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PubMed1994

Relationship of APP mRNA transcripts and levels of NGF and low-affinity NGF receptors to behavioral measures of age-related cognitive dysfunction.

This study was designed to examine the relationship between cognitive function and endogenous levels of NGF, low-affinity NGF receptor (LNGFR), and amyloid precursor protein (APP) mRNAs. Using 3 month (n = 5), 18 month (n = 40), and 29 month (n = 17) Fischer-344 male rats, cognitive function was assessed with the Morris water maze, reverse transcription and polymerase chain reaction were used to quantify APP mRNAs, and NGF and LNGFR levels were determined with an ELISA. Cognitive function declined progressively with age from 3 months to 18 months, and from 18 months to 29 months, but only RNA content in the tissue declined significantly from 3 months to 18 months. Between 18 month and 29 month rats were small but statistically significant decreases only for Kunitz protease inhibitor (KPI)-inclusive mRNAs and cortical NGF levels. There was a small but statistically significant correlation between cognitive function and %KPI (the amount of KPI APP mRNAs relative to the total amount of APP mRNA), with lower %KPI related to more impaired spatial learning. No other statistically significant correlation or linear relationship could be detected between cognitive function and any of the other neurological measures or any combination of these measures (i.e., hippocampal levels of APP 695 mRNA, cortical and hippocampal levels of NGF, and cortical, hippocampal, and basal forebrain levels of LNGFR).(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1996

Negative transactivation of cAMP response element by familial Alzheimer's mutants of APP.

In familial Alzheimer's disease (FAD), missense point mutations V642I/F/G, which co-segregate with the disease phenotype, have been discovered in amyloid precursor APP695. Here, we report that three FAD mutants (FAD-APPs) negatively regulated the transcriptional activity of cAMP response element (CRE) by a G(o)-dependent mechanism, but expression of wildtype APP695 had no effect on CRE. Experiments with various Galpha(s) chimeras demonstrated that Phe-APP coupled selectively to the C-terminus of Galpha(0). Again, wild-type APP695 had no effect on its C-terminus. These data indicate that FAD-APPs are gain-of-function mutants of APP695 that negatively regulate the CRE activity through G(o). This negative transactivation of CRE is the first biochemically analyzed signal evoked by the three FAD-APPs, but not by wild-type APP695, in a whole-cell system. We discuss the significance of constitutive CRE suppression by FAD-APPs, which is potentially relevant to synaptic malplasticity or memory disorders.

Alzheimer Disease↗
PubMed1998

Post-ischemic changes in the expression of Alzheimer's APP isoforms in rat cerebral cortex.

A significant porportion (25%) of patients with Alzheimer's disease (AD) also shows vascular pathology. Recent ultrastructural studies demonstrated characteristic and extensive angio-architectural distortions of cerebral capillaries in AD brains. We examined the expression of APP mRNA isoforms of cerebral cortex after transient ischemia by middle cerebral artery occlusion, using RT-PCR. Neuronal damage and glial fibrillary acidic protein immunohistochemistry were also examined histologically. After transient ischemia, the Kunitz protease inhibitor-bearing isoforms (KPI-APP) were increased whereas APP 695, which lacks KPI domain, was decreased. Neuronal damage and GFAP-immunoreactive astrocytes were also observed. These results show that focal, transient ischemia alters KPI-APP/APP 695 ratio in cerebral cortex and this shift in APP isoforms could be related to neurodegeneration and/or activation of astrocytes during the ischemic process.

Alzheimer Disease↗
PubMed2005

Metal-binding properties of the peptide APP170-188: a model of the ZnII-binding site of amyloid precursor protein (APP).

Amyloid precursor protein (APP) plays a key role in Alzheimer's disease (AD), although the function of this membrane protein is still unclear. Metal ions are implicated in AD and they also interact with APP. APP possesses a strong ZnII binding site, which is evolutionary conserved. In this paper a synthetic peptide, APP170-188, with a sequence corresponding to the conserved ZnII-binding domain of APP, was synthesised and its metal-binding properties analysed. Titration experiments pointed to the binding of a stoichiometric amount of divalent ions. Further studies indicated that the binding of divalent metals like ZnII, CdII and CoII induces the dimerisation of the peptide. This dimer contains a dinuclear cluster in which the two divalent metals are bridged by two thiolate ligands from cysteine residues. The other two ligands of the tetrahedral coordination sites of each metal ion are terminal thiolate ligands. This structure was supported by the following arguments. The complex formed with CoII presents the characteristic features for tetrahedral tetrathiolate coordination in its UV-visible spectrum. The sequence of APP170-188 contains only three cysteine residues, which is incompatible with a monomeric CoII-APP170-188 complex. EPR measurements of the complex with one equivalent of CoII show almost no signal at 4 K, which is compatible with an antiferromagnetic spin-coupling of the metal ions in a cluster structure. Size-exclusion chromatography indicated that the elution time for the complexes with ZnII and CdII corresponds to the expected molecular weight of a dimer. The circular dichroism (CD) spectrum of the complex with one equivalent of CdII shows a band at 265 nm+, and an ellipticity similar to those observed for similar CdII-thiolate clusters. Possible biological implications of the ZnII binding site and the metal-induced dimerisation are discussed.

Amyloid beta-Protein Precursor↗
PubMed1983

NADPH-diaphorase: a selective histochemical marker for striatal neurons containing both somatostatin- and avian pancreatic polypeptide (APP)-like immunoreactivities.

Certain neurons in the brain are specifically and intensely stained by a histochemical method which demonstrates nicotinamide adenine dinucleotide phosphate NADPH-diaphorase activity. The cell types containing this enzyme in certain areas of the rat forebrain were examined by combining NADPH-diaphorase histochemistry with the indirect immunofluorescence technique. Neurons containing somatostatin- or avian pancreatic polypeptide (APP)-like immunoreactivities were found throughout the forebrain including the striatum and neocortex. These two neuropeptides were also found to coexist in many telencephalic neurons. After photography, the sections processed for immunohistochemistry were stained for NADPH-diaphorase activity by a histochemical method. It was found that within the striatum all of the neurons that were selectively stained by this technique also contained both somatostatin- and APP-like immunoreactivities. Also in the neocortex NADPH-diaphorase was found only in those neurons displaying somatostatin- or APP-like immunoreactivity. In other brain regions such as the nucleus laterodorsalis tegmenti, NADPH-diaphorase-containing cells did not contain these neuropeptides. The results indicate that NADPH-diaphorase histochemistry provides a simple, reliable, histochemical method to demonstrate those striatal neurons in which somatostatin- and APP-like immunoreactivities coexist. The selective occurrence of this enzyme within these neurons may provide a useful target for pharmacological studies of these neuropeptide-containing cells.

Animals↗
PubMed2002

APP knockout attenuates microglial activation and enhances neuron survival in substantia nigra compacta after axotomy.

Focal microglial activation and progressive dopaminergic neurodegeneration in substantia nigra compacta (SNc) have characterized Parkinson's disease (PD). We have hypothesized that the microglial response may be provoked by molecular signals from chronically stressed SNc neurons. To test whether amyloid precursor protein (APP) could serve as such a signal, we evaluated microglial activation in SN after unilateral transection of the medial forebrain bundle (MFB) in mice either wild-type (WT) or null (KO) for APP. WT and KO mice displayed comparable microglial response at the MFB transection site. In WT mice microglial activation was first apparent in the ipsilateral SN at 3 days postlesion (dpl), marked by morphological change and increased isolectin immunoreactivity. The microglial response intensified at 7 dpl and persisted in the medial nigra through 14 dpl. In contrast, in KO mice activated microglia appeared predominantly at 7 dpl, with little activation at 3 dpl and none at 14 dpl. Neuron number in affected WT SNc at 14 dpl was significantly reduced compared with loss in affected KO SNc. The delayed and limited local microglial activation and increased neuron survival in response to distal axotomy of SNc neurons in APP KO mice are consistent with the important role APP in neuronal stress responses in vivo.

Amyloid beta-Protein Precursor↗
PubMed2005

Short-term interleukin-1(beta) increases the release of secreted APP(alpha) via MEK1/2-dependent and JNK-dependent alpha-secretase cleavage in neuroglioma U251 cells.

Several lines of neuroimmunological evidence correlate the development of the inflammatory responses of the brain with the formation of amyloid plaques associated with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within this context, we tested the ability of interleukin-1beta (IL-1beta) to regulate the processing of beta-amyloid precursor protein (beta-APP) in neuroglioma U251 cells. Our findings have shown that short-term treatment with IL-1beta (2 hr) resulted in a concentration-dependent decrease in the amount of the cell-associated form of beta-APP in U251 cells as compared to untreated cells, whereas a 2-hr treatment with IL-1beta led to increased release of secreted APP(alpha) fragment (sAPP(alpha)) into the conditioned media of the cells. The fact that sAPP(alpha) is an alpha-secretase cleavage metabolite of the cell-associated form of beta-APP, and the observation that IL-1beta-induced sAPP(alpha) release could be blocked by tissue inhibitors of metalloproteinases-1 (alpha-secretase inhibitors), suggested that alpha-secretase might be involved in IL-1beta-induced-sAPP(alpha) release. Moreover, to determine whether an intracellular signaling pathway mediates the IL-1beta-induced increase in sAPP(alpha) secretion, we used various specific signaling inhibitors and found that sAPP(alpha) release is significantly blocked by the mitogen-activated protein kinase (MEK1/2) inhibitor PD98059 and the c-Jun N-terminal kinase inhibitor SP600125. These findings suggested that the mechanism of IL-1beta-induced-sAPP(alpha) release is dependent on MEK1/2- and JNK-activated alpha-secretase cleavage in neuroglioma U251 cells.

Amyloid Precursor Protein Secretases↗
PubMed2000

V642I APP-inducible neuronal cells: a model system for investigating Alzheimer's disorders.

APP is a precursor of beta amyloid deposited in Alzheimer's disease (AD). Although genetic studies established that mutations in APP cause familial AD (FAD), the mechanism for neuronal death by FAD mutants has not been well understood. We established neuronal cells (F11/EcR/V642I cells) in which V642I APP was inducibly expressed by ecdysone. Treatment with ecdysone, but not vehicle, killed most cells within a few days, with rounding, shrinkage, and detachment as well as nuclear fragmentation. Death was suppressed by Ac-DEVD-CHO and pertussis toxin. Electron microscopic analysis revealed that apoptosis occurred in ecdysone-treated cells. V642I-APP-induced death was suppressed by the anti-AD factors estrogen and apoE2. These data demonstrate not only that expression of this FAD gene causes neuronal apoptosis, but that F11/EcR/V642I cells, the first neuronal cells with inducible FAD gene expression, provide a useful model system in investigating AD disorders.

Alzheimer Disease↗
PubMed2002

The effects of long-term treatment with metrifonate, a cholinesterase inhibitor, on cholinergic activity, amyloid pathology, and cognitive function in APP and PS1 doubly transgenic mice.

Recent studies in cell cultures have shown that modulating the cholinergic activity can influence the processing and metabolism of amyloid precursor protein (APP). To investigate whether acetylcholinesterase inhibitors (ChEIs) could decrease production of amyloid beta-peptide (A(beta)) and slow down the accumulation of A(beta) also in vivo, we chronically administered metrifonate (100 mg/kg, po), a second-generation ChEI, to 7-month-old doubly transgenic APP+PS1 mice and their nontransgenic littermate controls for 7 months. Behavioral studies, including open field test, T maze, and water maze, were conducted after 6 months treatment with metrifonate, and the mice were sacrificed at the age of 14 months for biochemical and histological analyses. The long-term treatment with metrifonate failed to inhibit the marked overproduction and deposition of A(beta) in the APP+PS1 mice; in contrast, it increased both A(beta)40 and A(beta)42 levels in the hippocampus. However, the A(beta)42 to 40 ratio was significantly reduced by the treatment. In addition, the number of amyloid plaques in the hippocampus did not differ between the treatment and the control groups. Tolerance to cholinesterase inhibition might be induced in the mouse brain because the inhibition rate of AChE was attenuated from about 80 to 50% during the experiment in both APP+PS1 and nontransgenic mice. The metrifonate treatment did not affect cognitive testing parameters but reduced swimming speed and locomotor activity in both genotypes. Our results do not support the idea that ChEIs would slow down the progression of amyloid pathology in Alzheimer's disease.

Alzheimer Disease↗
PubMed1997

Neuronal APP accumulates in toxic membrane blebbings.

The occurence of plasma membrane blebbings is an early cytotoxic event, associated with the reorganization of cytoskeletal proteins, the alteration of interactions between the plasma membrane and the underlying cytoskeleton. The blebbing formation remains poorly understood but the involvement of cytosolic Ca2+ and the production of free radicals may contribute to this cellular phenomenom. The amyloid precursor protein (APP), is a transmembrane protein that can be cleaved to produce the beta amyloid peptide (Abeta) which accumulates in brain senile plaques of Alzheimer's disease. Our study reveals that the exposure of rat and human (hNT) neuronal cultures to a mild concentration of the excitotoxin NMDA slowly induces perturbations of the neuronal cytoskeleton and the occurence of plasma membrane blebbings. An immunocytochemical study using four different APP antibodies demonstrates that these membrane blebs are also associated with a redistribution and an accumulation of cellular APP. This phenomenon is linked to a Ca2+-influx through NMDA-receptors since it is prevented by the NMDA antagonist MK801 or by Ca2+-depleted conditions. In conclusion this study shows that neuronal degeneration induced by slow excitotoxicity, is associated with the presence of APP-accumulating blebs, that can be secondly released in the extracellular region.

Amyloid beta-Protein Precursor↗
PubMed2007

Copper and clioquinol treatment in young APP transgenic and wild-type mice: effects on life expectancy, body weight, and metal-ion levels.

There is mounting evidence that the amyloid precursor protein (APP), the key protein in Alzheimer's disease (AD) is involved in the copper (Cu) homeostasis in the brain. Conflicting results about the potential use of dietary Cu and clioquinol (CQ), a known Cu chelator, have been reported using APP transgenic mice. Previously, in vitro studies have demonstrated that CQ can act as a Cu transporter. To analyze the potential function of CQ as a Cu transporter in vivo, the nutritional effect of Cu and CQ was analyzed in young APP transgenic mice and nontransgenics with food pellets containing either Cu, CQ, Cu plus CQ (Cu + CQ), or without addition of supplements (control). The offspring were fed with corresponding food pellets until the age of 14 weeks. We observed an increased lethality of APP transgenics upon CQ treatment, which could be rescued by a co-treatment with Cu. The exposure of Cu + CQ led to a modest but significant increase in cerebral Cu levels, most likely due to an enhanced transport of CQ-Cu complexes. In CQ or Cu + CQ treatment groups, the plasma levels of Cu, zinc, and iron were reduced in all animals; moreover, Cu treatment alone reduced only plasma iron levels. We conclude not only that CQ has certain toxicity but also that the chelating effect, perhaps, plays a secondary role with respect to its properties as an intracellular Cu transporter, thus, counteracting the supposed therapeutic effects of CQ as an agent for chelating therapy in AD.

Alzheimer Disease↗
PubMed1992

Proteolytic processing of amyloid beta protein precursor (APP) by thrombin.

Search for proteases responsible for an altered processing of APP which generates intermediates containing beta/A4 peptide is preceding to understand the formation of beta amyloid deposits characteristic of Alzheimer's disease, since many studies reveal that APP is ordinarily processed so as not to generate beta amyloid. Here, we have examined the action of thrombin, a serine protease in the blood clotting, in APP processing. Thrombin cleaved the mouse recombinant APP695 in vitro, resulting in the accumulation of 28 kDa fragment. The immunoblot analysis showed that the fragment is derived from the carboxy-terminal side of the recombinant APP695. Further, amino acid sequencing exhibited that the fragment is generated by the cleavage at Arg 510-Ile 511 and therefore includes entire beta/A4 peptide. We consider that the 28 kDa fragment is a possible intermediate for beta/A4 peptide. Thus thrombin may be involved in the altered processing of APP.

Amino Acid Sequence↗
PubMed1991

Expression of APP in the early stage of brain damage.

We immunocytochemically studied the expression of various epitopes of amyloid beta/A4 protein precursor (APP) after brain damage by kainic acid injection. After 3 h, APP695 rapidly accumulated in dystrophic neurites near the damaged site. After 3 days, APP with Kunitz-type protease inhibitor domain was expressed in reactive astrocytes in the lesion and ipsilateral hippocampus. APP rapidly accumulated in dystrophic neurites, and different types of APP were expressed in different cell types in the damaged brain.

Amyloid beta-Peptides↗
PubMed1996

Sprouting and abnormal contacts of nonmedullated axons, and deposition of extracellular material induced by the amyloid precursor protein (APP) and other protease inhibitors.

We have reported that the local administration of serine protease inhibitors (amyloid precursor protein with the Kunitz insert (APP K+), aprotinin, and leupeptin) to the rat sciatic nerve determines a sprouting response of myelinated axons, proliferation of Schwann cells, and demyelination, 5 to 7 days later. Further study of these nerves with the electron microscope revealed (i) a sprouting response of nonmedullated axons, (ii) the appearance of fine axons with a few turns of compact myclin, (iii) abnormal contracts of axons with basal laminae, with fibroblast-like cells, and between them, (iv) the occurrence of hemidesmosome- and desmosome-like junctions between Schwann cell processes, and between Schwann cells and axons, and (v) the appearance of amorphous and fibrillary extracellular deposits alongside the axolemma. The adjacent proximal and distal segments were normal, i.e., axons remained continuous, and the alterations were confined to the segment exposed to the protease inhibitors. Heated APP Kappa +, APP without the Kunitz insert (APP K-), bovine serum albumin, and saline, did not elicit cytological alterations. Our results suggest that these inhibitors of serine proteases (i) set free a sprouting drive of axons by disrupting an ongoing repressive mechanism: (ii) modify the adhesive properties of axons and Schwann cells, and (iii) alter the natural history of an extracellular material. The imbalance of an extracellular protease system may participate in the pathogenesis of Alzheimer's disease.

Amyloid beta-Protein Precursor↗
PubMed1991

Differential APP gene expression in rat cerebral cortex, meninges, and primary astroglial, microglial and neuronal cultures.

Differential amyloid precursor protein (APP) gene expression was investigated in primary cultures of astrocytes, neurons and microglia from neonatal rat cerebral cortex as well as in meninges, and young and adult cerebral cortex tissues in order to define the possible contribution of individual CNS cell types in beta AP deposition. Meninges and neurons contained higher levels of total APP mRNA than glial cells and APP695 mRNA was abundant in neurons while glial cells and meninges contained higher levels of KPI-containing mRNAs. These results demonstrate cell-specific transcriptional and post-transcriptional regulation of APP gene expression in CNS cell types. In addition, the steady-state level of APPs in each cell type did not reflect mRNA levels indicating translational or post-translational regulation.

Amyloid beta-Protein Precursor↗
PubMed1994

Towards a pharmacological approach of Alzheimer's disease based on the molecular biology of the amyloid precursor protein (APP).

After heart disease, cancer and stroke, Alzheimer's disease (AD) is the fourth major cause of death in the developed countries. Due to demographic changes, this situation will further worsen in the future. With the use of molecular biology techniques, important progress has recently been made in the understanding of the molecular changes leading to some forms of this disabling illness. The first step was the partial sequencing of the amyloid protein accumulating in the senile plaques and vascular deposits characteristic of AD. This allowed the cloning of a cDNA coding for a long amyloid precursor protein (APP). During the last few years, independent reports have described the presence of several reproducible point mutations in specific codons of APP in early onset familial Alzheimer patients. These mutations are responsible for an abnormal processing of APP, leading to the formation of pathological beta/A4 amyloid deposits. beta/A4 has been shown to possess neurotrophic properties in embryonic neurones and to be a potent neurotoxic agent in differentiated hippocampal neurones. More recently, modifications of intracellular calcium, activation of kinases, free radical generation and anomalies in potassium channels have been described as possible mechanisms of beta/A4 toxicity. Some forms of Apo-E lipoprotein may be an additional risk factor. Hence, it now seems possible to elaborate a coherent theory to explain the cascade of events leading to the development of AD. Genetically induced point mutations or environmental factors may produce a modification of the APP metabolism and processing. As a consequence, abnormal deposits of beta/A4 are formed. They may exert direct or indirect neurotoxic actions. A degeneration of cholinergic, catecholaminergic and other neurones follows, leading to the well known cognitive and behavioural changes of AD.

Alzheimer Disease↗
PubMed1992

A novel but non-pathogenic mutation in exon 4 of the human amyloid precursor protein (APP) gene.

Mutations in the beta-amyloid precursor protein (APP) gene have been associated with both familial Alzheimer disease (FAD) and with hereditary cerebral haemorrhage. The polymerase chain reaction was used to both amplify and sequence exon 4 of the APP gene from genomic DNA of subjects with FAD and normal control subjects. A novel, rare, conservative DNA sequence variant was discovered at nucleotide 459 of codon 153 (valine) in exon 4 of the APP gene in an affected member of a large FAD pedigree. Segregation studies indicate that this mutation is likely to be non-pathogenic, but must be recognized and discriminated from pathogenic mutations during sequencing studies of the APP gene in patients with FAD.

Amyloid beta-Protein Precursor↗
PubMed2004

Antisense directed at the Abeta region of APP decreases brain oxidative markers in aged senescence accelerated mice.

Amyloid beta-peptide (Abeta) is known to induce free radical-mediated oxidative stress in the brain. Free radical-mediated damage to the neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD). Abeta is produced by proteolytic processing of the amyloid precursor protein (APP). The senescence accelerated mouse prone 8 (SAMP8) strain was developed by phenotypic selection from a common genetic pool. The SAMP8 strain exhibits age-related deterioration in memory and learning as well as Abeta accumulation, and it is considered an effective model for studying brain aging in accelerated senescence. Previous research has shown that a phosphorothiolated antisense oligonucleotide directed against the Abeta region of APP decreases the expression of APP and reverses deficits in learning and memory in aged SAMP8 mice. Consistent with other reports, our previous study showed that 12-month-old SAMP8 mice have increased levels of oxidative stress markers in the brain compared with that in brains from 4-month-old SAMP8 mice. In the current study, 12-month-old SAMP8 mice were treated with antisense oligonucleotide directed against the Abeta region of APP, and the oxidative markers in brain were decreased significantly. Therefore, we conclude that Abeta may contribute to the oxidative stress found in aged SAMP8 mice that have learning and memory impairments. These results are discussed in reference to AD.

Aging↗