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 847 records · Page 47Linked to original sources
PubMed1992

Regulated splicing of the amyloid precursor protein gene during postnatal development of the rat basal forebrain.

The expression of the amyloid precursor protein (APP) gene has been examined in the basal forebrain of rats from birth to adulthood. Levels of total APP mRNA are highest at birth and at postnatal day 15 (P15). The most abundant transcript in rat brain is APP-695, whose expression has previously been found to be largely restricted to the central nervous system. Comparison of the developmental profiles of APP-695 mRNA with that of Kunitz-protease inhibitor (KPI)-containing APP mRNA shows that the greatest difference in expression occurs at P15, when APP-695 message levels are over 6-fold higher than KPI-containing APP mRNA (APP-751, APP-770). This is the largest difference in the APP-695/KPI-APP ratio observed during postnatal development and coincides with the period of maximal neurotrophic responsiveness in the basal forebrain. These results suggest that the APP gene is alternatively spliced during postnatal development and that regulated expression of APP-695 may be influenced by neurotrophic factors in vivo.

Amyloid beta-Protein Precursor↗
PubMed1987

Structural relationships of the major glycoproteins from human alveolar proteinosis surfactant.

Alveolar proteinosis is a disease characterized by accumulation of proteinaceous material in the alveolar space of the lung. Two major collagenase-sensitive polypeptides, alveolar proteinosis peptides of 34 kDa kilodaltons (APP-34) and of 62 kDa (APP-62), were isolated from bronchioalveolar lavage of patients with alveolar proteinosis. These proteins co-purified during fast-performance liquid chromatography (FPLC) chromatofocusing and were separated from each other by electroelution following SDS-polyacrylamide gel electrophoresis. Immunoblot analysis of these proteins demonstrated that both shared antigenic sites with the normal human surfactant-associated protein of Mr 34,000 (SAP-34) using both polyclonal and monoclonal antibodies generated against SAP-34. Removal of asparagine-linked oligosaccharides from the 34 kDa and 62 kDa alveolar proteinosis proteins with endoglycosidase F resulted in polypeptides of 28 kDa from APP-34 and 56 kDa from APP-62. Amino acid analysis and tryptic peptide maps of the electroeluted APP-34 and APP-62 proteins were essentially identical and similar to that previously reported for human SAP-34, supporting the likely relationship of APP-34 and APP-62 as monomer and dimer of the normal SAP-34. APP-34 and APP-62 were both sensitive to bacterial collagenase, yielding collagenase-resistant fragments of 21 kDa, similar in migration and amino acid composition to the fragment generated by collagenase digestion of normal human SAP-34. High molecular weight aggregates of APP-34 and APP-62 were the result of sulfhydryl-dependent and non-sulfhydryl-dependent cross-linking. A domain in the C-terminal non-collagenous portion of the molecules which forms sulfhydryl-dependent oligomers was identified. The two major polypeptides accumulating in the airway of patients with alveolar proteinosis are monomeric (34 kDa) and dimeric (62 kDa) forms of the major surfactant-associated glycoprotein, SAP-34.

Amino Acid Sequence↗
PubMed1994

Regulated cleavage of the Alzheimer amyloid precursor protein: molecular and cellular basis.

The relative utilization of alternative processing pathways for APP can be regulated by the activation state of certain protein phosphorylation signal transduction pathways. For example, activation of protein kinase C (PKC), or inactivation of protein phosphatases 1 and 2A, leads to a relative increase in utilization of the nonamyloidogenic, 'alpha-secretase' cleavage pathway for APP processing at the expense of other pathways. The molecular and cellular basis for this regulatory event is unknown. The possible mechanisms of regulated APP cleavage include (either singly or in combination): 1) substrate (ie APP) activation; 2) substrate redistribution; 3) enzyme (ie alpha-secretase) activation; or 4) enzyme redistribution. APP is a phosphoprotein; however, recent evidence from studies of the metabolism of mutant APP molecules suggests that changes in the APP cytoplasmic tail phosphorylation state may not be necessary for the phosphorylation-dependent activation of 'alpha-secretase' cleavage. Further, indirect immunofluorescent studies of the subcellular distribution of APP in the absence or presence of phorbol esters (PKC activators) fail to disclose obvious phorbol-induced redistribution of APP immunoreactivity. Taken together, current data suggest that major candidate phosphorylation-state sensitive targets relevant to the molecular basis of PKC-activated processing (or 'regulated cleavage') of APP include the APP ectodomain as well as secretase enzymes and/or other components of the APP trafficking/processing apparatus. Progress in distinguishing among these possibilities is discussed.

Alzheimer Disease↗
PubMed2000

Alzheimer's disease: a dysfunction of the amyloid precursor protein(1).

In this review, we argue that at least one insult that causes Alzheimer's disease (AD) is disruption of the normal function of the amyloid precursor protein (APP). Familial Alzheimer's disease (FAD) mutations in APP cause a disease phenotype that is identical (with the exception that they cause an earlier onset of the disease) to that of 'sporadic' AD. This suggests that there are molecular pathways common to FAD and sporadic AD. In addition, all individuals with Down syndrome, who carry an extra copy of chromosome 21 and overexpress APP several-fold in the brain, develop the pathology of AD if they live past the age of 40. These data support the primacy of APP in the disease. Although APP is the source of the beta-amyloid (Abeta) that is deposited in amyloid plaques in AD brain, the primacy of APP in AD may not lie in the production of Abeta from this molecule. We suggest instead that APP normally functions in the brain as a cell surface signaling molecule, and that a disruption of this normal function of APP is at least one cause of the neurodegeneration and consequent dementia in AD. We hypothesize in addition that disruption of the normal signaling function of APP causes cell cycle abnormalities in the neuron, and that these abnormalities constitute one mechanism of neuronal death in AD. Data supporting these hypotheses have come from investigations of the molecular consequences of neuronal expression of FAD mutants of APP or overexpression of wild type APP, as well as from identification of binding proteins for the carboxyl-terminus (C-terminus) of APP.

Alzheimer Disease↗
PubMed1999

TGF-beta(1), regulation of alzheimer amyloid precursor protein mRNA expression in a normal human astrocyte cell line: mRNA stabilization.

The transforming growth factor, TGF-beta(1), has been found to be increased in the central nervous system of Alzheimer's disease (AD) patients, elevates amyloid precursor protein (APP) mRNA levels in rat primary astrocytes, and may initiate or promote the deposition of amyloid-beta (Abeta) peptide in AD. Excess APP production in AD, which potentially leads to amyloidogenesis, is in part due to over expression of APP mRNA. The production of APP in a normal human cell line in contrast to transformed or animal cells provides a meaningful model to study the regulation of APP gene expression by cytokines that promotes amyloidogenesis. Here, we report that TGF-beta(1) treatment of human astrocytes markedly elevated APP mRNA levels, and also increased the half-life of APP message by at least five-fold. Under this condition, as detected by mobility shift and UV cross-linking analysis, a novel 68 kDa RNA-protein complex was formed, involving an 81 nucleotide (nt) fragment within the 3'-untranslated region (UTR), but not the 5'-UTR and coding region of APP mRNA. Insertion of the 3'-UTR onto the chloramphenicol acetyl transferase (CAT) mRNA conferred TGF-beta(1) mediated mRNA stability in transfected human astrocytes. On the other hand, the same insert carrying a deletion of the APP mRNA cis-element fragment had no effect on CAT mRNA stability. A model of APP mRNA regulation is presented in which TGF-beta(1) induced stabilization of APP message involves the binding activity of a 68 kDa RNA-protein complex within the 3'-UTR, which is likely linked to a reduction in the rate of APP mRNA decay.

3' Untranslated Regions↗
PubMed2004

Insertion of the amyloid precursor protein into lipid monolayers: effects of cholesterol and apolipoprotein E.

APP (amyloid precursor protein), together with Chol (cholesterol) and ApoE (apolipoprotein E), has been linked to Alzheimer's disease. We have examined the hypothesis that interaction of APP with the lipid membranes is modulated by Chol and ApoE. Insertion of APP into lipid monolayers was first evidenced as an increase in the surface pressure. APP injected into a subphase induced a substantial increase in the surface pressure of monolayers prepared from PC (L-alpha-phosphatidylcholine), Chol, SPM (sphingomyelin) and PS (L-alpha-phosphatidylserine), the major lipids present in the plasma membranes of brain cells. At a given initial pressure, the insertion of APP into expanded monolayers is higher than that in condensed monolayers, in the order Chol>PC>SPM>PS. The membrane insertion capacity of APP was also measured from surface pressure versus area (pi-A) isotherms of APP-lipid monolayers. The increase in the mean area per molecule in protein-lipid monolayers, in the order PC>Chol>PS>SPM, provides further evidence for protein-lipid interactions. These interactions occurred at optimum salt levels and optimum pH values close to physiological conditions (150 mM NaCl and pH 7.4). In addition, ApoE4 affected the insertion of APP into lipid films. APP-ApoE complexes showed a decreased ability to penetrate lipid monolayers at a constant area. APP-ApoE complexes expanded the pi-A isotherm of a Chol monolayer to a lesser extent than APP alone. These experiments demonstrate the roles of Chol and ApoE in the modulation of membrane insertion of APP.

Amyloid beta-Protein Precursor↗
PubMed1997

Insertion of lysosomal targeting sequences to the amyloid precursor protein reduces secretion of beta A4.

The processing of the amyloid precursor protein (APP) was investigated in cells stably expressing different APP hybrid proteins. The cytoplasmic domain of APP was either deleted or replaced by the corresponding domain of the membrane protein TGN38, lamp-1, or LIMPII. The cytosolic domain of TGN38 in the APP molecule did not alter the secretion of beta A4 when compared with the wild-type APP; however, APP associated with the cell surface and the nonamyloidogenic processing of APP were reduced. With the APP molecules carrying the lysosomal targeting signals of lamp-1 or LIMPII, a decrease in the secretion of beta A4 was observed. Cell surface association and nonamyloidogenic processing were also impaired. This suggests increased degradation of APP and thus efficient targeting to the lysosomal system. Cells expressing the Swedish APP variant generated intracellular beta A4 that accumulated after treatment with chloroquine. This effect was more dramatic with APP mutants carrying lysosomal targeting signals than with full-length APP. Our data suggest the existence of an intracellular site of beta A4 generation from where beta A4 is degraded rather than secreted.

Amino Acid Sequence↗
PubMed1998

p75 and TrkA receptor signaling independently regulate amyloid precursor protein mRNA expression, isoform composition, and protein secretion in PC12 cells.

The pheochromocytoma PC12 cell line was used as a model system to characterize the role of the p75 neurotrophin receptor (p75NTR) and tyrosine kinase (Trk) A nerve growth factor (NGF) receptors on amyloid precursor protein (APP) expression and processing. NGF increased in a dose-dependent fashion neurite outgrowth, APP mRNA expression, and APP secretion with maximal effects at concentrations known to saturate TrkA receptor binding. Displacement of NGF binding to p75NTR by addition of an excess of brain-derived neurotrophic factor abolished NGF's effects on neurite outgrowth and APP metabolism, whereas addition of brain-derived neurotrophic factor alone did not induce neurite outgrowth or affect APP mRNA or protein processing. However, treatment of PC12 cells with C2-ceramide, an analogue of ceramide, the endogenous product produced by the activity of p75NTR-activated sphingomyelinase, mimicked the effects of NGF on cell morphology and stimulation of both APP mRNA levels and APP secretion. Specific stimulation of TrkA receptors by receptor cross-linking, on the other hand, selectively stimulated neurite outgrowth and APP secretion but not APP mRNA levels, which were decreased. These findings demonstrate that in PC12 cells expressing p75NTR and TrkA receptors, binding of NGF to the p75NTR is required to mediate NGF effects on cell morphology and APP metabolism. Furthermore, our data are consistent with NGF having specific effects on p75NTR not shared with other neurotrophins. Lastly, we have shown that specific activation of TrkA receptors--in contrast to p75NTR-associated signaling--stimulates neurite outgrowth and increases nonamyloidogenic secretory APP processing without increases in APP mRNA levels.

Amyloid beta-Protein Precursor↗
PubMed1997

Stimulation of amyloid precursor protein synthesis by adrenergic receptors coupled to cAMP formation.

Amyloid plaques in Alzheimer disease are primarily aggregates of Abeta peptides that are derived from the amyloid precursor protein (APP). Neurotransmitter agonists that activate phosphatidylinositol hydrolysis and protein kinase C stimulate APP processing and generate soluble, non-amyloidogenic APP (APPs). Elevations in cAMP oppose this stimulatory effect and lead to the accumulation of cell-associated APP holoprotein containing amyloidogenic Abeta peptides. We now report that cAMP signaling can also increase cellular levels of APP holoprotein by stimulating APP gene expression in astrocytes. Treatment of astrocytes with norepinephrine or isoproterenol for 24 h increased both APP mRNA and holoprotein levels, and these increases were blocked by the beta-adrenergic antagonist propranolol. Treatment with 8-bromo-adenosine 3',5'-cyclic monophosphate or forskolin for 24 h similarly increased APP holoprotein levels; astrocytes were also transformed into process-bearing cells expressing increased amounts of glial fibrillary acidic protein, suggesting that these cells resemble reactive astrocytes. The increases in APP mRNA and holoprotein in astrocytes caused by cAMP stimulation were inhibited by the immunosuppressant cyclosporin A. Our study suggests that APP overexpression by reactive astrocytes during neuronal injury may contribute to Alzheimer disease neuropathology, and that immunosuppressants can inhibit cAMP activation of APP gene transcription.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1999

Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis.

Amyloid precursor proteins (APPs) are expressed in multiple organs and cell types in diverse species. Their conservation across species and high abundance in brain and the association of various APP missense mutations with autosomal dominant forms of familial Alzheimer's disease (FAD) suggest important roles for APP in the central nervous system. However, the basic functions of APP in the central nervous system remain largely unknown. To assess potential effects of APP on neuronal death and survival, we transfected APP-deficient rat neuroblastoma cells (B103) with DNA constructs encoding wild-type or FAD-mutant human APP. Wild-type, but not FAD-mutant, APP effectively protected cells against apoptosis induced by ultraviolet irradiation, staurosporine, or p53. Wild-type APP also strongly inhibited p53 DNA-binding activity and p53-mediated gene transactivation, whereas FAD-mutant APP did not. We conclude that APP protects neuronal cells against apoptosis by controlling p53 activation at the post-translational level. Disruption of this function by mutations or alterations in APP processing could enhance neuronal vulnerability to secondary insults and contribute to neuronal degeneration.

Alzheimer Disease↗
PubMed1999

Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation.

A number of in vitro studies have shown that activation of muscarinic receptors by cholinergic agonists stimulates the nonamyloidogenic, alpha-secretase-processing pathway of amyloid precursor protein (APP). To determine whether increased cholinergic neurotransmission can modify the APP processing in vivo, we administered a muscarinic receptor agonist (RS86) to normal or aged rats and rats with severe basal forebrain cholinergic deficits (induced by 192 IgG-saporin). The levels of the cell-associated APP in neocortex, hippocampus, and striatum, as well as the secreted form of APP (APPs) in cerebrospinal fluid, were examined by Western blots. Additionally, we investigated the association between the altered APP levels and behavioral deficits caused by cholinergic lesions. We found that treatment with muscarinic receptor agonist resulted in decreased APP levels in neocortex and hippocampus and increased levels of APPs in cerebrospinal fluid. Regulation of APP processing by the muscarinic agonist treatment occurred not only in normal rats, but also in aged and cholinergic denervated rats that model this aspect of Alzheimer's disease. Interestingly, we found that elevation of APP in neocortex correlated with the cognitive deficits in water-maze testing of rats with cholinergic dysfunction. These data indicate that increased cholinergic neurotransmission can enhance nonamyloidogenic APP processing in intact and lesioned rats and that APP may be involved in cognitive performance.

Aging↗
PubMed1998

Regulation of amyloid precursor protein secretion by glutamate receptors in human Ntera 2 neurons.

The amyloid precursor protein (APP) can be cleaved by a beta-secretase to generate a beta-amyloid peptide, which has been implicated in the pathogenesis of Alzheimer's disease. However, APP can also be cleaved by an alpha-secretase to form a non-amyloidogenic secreted form of APP (APP-S). APP-S secretion can be physiologically regulated. This study examined the glutamatergic regulation of APP in the human neuronal Ntera 2 (NT2N) cell line. Metabotropic glutamate receptor subtypes 1alpha/beta and 5alpha were identified in the NT2N neurons by reverse transcription-polymerase chain reaction. Stimulation of these phosphatidylinositol-linked receptors with glutamate or specific receptor agonists resulted in a dose- and time-dependent increase in the secretion of the amyloid precursor protein (APP-S), measured by the immunoprecipitation of APP-S from the medium of [35S]methionine-labeled NT2N neurons. The glutamate-induced APP-S secretion was maximal at 30 min and at a concentration of 1 mM glutamate. Glutamate-induced APP-S secretion required activation of phospholipase C, which resulted in inositol 1, 4,5-trisphosphate production, as shown by the rapid glutamate-induced accumulation of inositol 1,4,5-trisphosphate. Glutamate also caused an increase in intracellular Ca2+. The protein kinase C activator phorbol 12-myristate 13-acetate, a phorbol ester, as well as 1-oleoyl-2-acetoyl-3-glycerol, a cell-permeable diacylglycerol analog, also stimulated APP-S secretion. These findings suggest that APP-S secretion from NT2N neurons can be regulated by the activation of phosphatidylinositol-linked metabotropic glutamate receptor signaling pathway.

Amyloid beta-Protein Precursor↗
PubMed2000

Identification of cis-elements regulating exon 15 splicing of the amyloid precursor protein pre-mRNA.

Alternative splicing of exon 15 of the amyloid precursor protein (APP) pre-mRNA generates two APP isoform groups APP(ex15) (containing exon 15) and L-APP (without exon 15), which show a cell-specific distribution in non-neuronal cells and neurons of rat. Both APP isoforms differ in regard to functional properties like post-translational modification, APP secretion, and proteolytic production of Abeta peptide from APP molecules. Since Abeta generation is an important factor in the development of Alzheimer's disease, one could anticipate that these major APP isoforms might contribute differentially to the mechanisms underlying neurodegeneration in Alzheimer's disease. In this study, we established an APP minigene system in a murine cell system to identify cis-acting elements controlling exon 15 recognition. A 12. 5-kilobase pair genomic fragment of the murine APP gene contained all cis-regulatory elements to reproduce the splicing pattern of the endogenous APP transcripts. By using this approach, two intronic cis-elements flanking exon 15 were identified that block the inclusion of exon 15 in APP transcripts of non-neuronal cells. Point mutation analysis of these intronic regions indicated that pyrimidine-rich sequences are involved in the splice repressor function. Finally, grafting experiments demonstrated that these regulatory regions cell-specifically enhance the blockage of a chimeric exon in the non-neuronal splicing system.

3T3 Cells↗
PubMed2001

Phosphorylation-dependent regulation of the interaction of amyloid precursor protein with Fe65 affects the production of beta-amyloid.

Neuronal Fe65 is an adapter protein that interacts with the cytoplasmic domain of the beta-amyloid precursor protein (APP). Although the interaction has been reported to occur between the second phosphotyrosine interaction domain of Fe65 and the YENPTY motif in the cytoplasmic domain of APP, the regulatory mechanism and biological function of this interaction remain unknown. We report here that (i) a single amino acid mutation at the Thr-668 residue of APP695, located 14 amino acids toward the amino-terminal end from the (682)YENPTY(687) motif, reduced the interaction between members of the Fe65 family of proteins and APP, whereas interaction of APP with the phosphotyrosine interaction domain of other APP binders such as X11-like and mammalian disabled-1 was not influenced by this mutation; (ii) the phosphorylation of APP at Thr-668 diminished the interaction of APP with Fe65 by causing a conformational change in the cytoplasmic domain that contains the Fe65-binding motif, YENPTY; and (iii) the expression of Fe65 slightly suppressed maturation of APP and decreased production of beta-amyloid (Abeta). Mutation at Thr-668 of APP abolished the effect of Fe65 on APP maturation. This mutation blocked the Fe65-dependent suppression of Abeta production and resulted in the release of increased levels of Abeta in the presence of Fe65. We previously reported that during maturation of APP in neurons, the protein is specifically phosphorylated at Thr-668 and undergoes O-glycosylation. The present results suggest that the phosphorylation of O-glycosylated mature APP at Thr-668 causes a conformational change in its cytoplasmic domain that prevents binding of Fe65 in neurons and may lead to an alteration in the production of Abeta.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1.

Site-specific proteolysis of the amyloid-beta precursor protein (APP) by BACE 1 and gamma-secretase, a central event in Alzheimer disease, releases a large secreted extracellular fragment (called APP(S)), peptides of 40-43 residues derived from extracellular and transmembrane sequences (Abeta), and a short intracellular fragment (APP intracellular domain) that may function as a transcriptional activator in a complex with the adaptor protein Fe65 and the nuclear protein Tip60. APP is closely related to APP-like protein (APLP) 1 and APLP2, but only APP is known to be cleaved by BACE 1 and to be involved in Alzheimer disease. We now demonstrate that similar to APP, APLP1 and APLP2 are also cleaved by BACE 1 but not by ADAM 9, another APP protease, and also transactivate nuclear Tip60 in a complex with Fe65. Paradoxically, although BACE 1 cleavage appears to be specific for APP and APLPs, their cleavage sequences exhibit no homology, and a short sequence (7 amino acids) from APP that when placed close to the membrane converts a membrane protein that is normally not cleaved by BACE 1 into a BACE 1 substrate. Our data demonstrate that APLPs and APP are processed similarly to act via the same nuclear target, suggesting that BACE 1 cleavage regulates a common function of APP and APLPs in neurons.

ADAM Proteins↗
PubMed1997

Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.

Missense mutations in the beta-amyloid precursor protein gene (APP) co-segregate with a small subset of autosomal dominant familial Alzheimer's disease (FAD) cases wherein deposition of the 39-43 amino acid beta-amyloid (A beta) peptide and neurodegeneration are principal neuropathological hallmarks. To accurately examine the effect of missense mutations on APP metabolism and A beta production in vivo, we have introduced yeast artificial chromosomes (YACs) containing the entire approximately 400 kbp human APP gene encoding APP harboring either the asparagine for lysine and leucine for methionine FAD substitution at codons 670 and 671 (APP(K670N/M671L)), the isoleucine for valine FAD substitution at codon 717 (APP(V7171)) or a combination of both substitutions into transgenic mice. We demonstrate that, relative to YAC transgenic mice expressing wild-type APP, high levels of A beta peptides are detected in the brains of YAC transgenic mice expressing human APP(K670N/M671L) that is associated with a concomitant diminution in the levels of apha-secretase-generated soluble APP derivatives. Moreover, the levels of longer A beta peptides (species terminating at amino acids 42/43) are elevated in YAC transgenic mice expressing human APP(V7171). These mice should prove valuable for detailed analysis of the in vivo effects of the APP FAD mutations in a variety of tissues and throughout aging and for testing therapeutic agents that specifically alter APP metabolism and A beta production.

Alzheimer Disease↗
PubMed1992

Kunitz protease inhibitor-containing amyloid beta protein precursor immunoreactivity in Alzheimer's disease.

The amyloid beta protein (beta/A4) that is deposited in senile plaques and in cerebral vessels in Alzheimer's disease (AD) is derived from a larger membrane-associated glycoprotein, the amyloid beta protein precursor (APP). The gene encoding APP produces at least four major transcripts. Three of the four transcripts contain an alternatively-spliced exon encoding a Kunitz protease inhibitor domain (KPI). We now report the results of a series of experiments using novel immunohistochemical reagents to anatomically localize beta/A4, APP, and KPI-containing forms of APP (APP-KPI) in the hippocampal formation and temporal neocortex. A new monoclonal antibody against beta/A4 recognized senile plaques and vascular amyloid, but no cellular elements. Anti-APP and anti-KPI monoclonal antibodies stained neurons, including proximal axons and dendrites. The neuritic component of some plaques in patients with AD and in elderly control individuals were also immunoreactive for both APP and APP-KPI. Quantitative assessment of senile plaques in temporal neocortex showed that, on average, about one-third of beta/A4 immunoreactive plaques stained with either anti-APP or anti-KPI. Amyloid beta protein precursor and APP-KPI immunoreactivity were also found in the white and grey matter vessels of both AD patients and control individuals. These results suggest that KPI-containing forms of APP are present in dystrophic neurites of senile plaques, and normally in neurons, neuronal processes, and in the vascular compartment in the brain. Thus, APP-KPI is in a position to be intimately associated with beta/A4 deposition in the neuropil, in plaques and in amyloid angiopathy.

Adult↗
PubMed1997

In vivo regulation of amyloid precursor protein secretion in rat neocortex by cholinergic activity.

The proteolytic cleavage of the amyloid precursor protein (APP) has been shown to be modulated through specific muscarinic receptor activation in vitro in both transfected cell lines and native brain slices, whereas a demonstration of receptor-mediated control of APP processing under in vivo conditions is still lacking. To simulate alterations in muscarinic receptor stimulation in vivo, we have (i) specifically reduced the cortical cholinergic innervation in rats using partial immunolesions with 192IgG-saporin, and (ii) restored cholinergic function in lesioned rats by transplantation of nerve growth factor producing fibroblasts. While total APP levels in cortical homogenates were unaffected by cholinergic deafferentation, we observed a significant reduction in the abundance of secreted APP and a concomitant increase in membrane-bound APP. These changes were reversed in immunolesioned rats with nerve growth factor-producing fibroblasts. There was a strong positive correlation between the ratio of secreted APP to membrane-bound APP and the activity of choline acetyltransferase and M1 muscarinic acetylcholine receptor density (measured by [3H]pirenzepine binding) in experimental groups. Additionally, we observed a transient decrease in the ratio of cortical APP transcripts containing the Kunitz protease inhibitor domain (APP 770 and APP 751) versus APP 695 in rats with cholinergic hypoactivity. The data presented suggest that cortical APP processing is under basal forebrain cholinergic control, presumably mediated through M1 muscarinic acetylcholine receptors on cholinoceptive cortical target cells.

3T3 Cells↗