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At least 199 records · Page 11Linked to original sources
PubMed2000

Behavioral deficits in APP(V717F) transgenic mice deficient for the apolipoprotein E gene.

Both the beta-amyloid precursor protein (APP) and the apoliprotein E (apoE) genes are involved in the pathogenesis of Alzheimer's disease (AD). We previously showed that mice over-expressing a human mutated form of APP (APP(V717F)) display age-dependent recognition memory deficits associated with the progression of amyloid deposition. Here, we asked whether 10- to 12-month-old APP(V717F) mice lacking the apoE gene, which do not present obvious amyloid deposition, differ from APP(V717F) mice in the object recognition task. The recognition performance is decreased in both transgenic mouse groups compared to control groups. Moreover, some behavioral disturbances displayed by APP mice lacking apoE are even more pronounced than those of APP mice expressing apoE. Our results suggest that the recognition memory deficits are related to high levels of soluble Abeta rather than to amyloid deposits.

Amyloid↗
PubMedDate not supplied

Positive inotropic and electrophysiological effects of APP 201-533 can be explained by an increase of cardiac cyclic AMP.

The possible mechanism of action of the positive inotropic agent APP 201-533 [3-amino-6-methyl-5-phenyl-2(1H)-pyridinone] was investigated. In guinea pig papillary muscles, APP 201-533 increased force of contraction concentration dependently at 10(-4)-10(-3) M. The effect was associated with an abbreviation of contraction and relaxation time. In guinea pig papillary muscles partially depolarized with 22 mM K+, APP 201-533 in concentrations of 10(-4) and 10(-5) M restored slow action potentials, which were not influenced by cimetidine, propranolol, and prazosin but were blocked by the Ca2+ antagonist PY 108-068 and by carbachol in an atropine-sensitive manner. The concentration-effect curve of histamine was shifted to the left in the presence of APP 201-533. These actions can be explained by the increase in cardiac cyclic AMP level that was found in rabbit papillary muscles and guinea pig left atria treated with APP 201-533 due to the known phosphodiesterase inhibitory effect of pyridinones. APP 201-533 increased the inotropic potency of dihydroouabain in guinea pig papillary muscles. It seems possible that this effect is based on an increased Ca2+ sensitivity of myocardial contractile structures as described previously for APP 201-533.

Action Potentials↗
PubMed2004

Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice.

Mice transgenic for mutated forms of the amyloid precursor protein (APP) plus presenilin-1 (PS1) genes (APP + PS1 mice) gradually develop memory deficits which correlate with the extent of amyloid deposition. The expression of several immediate-early genes (IEGs: Arc, Nur77 and Zif268) and several other plasticity-related genes (GluR1, CaMKIIalpha and Na-K- ATPase alphaIII) critical for learning and memory was normal in young APP + PS1 mice preceding amyloid deposition, but declined as mice grew older and amyloid deposits accumulated. Gene repression was less in APP + PS1 mouse brain regions that contain less Abeta and in APP mice compared with APP + PS1 mice, further linking the extent of amyloid deposition and the extent of gene repression. Critically, we demonstrated that amyloid deposition led specifically to impaired induction of the IEGs with no effects on basal expression using exposure to a novel environment 30 min prior to being killed to induce IEGs. These data imply that Abeta deposition can selectively reduce expression of multiple genes linked to synaptic plasticity, and provide a molecular basis for memory deficiencies found in transgenic APP mice and, most likely, in early stage Alzheimer's disease (AD). Presumably, pharmacological agents blocking the Abeta-related inhibition of gene expression will have benefit in AD.

Amyloid↗
PubMed2004

Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer's disease.

Melatonin is an endogenous antioxidant and free radical scavenger. A transgenic (Tg) mouse model for Alzheimer's disease mimics the accumulation of senile plaques, neuronal apoptosis and memory impairment. Previous studies indicated that melatonin reduced beta-amyloid (Abeta)-induced neurotoxicity. In this study, after giving melatonin at 10 mg/kg to APP 695 transgenic (APP 695 Tg) mice for 4 months, we evaluated the long-term influence of melatonin on behavior, biochemical and neuropathologic changes in APP 695 Tg mice. Step-down and step-through passive avoidance tests suggested that 8-month-old APP 695 Tg mice showed decreases in step-down latency and step-through latency and increases in count of error throughout the entire learning trial and memory session, which suggested learning and memory impairment. However, melatonin alleviated learning and memory deficits. Additionally, choline acetyltransferase (ChAT) activity also decreased in the frontal cortex and hippocampus of APP 695 Tg mice compared with non-Tg littermates. Melatonin supplementation increased ChAT activity in the frontal cortex and hippocampus. DNA fragmentation was present in the frontal cortex of the APP 695 Tg mice; melatonin reduced the number of apoptotic neurons. Congo Red staining and Bielschowsky silver impregnation both showed the apparent extracellular Abeta deposition in frontal cortex of APP 695 Tg mice. However, melatonin decreased the Abeta deposits. Our results indicate that neuroprotection by melatonin is partly related to modulation of apoptosis and protection of the cholinergic system. Early rational melatonin interventions may be one of the most promising strategies in the development of approaches to retard or prevent Abeta-mediated disease progression.

Alzheimer Disease↗
PubMed2006

Presenilin-1-mediated retention of APP derivatives in early biosynthetic compartments.

Processing of the amyloid precursor protein (APP) leads to the production of amyloid-beta (Abeta), the major component of extracellular plaques in the brains of Alzheimer's disease (AD) patients. Presenilin-1 (PS-1) plays a key role in the final step of Abeta formation, the gamma-secretase cleavage. Previously, we showed that PS-1 is retained in pre-Golgi compartments by incorporation into COPI-coated membranes of the vesicular tubular clusters (VTCs) between endoplasmic reticulum (ER) and Golgi complex. Here, we show that PS-1 also mediates the retention of the beta-cleavage-derived APP-C-terminal fragment (CTFbeta) and/or Abeta in pre-Golgi membranes. Overexpression of PS-1 increased the percentage of CTFbeta and/or Abeta in VTCs as well as their distribution to COPI-coated VTC membranes. By contrast, overexpression of the dominant-negative aspartate mutant PS-1(D257A) or PS-knockout decreased incorporation of these APP derivatives into COPI-coated membranes. Sorting of APP derivatives to COPI-coated VTC membranes was not depending on the APP cytosolic tail. In post-Golgi compartments, PS-1 expression enhanced the association of full-length APP/APPs with endosomal compartments at the expense of plasma membrane-bound APP. We conclude that PS-1, in addition to its role in gamma-secretase cleavage, is also required for the subcellular routing of APP and its derivatives. Malfunctioning of PS-1 in this role may have important consequences for the progress of AD.

Alzheimer Disease↗
PubMed2006

Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides.

Amyloid-beta, a peptide derived from the precursor protein APP, accumulates in the brain and contributes to the neuropathology of Alzheimer's disease. Increased generation of amyloid-beta might be caused by axonal transport inhibition, via increased dwell time of APP vesicles and thereby higher probability of APP cleavage by secretase enzymes residing on the same vesicles. We tested this hypothesis using a neuronal cell culture model of inhibited axonal transport and by imaging vesicular transport of fluorescently tagged APP and beta-secretase (BACE1). Microtubule-associated tau protein blocks vesicle traffic by inhibiting the access of motor proteins to the microtubule tracks. In neurons co-transfected with CFP-tau, APP-YFP traffic into distal neurites was strongly reduced. However, this did not increase amyloid-beta levels. In singly transfected axons, APP-YFP was transported in large tubules and vesicles moving very fast (on average 3 microm/s) and with high fluxes in the anterograde direction (on average 8.4 vesicles/min). By contrast, BACE1-CFP movement was in smaller tubules and vesicles that were almost 2x slower (on average 1.6 microm/s) with approximately 18x lower fluxes (on average 0.5 vesicles/min). Two-colour microscopy of co-transfected axons confirmed that the two proteins were sorted into distinct carriers. The results do not support the above hypothesis. Instead, they indicate that APP is transported on vesicles distinct from the secretase components and that amyloid-beta is not generated in transit when transport is blocked by tau.

Amyloid beta-Peptides↗
PubMed1993

Expression of L-APP mRNA in brain cells.

Several reports addressed the issue of how the alternative splicing of exon 7 and 8 in the APP pre-mRNA is regulated in different tissues. Of special interest here was the potential involvement of exon 7 containing APP splice isoforms, since this exon codes for a serine protease inhibitor and is therefore of putative relevance for amyloidogenic catabolism of the precursor protein. The recent identification of a third alternative splice site in close proximity to the beta A4-amyloid portion in the APP gene which may also increase APP amyloidogenicity, allowed us to investigate its regulation in cells of the central nervous system. With our assay, we were able to resolve six different APP isoforms of the eight potential isoforms which can be generated from the three alternatively spliced exons 7, 8, and 15. We demonstrate here that, in addition to rat brain microglia cells, astrocyte-enriched cultures also skip the novel alternative 3'-splice site in front of exon 15, generating L-APP mRNA. Neurons are the only cells in the central nervous system which seem to use the 3'-splice site of intron 14 nearly 100%. Interestingly, this very 3'-splice site is the only one present in the APP gene that completely matches the consensus sequence for the branchpoint sequence proposed for introns. We would therefore suggest that neurons lack a specific splicing factor which inhibits the use of the rather strong 3'-splice site in front of exon 15. It remains to be shown whether this is also the case for neurons in Alzheimer's disease.

Alternative Splicing↗
PubMed2002

Regulation of promoter activity of the APP gene by cytokines and growth factors: implications in Alzheimer's disease.

One of the major pathological hallmarks of Alzheimer's disease (AD) is the presence of brain depositions of senile plaques that are primarily composed of potentially toxic amyloid beta-peptide (Abeta), which is generated from a family of Abeta-containing precursor proteins (APP; 695-770 amino acids). The role of inflammatory cytokines and growth factors has been implicated in the pathogenesis of AD. Our goal is to study the effects of these factors on the regulation of APP gene expression. Here we compared APP promoter activity in the presence of different growth factors and cytokines such as brain-derived neurotrophic factor (BDNF), interleukin (IL-1), nerve growth factor (NGF), neurotrofin-3 (NT-3), transforming growth factor (TGF-beta1), and tumor necrosis factor (TNF-alpha1). PC12 neuronal cells, which were treated separately with these agents, were transfected with the construct containing either 190 bp APP proximal promoter region (-46 to 144 bp with respect to the transcription start site [+1]), 94 bp APP 5'-untranslated region (UTR, +50 to 144) or other 5'-UTR-deleted regions. Each construct was cloned upstream of a reporter chloramphenicol acetyl transferase gene (CAT). The treatment of PC12 cells with NGF stimulated reporter activity in all constructs tested. The treatment of cells with BDNF, NT3, TGF-beta1, or TNF-alpha stimulated reporter activity in a promoter/UTR-specific manner. Transfection with the complete -46 to 144 region retained the maximum stimulatory activity for any treatment tested in PC12 cells. These results suggest that the regulatory elements of the APP gene respond to the stimulation of different growth factors, cytokines, and interleukins. This is consistent with the effects of the different growth factors, cytokines, and interleukins on APP message and protein levels.

5' Untranslated Regions↗
PubMed1999

C-terminal maturation fragments of presenilin 1 and 2 control secretion of APP alpha and A beta by human cells and are degraded by proteasome.

BACKGROUND: Most early-onset forms of Alzheimer's disease are due to missense mutations located on two homologous proteins named presenilin 1 and 2 (PS1 and PS2). Several lines of evidence indicate that PS1 and PS2 undergo various post-transcriptional events including endoproteolytic cleavages, giving rise to 28-30 kD N-terminal (NTF) and 18-20 kD C-terminal (CTF) fragments that accumulate in vivo. Whether the biological activity of presenilins is borne by the processed fragments or their holoprotein precursor remains in question. We have examined the putative control of beta APP maturation by CTF-PS1/PS2 and the catabolic process of the latter proteins by the multicatalytic complex, proteasome. MATERIALS AND METHODS: We transiently and stably transfected HEK293 cells with CTF-PS1 or CTF-PS2 cDNA. We examined these transfectants for their production of A beta 40, A beta 42, and APP alpha by immunoprecipitation using specific polyclonals. The effect of a series of proteases inhibitors on the immunoreactivity of CTF-PS1/PS2 was examined by Western blot. Finally, the influence of proteasome inhibitors on the generation of beta APP fragments by CTF-expressing cells was assessed by combined immunoprecipitation and densitometric analyses. RESULTS: We showed that transient and stable transfection of CTF-PS1 and CTF-PS2 cDNAs in human cells leads to increased secretion of APP alpha and A beta, the maturation products of beta APP. Furthermore, we demonstrated that two proteasome inhibitors, lactacystin and Z-IE(Ot-Bu)A-Leucinal, prevent the degradation of both CTFs. Accordingly, we established that proteasome inhibitors drastically potentiate the phenotypic increased production of APP alpha and A beta elicited by CTF-PS1/PS2. CONCLUSION: Our data establish that the C-terminal products of PS1 and PS2 maturation exhibit biological activity and in particular control beta APP maturation upstream to alpha-and beta/gamma-secretase cleavages. This function is directly controlled by the proteasome that modulates the intracellular concentration of CTFs.

Acetylcysteine↗
PubMed2002

[alpha]-Secretase ADAM10 as well as [alpha]APPs is reduced in platelets and CSF of Alzheimer disease patients.

BACKGROUND: Members of membrane-bound disintegrin metalloproteinases (ADAMs) were shown to be capable of cleaving amyloid precursor protein (APP) at the alpha-cleavage site in different cell systems. One of the candidate alpha-secretases identified in this family is ADAM10. The present study addresses the following major questions: 1) Are the levels of an alpha-secretase candidate (i.e., ADAM10) reduced in accessible cells of Alzheimer Disease (AD) patients? 2) Are ADAM10 levels in the peripheral cells of AD patients related to a concomitant decrease in alpha APPs? MATERIALS AND METHODS: Western Blot analysis of ADAM10 is performed on platelet homogenates from 33 sporadic AD patients and on 26 age-matched control subjects. Moreover, the levels of alpha-secretase metabolite (alpha APPs) are tested both in platelets and cerebrospinal fluid (CSF) of the same pool of subjects by means of Western blot with a specific antibody. RESULTS: A significant decrease of platelet ADAM10 levels is observed in patients affected by probable AD when compared to control subjects and this is paralleled by a reduced level of alpha APPs released from platelets. Moreover, in the same pool of AD patients, alpha APPs levels were reduced concomitantly in CSF. CONCLUSIONS: ADAM10 is expressed in platelets. A reduced level of ADAM10 is observed in platelets obtained from AD patients compared to age-matched controls. Further, in the same pool of AD patients, a qualitatively and quantitatively similar decrease in alpha APPs is present both in thrombin-activated platelets and CSF, thus suggesting that alterations of APP processing might occur both in the neuronal compartment and peripheral cells.

ADAM Proteins↗
PubMed2005

[Study on expression of PS1 in APP-PS1 double gene stably transfected cell lines and its relation to gamma-secretase].

OBJECTIVE: To study the role of presenilin1 (PS1) in the processing of beta-amyloid precursor protein (APP) to amyloid beta-peptide (Abeta) and its relation to gamma-secretase in the pathogenesis of Alzheimer's disease (AD). METHODS: Several CHO cell lines stably transfected with either wide-type or mutant PS1 (M(146)L) along with APP(751) genes were established. The expression of PS1 and its half-life were determined by immunoprecipitation, Western blotting and pulse-chase experiment. Abeta released into the conditional media was quantitated by ELISA. RESULTS: PS1 transfected CHO cells expressed an expected 45,000 full length protein. This over-expressed full length PS1 was subject to fast degradation with a half-life of less than 1 hour. In contrast to full length PS1, the truncated N-terminal and C-terminal proteins of PS1 were significantly more stable with a longer half-life of nearly 16 hours. Although the total amount of Abeta released into the conditional media did not show a significant difference between wild-type and mutant PS1 (M(146)L) transfected APP cells, mutant PS1 (M(146)L) transfected APP cells increase Abeta(1 - 42) (a subspecies of total Abeta) production with nearly a 2 fold increase, comparing to untransfected or wild-type PS1 transfected APP cells. CONCLUSION: PS1 is involved in the processing of APP to Abeta, a nearly 2 fold increase of Abeta production in mutant PS1 (M(146)L) transfected APP cells indicates that PS1 may be the expected gamma-secretase itself.

Alzheimer Disease↗
PubMed2000

Hemisynaptic distribution patterns of presenilins and beta-APP isoforms in the rodent cerebellum and hippocampus.

Healthy brain neurons co-express Alzheimer's disease (AD) related proteins presenilins (PS) and beta-amyloid precursor protein (beta-APP). Deposition of beta-amyloid and PS in the senile plaques of AD brain and their ability to interact in vitro suggest that AD pathology could arise from a defect in the physiological interactions between beta-APP and PS within and/or between neurons. The present study compares the immunocytochemical distribution of PS (1 and 2) and beta-APP major isoforms (695 and 751/770) in the synapses of the cerebellum and hippocampus of the adult rat and mouse. In the cerebellar cortex of both species, the four molecules are immunodetected in the presynaptic or the postsynaptic compartments of synapses, suggesting that they are involved in interneuronal relationships. In contrast, PS and beta-APP are postsynaptic in almost all the immunoreactive synapses of the hippocampus. The different distribution patterns of these proteins in cerebellar and hippocampal synapses may reflect specific physiological differences, responsible for differential vulnerability of neurons to AD synaptic pathology. Defective interactions between beta-APP and PS at the synapses could impede the synaptic functions of beta-APP, inducing the selective loss of synapses that accounts for cognitive impairment in AD.

Amyloid beta-Protein Precursor↗
PubMed2006

Avian pancreatic polypeptide fragments refold to native aPP conformation when combined in solution: a CD and VCD study.

An equimolar mixture of avian pancreatic polypeptide (aPP) fragments aPP(1-11)-NH2 and Ac-aPP(12-36) had an electronic circular dichroism (ECD) spectrum that was similar to that of whole aPP in H2O and even more so in 30% (v/v) trifluoroethanol (TFE) in 15 mM Na2HPO4, but was different from the sum of the spectra of the individual fragments. The vibrational circular dichroism (VCD) spectrum of the combined fragments in 30% (v/v) TFE in 15 mM Na2HPO4 in D2O was also similar to that of the intact aPP and unlike the sum of the VCD spectra of the fragments. The interaction of these fragments is thus sufficient to support the conformation of whole aPP. This study demonstrates that VCD, in combination with ECD, is useful for the study of protein-protein interactions.

Amino Acid Sequence↗
PubMed2006

Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment.

Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Abeta42 peptide, either by increasing Abeta42 or decreasing Abeta40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Abeta42 and a decrease in Abeta40 levels resulting in a near three-fold increase of the Abeta42/Abeta40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.

Aged↗
PubMed1995

Enhanced processing of APP induced by IL-1 beta can be reduced by indomethacin and nordihydroguaiaretic acid.

Abnormal processing of the amyloid precursor protein (APP) is thought to contribute to the formation of amyloid plaques in Alzheimer's disease. Several studies suggest that inflammation, and possibly the cytokines released during the inflammatory process, may participate in the plaque formation. We have utilized a cell culture system to examine the effects of the cytokine interleukin-1 beta (IL-1 beta) on the processing of APP. We present data to show that IL-1 beta increases the maturation of APP and causes enhanced processing of the full length APP isoforms. In addition, as reported previously in HUVEC cells, IL-1 beta increases the secretion of APP in PC12 cells. Indomethacin and NDGA, reported inhibitors of the cyclooxygenase and lipoxygenase pathways, respectively, block these effects, suggesting the involvement of prostaglandins and leukotrienes in IL-1 beta mediated APP processing.

Amyloid↗
PubMed1998

Neurotrophin binding to the p75 neurotrophin receptor is necessary but not sufficient to mediate NGF-effects on APP secretion in PC-12 cells.

In the present study the pheochromocytoma cell line (PC-12) was used as a model system to determine the role of the two neurotrophin receptors in the regulation of amyloid precursor protein (APP) secretion by nerve growth factor (NGF). To stimulate TrkA and/or p75NTR signaling in PC-12 cells, we used NGF, brain-derived neurotrophic factor (BDNF), and NGF in the presence of an excess of BDNF or the monoclonal antibody 192IgG, to block p75NTR binding to NGF. Our results demonstrate that NGF stimulates APP secretion in a dose dependent fashion with maximum effects at 10 ng/ml, known to saturate high-affinity NGF binding sites. Treatment of PC-12 cells with varying concentrations of BDNF, 1-1,000 ng/ml, did not alter APP secretion, suggesting that binding to p75NTR alone is not sufficient to affect APP secretion. When blocking NGF binding to p75NTR with BDNF or 192IgG, on the other hand, NGF effects on APP secretion were abolished. These findings suggest that in cells expressing p75NTR and TrkA receptors, binding of NGF to the p75NTR is required to mediate NGF effects on APP secretion. Our data are also consistent with a proposed function of the p75NTR in receptor recruitment and "presentation" of NGF to receptors.

Amyloid beta-Protein Precursor↗
PubMed2000

Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice.

Apolipoprotein E (apoE) has been implicated as a risk factor for Alzheimer's disease and in the deposition, fibrillogenesis, and clearance of the amyloid beta-peptide (Abeta). To examine the in vivo interactions between apoE and Abeta deposition, we examined 12-month-old transgenic (tg) mice expressing human amyloid precursor protein (APP) with the V717F mutation (APP(V717F) homozygous) on an APOE null background. Elimination of APOE resulted in a redistribution and alteration in the character of Abeta deposition in homozygous APP(V717F) tg mice, with a dramatic reduction in cortical and dentate gyrus deposition, prominent increase in diffuse CA1 and CA3 deposition, and prevention of the formation of thioflavin-S-positive deposits. These alterations in Abeta deposition were not mediated by significant changes in regional APP expression, low-density lipoprotein receptor-related protein expression, or soluble Abeta levels. Thus, apoE in APP(V717F) tg mice not only affects the amount and form of Abeta deposition, but also the anatomical distribution of diffuse Abeta deposits. The APP(V717F) tg mouse can serve as a model to investigate genetic influences on the vulnerability of specific neuroanatomical regions to Abeta deposition.

Amyloid beta-Peptides↗
PubMed1995

Chronic elevation of S100 beta protein does not alter APP mRNA expression or promote beta-amyloid deposition in the brains of aging transgenic mice.

S100 beta protein, a member of a Ca(2+)-binding protein family present primarily in the nervous system, affects the survival and differentiation of both neurons and glia cells. Elevated levels of S100 beta protein have been observed in the brains of individuals with Alzheimer Disease (AD), as well as in those with Down Syndrome (DS). We have examined transcript levels from the gene encoding the amyloid precursor protein (APP) in four brain regions of mice from 1 to 24 months of age. After stable adult levels of expression are reached, APP mRNA levels do not change with aging. APP mRNA levels are independent of normal regional variation in S100 beta mRNA and protein. Further, chronic exposure to S100 beta elevated 2- or 7-fold above normal did not alter the transcript levels of APP in transgenic mice. These results leave open the possibility of focal changes in APP transcription and do not address possible effects of S100 beta on the complex processing known to occur with APP protein. However, neither control nor transgenic aged mice showed any evidence of abnormal deposition of amyloid in neuritic plaques. These results are discussed in the context of hypotheses about the role of elevated S100 beta in DS and AD.

Aging↗