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 55 records · Page 3Linked to original sources
PubMed2006

Deficits in synaptic transmission and learning in amyloid precursor protein (APP) transgenic mice require C-terminal cleavage of APP.

Synaptic dysfunction has been shown to be one of the earliest correlates of disease progression in animal models of Alzheimer's disease. Amyloid-beta protein (Abeta) is thought to play an important role in disease-related synaptic dysfunction, but the mechanism by which Abeta leads to synaptic dysfunction is not understood. Here we describe evidence that cleavage of APP in the C terminus may be necessary for the deficits present in APP transgenic mice. In APP transgenic mice with a mutated cleavage site at amino acid 664, normal synaptic transmission, synaptic plasticity, and learning were maintained despite the presence of elevated levels of APP, Abeta42, and even plaque accumulation. These results indicate that cleavage of APP may play a critical role in the development of synaptic and behavioral dysfunction in APP transgenic mice.

Alzheimer Disease↗
PubMed2005

Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2.

Biochemical and genetic studies place the amyloid precursor protein (APP) at the center stage of Alzheimer's disease (AD) pathogenesis. Although mutations in the APP gene lead to dominant inheritance of familial AD, the normal function of APP remains elusive. Here, we report that the APP family of proteins plays an essential role in the development of neuromuscular synapses. Mice deficient in APP and its homolog APP-like protein 2 (APLP2) exhibit aberrant apposition of presynaptic marker proteins with postsynaptic acetylcholine receptors and excessive nerve terminal sprouting. The number of synaptic vesicles at presynaptic terminals is dramatically reduced. These structural abnormalities are accompanied by defective neurotransmitter release and a high incidence of synaptic failure. Our results identify APP/APLP2 as key regulators of structure and function of developing neuromuscular synapses.

Amyloid beta-Protein Precursor↗
PubMed1990

Amyloid beta-protein precursor (APP) of cultured cells: secretory and non-secretory forms of APP.

Overproduction or aberrant catabolism of the predicted amyloid beta-protein precursor (APP) is suspected as the cause of amyloid deposition in Alzheimer's disease and Down's syndrome brains. For possible in vitro experiments of amyloid formation, we have examined the expression of APP in various cultured cells. We found two types of APP producing cell lines. PC12h (rat pheochromocytoma) and HL-60 (human acute promyelocytic leukemia) cells produce a secretory form that is released into the culture medium, while Bu-17 (human glioma) cells synthesize only a non-secretory form that accumulates at the cell surface. APP immunoreactivity on the latter cells was detected at the tips of cell processes or growth cones. These observations indicate that the nonsecretory form of APP may play a role in cell contact or adhesion.

Alzheimer Disease↗
PubMed1995

Levels and alternative splicing of amyloid beta protein precursor (APP) transcripts in brains of APP transgenic mice and humans with Alzheimer's disease.

Abnormal expression of human amyloid precursor protein (hAPP) gene products may play a critical role in Alzheimer's disease (AD). Recently, a transgenic model was established in which platelet-derived growth factor (PDGF) promoter-driven neuronal expression of an alternatively spliced hAPP minigene resulted in prominent AD-type neuropathology (Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido, T., Hagopian, S., Johnson-Wood, K., Khan, K., Lee, M., Leibowitz, P., Lieberburg, I., Little, S., Masliah, E., McConlogue, L., Montoya-Zavala, M., Mucke, L., Paganini, L., and Penniman, E. (1995) Nature 373, 523-527). Here we compared the levels and alternative splicing of APP transcripts in brain tissue of hAPP transgenic and nontransgenic mice and of humans with and without AD. PDGF-hAPP mice showed severalfold higher levels of total APP mRNA than did nontransgenic mice or humans, whereas their endogenous mouse APP mRNA levels were decreased. This resulted in a high ratio of mRNAs encoding mutated hAPP versus wild-type mouse APP. Modifications of hAPP introns 6, 7, and 8 in the PDGF-hAPP construct resulted in a prominent change in alternative splice site selection with transcripts encoding hAPP770 or hAPP751 being expressed at substantially higher levels than hAPP695 mRNA. Frontal cortex of humans with AD showed a subtle increase in the relative abundance of hAPP751 mRNA compared with normal controls. These data identify specific intron sequences that may contribute to the normal neuronspecific alternative splicing of APP pre-mRNA in vivo and support a causal role of hAPP gene products in the development of AD-type brain alterations.

Aged↗
PubMed2006

Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration.

Amyloid precursor protein (APP) has eight potential phosphorylation sites in its cytoplasmic domain. Recently, it has demonstrated that the constitutive phosphorylation of APP at T668 (APP695 isoform numbering) was observed specifically in the brain. Neuron-specific phosphorylation of APP at T668 is thought to be important for neuronal functions of APP, although its exact physiological significance remains to be clarified. In this study, we show that the phosphorylation of the APP intracellular domain (AICD) at T668 is essential for its binding to Fe65 and its nuclear translocation and affects the resultant neurotoxicity, possibly mediated through the induction of glycogen synthase kinase 3beta and tau phosphorylation by enhancing the formation of a ternary complex with Fe65 and CP2 transcription factor. Taken together, these results suggest that the phosphorylation of AICD at T668 contributes to the neuronal degeneration in Alzheimer's disease (AD) by regulating its translocation into the nucleus and then affects neurodegeneration; therefore, the specific inhibitor of T668 phosphorylation might be the target of AD therapy.

Active Transport, Cell Nucleus↗
PubMed2005

APP processing and the APP-KPI domain involvement in the amyloid cascade.

Alternative APP mRNA splicing can generate isoforms of APP containing a Kunitz protease inhibitor (KPI) domain. KPI is one of the main serine protease inhibitors. Protein and mRNA KPI(+)APP levels are elevated in Alzheimer's disease (AD) brain and are associated with increased amyloid beta deposition. In the last years increasing evidence on multiple points in the amyloid cascade where KPI(+)APP is involved has been accumulated, admitting an outstanding position in the pathogenesis of AD to the KPI domain. This review focuses on the APP processing, the molecular activity of KPI and its physiological and pathological roles and the KPI involvement in the amyloid cascade through the nerve growth factor, the lipoprotein receptor-related protein, the tumor necrosis factor-alpha converting enzyme and the Notch1 protein.

Aged↗
PubMed1994

Accumulation of amyloid beta-protein precursor (APP) in Purkinje cells and increase of amino-terminal fragments of APP in cerebrum and cerebellum of aged rat brain.

In aged rat brain, amyloid beta-protein precursor (APP) is accumulated in dendrites and cell bodies of Purkinje cells as full-length or truncated APP, because dendrites and cell bodies are positively stained by antibodies against both the amino- and carboxy-termini of APP. Western blot analysis of homogenates of brains of aged and young rats showed no apparent differences except for an increase in amino-terminal fragments in cerebrum and cerebellum of aged rat. These results indicate that the expression, transport or metabolism of APP in specific regions of brains may be affected by the aging process.

Aging↗
PubMed2001

beta-site APP cleaving enzyme mRNA expression in APP transgenic mice: anatomical overlap with transgene expression and static levels with aging.

The principal enzyme responsible for the beta-site cleavage of amyloid precursor protein (APP) in the brain is a membrane-bound aspartyl protease beta-site APP cleaving enzyme (BACE). We examined human APP (hAPP) and BACE mRNA expression by in situ hybridization in young and old hAPP transgenic mice from two lines: Tg2576, hAPP KM670-671NL (hAPP(Sw)) at 4 and 15 months; and PDAPP, hAPP V717F, at 4 and 11 months. In transgene-positive mice from both lines, hAPP expression was most prominent in cortical, cerebellar, and hippocampal neuronal populations. Cingulate, entorhinal, and hippocampal amyloid burden in transgene-positive 16-month Tg2576 mice was 4 to 8%, and in 12-month PDAPP mice, 2 to 4%; there was no cerebellar amyloid deposition. BACE expression in transgenic and nontransgenic mice was highest in the cerebellar granule cell layer and hippocampal neuronal layers, intermediate in cortex, lower in subcortical regions, and minimal or absent in white matter of the cerebellum. Emulsion-dipped sections confirmed a predominantly neuronal pattern of expression. The amount of hybridization signal did not differ between transgenic and nontransgenic mice, or young and old mice, within each line. Thus, hAPP and endogenous BACE expression in similar anatomical localizations allow for processing of hAPP and Abeta formation in hAPP transgenic mice, but these are modified by additional age-related and anatomical factors.

Aging↗
PubMed1998

The role of the amyloid protein precursor (APP) in Alzheimer's disease: does the normal function of APP explain the topography of neurodegeneration?

Alzheimer's disease (AD) is the most common form of dementia in the aged population. Early-onset familial AD (FAD) involves mutations in a gene on chromosome 21 encoding the amyloid protein precursor or on chromosomes 14 or 1 encoding genes known as presenilins. All mutations examined have been found to increase the production of amyloidogenic forms of the amyloid protein (A beta), a 4 kDa peptide derived from APP. Despite the remarkable progress in elucidating the biochemical mechanisms responsible for AD, little is known about the normal function of APP. A model of how APP and A beta are involved in pathogenesis is presented. This model may explain why certain neuronal populations are selectively vulnerable in AD. It is suggested that those neurons which more readily undergo neuritic sprouting and synaptic remodelling are more vulnerable to A beta neurotoxicity.

Alzheimer Disease↗
PubMed2003

Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain.

Epidemiological studies indicate that long term use of nonsteroidal anti-inflammatory drugs (NSAIDs) confers protection from Alzheimer's disease, and some NSAIDs were shown to specifically decrease production of the amyloidogenic Abeta42 peptide, most likely by direct modulation of gamma-secretase activity. In contrast to gamma-secretase inhibitors, Abeta42-lowering NSAIDs do not impair S3 cleavage in the NOTCH receptor and release of the NOTCH intracellular domain, a finding with conceptual implications for the development of safer drugs targeting Abeta production through gamma-secretase modulation. Intramembrane cleavage and release of an intracellular signaling domain has recently been demonstrated in a number of additional gamma-secretase substrates. We now show in cell-based assays that intramembrane cleavage of APP and ErbB-4 receptor is not impaired by the Abeta42-lowering NSAIDs, sulindac sulfide and ibuprofen. Generation of the APP intracellular domain (AICD) was further not inhibited in a cell-free assay at concentrations far exceeding those effective in reducing Abeta42 production. Closer inspection of AICD signaling showed that stabilization of the AICD peptide by FE65 and AICD-mediated transcription were also retained at Abeta42-lowering concentrations. These results demonstrate that S3-like/intramembrane cleavage is preserved by Abeta42-lowering NSAIDs in at least three substrates of gamma-secretase APP, ErbB-4, and NOTCH and underline the striking specificity by which these drugs target Abeta42 production.

Amino Acid Sequence↗
PubMed1996

APP gene family. Alternative splicing generates functionally related isoforms.

The Alzheimer's beta A4-amyloid protein precursor (APP) and the APP-like proteins (APLPs) are transmembrane glycoproteins with a similar modular domain structure. APP exists in 8 isoforms generated by alternative splicing of exons 7, 8, and 15, of which the L-APP mRNAs lacking exon 15 are ubiquitously expressed in rat tissues but not in neurons. Rat APLP2, the nearest relative of APP, is similarly expressed in 4 different isoforms due to alternative splicing of inserts encoding a Kunitz protease inhibitor domain (KPI, homologous to exon 7 of APP) and a divergent region of 12 amino acids on the NH2-terminal side of the transmembrane domain (12 aa exon). KPI-APLP2 transcripts are highly expressed in neurons, in contrast to KPI-APPs, while L-APLP2 mRNA isoforms lacking the 12 aa exon are predominantly expressed in non-neuronal rat tissues, similar to L-APPs. Further examination of the divergent domains in APP and APLP2 harboring the similarly alternatively spliced APP exon 15 and the 12 aa exon of APLP2 revealed some structural similarities of the amino acid sequences and the predicted secondary structures. In both L-APLP2 and L-APP, a putative xylosyl-transferase recognition site for chondroitin sulfate glycosaminoglycan attachment is present that is interrupted in APP and APLP2 isoforms expressing APP exon 15 or the 12 aa exon of APLP2. Thus, a related function of the divergent domains and the corresponding alternatively spliced APP and APLP2 isoforms in regulation of the binding properties of the ectodomain is suggested. Additionally, beta-secretase cleavage of APP might be sterically hindered selectively in proteoglycan L-APP but not in APP lacking the proteoglycan attachment site. Neurons which have a uniquely low portion of L-APP and high content of APP might therefore be especially susceptible to beta A4-protein liberation. This could explain the selective vulnerability of neurons that is observed in Alzheimer's disease.

Alternative Splicing↗
PubMed2004

The integrated role of desferrioxamine and phenserine targeted to an iron-responsive element in the APP-mRNA 5'-untranslated region.

The Alzheimer's amyloid precursor protein (APP) is the metalloprotein that is cleaved to generate the pathogenic Abeta peptide. We showed that iron closely regulated the expression of APP by 5'-untranslated region (5'-UTR) sequences in APP mRNA. Iron modulated APP holoprotein expression by a pathway similar to iron control of the translation of the ferritin-L and -H mRNAs by iron-responsive elements in their 5'-UTRs. APP gene transcription is also responsive to copper deficit where the Menkes protein depleted fibroblasts of copper to suppress transcription of APP through metal regulatory and copper regulatory sequences upstream of the APP 5' cap site. APP is a copper-zinc metalloprotein and chelation of Fe(3+) by desferrioxamine and Cu(2+) by clioquinol appeared to provide effective therapy for the treatment of AD in limited patient studies. We have introduced an RNA-based screen for small APP 5'-UTR binding molecules to identify leads that limit APP translation (but not APLP-1 and APLP-2) and amyloid Abeta peptide production. A library of 1200 drugs was screened to identify lead drugs that limited APP 5'-UTR-directed translation of a reporter gene. The efficacy of these leads was confirmed for specificity in a cell-based secondary assay to measure the steady-state levels of APP holoprotein relative to APLP-1/APLP-2 by Western blotting. Several chelators were identified among the APP 5'-UTR directed leads consistent with the presence of an IRE stem-loop in front of the start codon of the APP transcript. The APP 5'-UTR-directed drugs--desferrioxamine (Fe(3+) chelator), tetrathiomolybdate (Cu(2+) chelator), and dimercaptopropanol (Pb(2+) and Hg(2+) chelator)--each suppressed APP holoprotein expression (and lowered Abeta peptide secretion). The novel anticholinesterase phenserine also provided "proof of concept" for our strategy to target the APP 5'-UTR sequence to identify "anti-amyloid" drugs. We further defined the interaction between iron chelation and phenserine action to control APP 5'-UTR-directed translation in neuroblastoma (SY5Y) transfectants. Phenserine was most efficient to block translation under conditions of intracellular iron chelation with desferrioxamine suggesting that this anticholinesterase operated through an iron (metal)-dependent pathway at the APP 5'-UTR site.

5' Untranslated Regions↗
PubMed1994

Identification and regulation of the high affinity binding site of the Alzheimer's disease amyloid protein precursor (APP) to glycosaminoglycans.

The specific binding of the amyloid protein precursor (APP) to glycosaminoglycans (GAG) suggests that APP is a cell adhesion molecule (CAM) and/or substrate adhesion molecule (SAM). In order to characterize this activity of APP in the brain at the molecular level, we have purified and characterized the major APP species from rat brain. The major isoform isolated was sequenced and found to be APP695. In a solid-phase binding assay, the specificity of this brain-specific APP isoform-GAG interaction was analysed. The binding of APP to the glycosaminoglycan heparin was found to be time-dependent and saturable. A strong heparin-binding site within a region conserved in rodent and human APP, APLP1 and APLP2, was identified. Saturable binding to heparin through this binding site was found to occur at nmol concentrations of APP. This putative high-affinity site was then located within a sequence of 22 amino acids in length corresponding to residues 316-337 of APP695. This sequence is encoded by APP exon 9 and the first three codons of exon 10. Since all APP and L-APP isoforms so far described include these exons, the strong heparin binding site is a ubiquitous feature of all APP and L-APP isoforms strongly suggesting that the brain-specific and neuronal, as well as the non-neuronal and peripheral APPs and L-APPs do have CAM- and SAM-like activities. Certain metal ions including zinc (II) have been proposed as risk factors in Alzheimer's disease (AD). Recently we showed that APP binds zinc (II) at higher nmol concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Alzheimer Disease↗