markedly lower in patients with Alzheimer disease and in elderly patients with Down syndrome than in control subjects. In young patients with Down syndrome, the ratio did not significantly differ from that in control subjects. CONCLUSIONS: A consistent alteration in platelet APP isoforms has been found in Alzheimer disease and Down syndrome. Further studies will determine whether this alteration could provide a peripheral biochemical marker of the disorder and whether it could intervene in the pathogenesis of Alzheimer disease.

Aged↗
PubMed2002

Age-dependent differential regulation of genes encoding APP and alpha-synuclein in hippocampal synaptic plasticity.

We investigated the modulation of the messenger RNA encoding the amyloid precursor protein (APP) and alpha-synuclein following induction of long-term potentiation (LTP) in the dentate gyrus of young and aged rats. Three hours after tetanic stimulation, LTP induced in the young rats was maintained; the aged rats, however, fell into two subgroups: those in which LTP was maintained, and those in which LTP had declined to basal levels. In young rats, the global expression of mRNAs of all isoforms of APP and in particular that of the isoform lacking the KPI domain were significantly upregulated. In aged rats, the global expression of mRNAs of all isoforms of APP was not modified, regardless of whether LTP was maintained or not. The level of mRNA encoding the Kunitz protease-inhibitory (KPI)-minus isoform of APP, however, was increased in aged rats in which LTP was maintained, suggesting that the gene of this isoform may be more specifically regulated by synaptic plasticity. In contrast, we found that the gene encoding alpha-synuclein showed a trend towards being downregulated at the mRNA level in young rats following LTP, and significantly so in aged rats in which LTP was maintained, whereas it was not downregulated in aged rats with decremental LTP. These data suggest that the regulated expression of APP isoforms is part of the tanscriptional response associated with the enduring forms of synaptic plasticity and is altered with age. Whereas the level of alpha-synuclein mRNA is not apparently modified in normal LTP, it may reflect a mechanism of apoptotic cell death in aging that is in part responsible for decremental synaptic plasticity.

Aging↗
PubMed1994

The survival of rat cerebral cortical neurons in the presence of trophic APP peptides.

One function of Alzheimer amyloid protein precursor (APP) is the regulation of growth and differentiation in several types of cells, including fibroblasts, PC12 cells, and neurons. This activity is represented by a small stretch of amino acids in the center of the molecule around RERMS. The APP 17-mer peptide containing the RERMS domain supported survival and neurite extension of rat cortical neurons in a dose-dependent and sequence-specific manner. The APP fragment synthesized in Escherichia coli supported the survival and neurite extension of rat cortical neurons, whereas the mutant APP fragment lacking the 30 amino acids around the RERMS domain had drastically reduced activity to support the survival and neurite extension. The current study established APP as a neuron survival factor and determined that the sequence around RERMS is important for this function.

Alzheimer Disease↗
PubMed1997

APP gene promoter constructs are preferentially expressed in the CNS and testis of transgenic mice.

Transgenic animals were used to examine the spatial and temporal regulation of the human beta amyloid precursor protein (APP) gene promoter region in vivo. A 2.9 kb DNA fragment encompassing the APP gene promoter was fused to the chloramphenical acetyltransferase (CAT) reporter gene (pAMY-CAT) or a partial cDNA encoding the potentially amyloidogenic C-terminal 100 amino acid region of APP (pAMY-C100). Expression of these transgenes occurred primarily, but not exclusively, in the central nervous system (CNS) and testis in multiple independent lineages of transgenic mice. Temporal expression of the CAT reporter gene during development paralleled that reported for the endogenous APP gene. These studies suggest that a CNS-responsive cis-acting element(s) may exist in the promoter/5'-flanking region of the APP gene.

Amyloid beta-Protein Precursor↗
PubMed2002

Hippocampal A beta 42 levels correlate with spatial memory deficit in APP and PS1 double transgenic mice.

We investigated the role of hippocampal amyloid pathology in spatial learning impairment of a new mouse line carrying mutated human amyloid precursor protein (APP) and presenilin-1 (PS1) transgenes. The APP + PS1 mice were tested in spatial navigation in the water maze and in position discrimination in the T-maze at ages of 3-4 and 11-12 months, before and after the appearance of first amyloid plaques. The APP + PS1 mice were impaired in water maze acquisition and retention only at the age of 11-12 months, but performed equally to controls in the T-maze task at both ages. In the impaired older age group, the levels of total Abeta1-42 in the hippocampus of APP + PS1 mice correlated negatively with the retention score. Here we show for the first time that the age-dependent impairment in memory retention in the traditional water maze of APP + PS1 mice correlates with the amount of total Abeta in hippocampus even at a stage when the amyloid deposits cover less than 1% of the hippocampal volume.

Age Factors↗
PubMed1995

Cells from peripheral tissues that exhibit high APP expression are characterized by their high membrane fusion activity.

The amyloid precursor protein of Alzheimer's disease (APP) is ubiquitously expressed suggesting a general function throughout the organism. We have used APP-specific antibodies to investigate the expression and localization of APP in different tissues from rat (testis, ovary, liver, kidney, spleen, pancreas, salivary gland). Immunohistochemistry demonstrated that APP is highly expressed in Sertoli cells, follicle cells, secretory cells, podocytes and macrophages. Features common to these cells include their high membrane turnover and their functional characteristics of endocytic and phagocytic retrieval and exocytosis. This suggests APP may participate in interactions of cells of the mononuclear phagocytic system, and function in relation to tissue maintenance and repair.

Amyloid beta-Protein Precursor↗
PubMed2005

Transgenic mouse models for APP processing and Alzheimer's disease: early and late defects.

Transgenic mice with neuronal expression of human AD-mutant APP[V7171] in their brain recapitulate robustly the amyloid pathology as seen in Alzheimer's disease (AD) patients. The AD related pathological phenotype consisting of amyloid plaques and vascular amyloid pathology, develop progressively and relative late in ageing APP transgenic mice, between 10 and 15 months of age. In contrast to the late - and clinically irrelevant - amyloid plaque-pathology, the early cognitive defects and behavioural features are clinically more interesting. This review discusses the generation and in depth phenotypic characterization of both aspects of the APP[V7171] transgenic mice. Attention is focussed on the relation of biochemical data of the different APP fragments and amyloid peptides to the formation of the typical early defects and the late parenchymal and vascular amyloid depositions. The APP[V7171] transgenic mice are a perfect model to characterize and investigate early biochemical and cognitive aspects and a potential resource to define pathological interactions of different factors known to be involved in AD. Finally, any therapeutic intervention can be directly tested and explored in these transgenic mice as excellent pre-clinical models.

Alzheimer Disease↗
PubMed1993

A physical map of the human APP gene in YACs.

Several point mutations within exons 16 and 17 of the amyloid precursor protein (APP) gene have been reported that are associated with Alzheimer's disease in a small number of familial cases. To determine the size of the APP gene and the organization of the exons within human genomic DNA, we have characterized 11 Yeast Artificial Chromosome (YAC) recombinants containing human APP gene sequences. The smallest YAC insert was 125 kb, and the largest was 1.4 Mb. The YACs were screened by polymerase chain reaction amplification of APP exons to determine which of the 18 exons coding for APP770 were present. Four of the YACs (D110G1, D110G6, D110E9, and B142F9) contain all 18 exons and at least part of the promoter. Construction of an overlapping map of the gene with all of the YACs demonstrated that 3 of the 11 YACs were chimeric. The orientation and position of the coding sequence on the map was determined by probing digests of the YAC DNA with exon PCR products and the vector arms. The coding region of the APP gene spans approximately 400 kb of genomic DNA.

Amyloid beta-Protein Precursor↗