Muscarinic Regulation of Alzheimer's Disease Amyloid Precursor Protein Secretion and Amyloid β-Protein Production in Human Neuronal NT2N Cells (*)

The Alzheimer amyloid precursor protein (APP) undergoes complex processing resulting in the production of a 4-kDa amyloid peptide (Aβ) which has been implicated in the pathogenesis of Alzheimer's disease. Recent studies have shown that cells can secrete carboxyl terminus truncated APP derivatives (APP-S) in response to physiological stimulus. We have used human central nervous system neurons (NT2N) derived from a teratocarcinoma cell line (NT2) to study the signal transduction pathways involved in APP-S secretion and Aβ production. Muscarinic receptors (m2 and m3) as well as the heterotrimeric GTP-binding protein Gq and the β1 isoform of phospholipase C were present in NT2N neurons. Stimulation of the muscarinic receptor with carbachol resulted in phospholipase C activation as shown by a transient increase in the second messengers 1,2-diacyl-sn-glycerol and inositol 1,4,5-trisphosphate. Carbachol also caused an increase in intracellular Ca2+ levels measured in single NT2N neurons. Under these conditions, carbachol caused a time-dependent 2-fold increase in APP-S secretion into the medium. In contrast, prolonged treatment with carbachol caused a decrease in Aβ production into the medium. These results suggest that APP-S secretion and Aβ production in NT2N neurons are regulated by the muscarinic/phospholipase C signal transduction pathway. Furthermore, activation of this pathway results in dissociation of APP-S secretion and Aβ production.

• Publication year

  1995

• Venue

  Journal of Biological Chemistry

• Publication date

  1995-03-03

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.270.9.4916PMID 7876266
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Pharmacologic Effects of the Red Blood Cell Substitutes Cross-Linked and Non-Cross-Linked Hemoglobins on Hematopoiesis in Rabbits

  1999cited by this paper
• Transfected muscarinic acetylcholine receptors selectively couple to Gi-type G proteins and Gq/11.

  1994cited by this paper
• Phosphoinositide metabolism, aging and Alzheimer's disease.

  1994cited by this paper
• Amyloid precursor protein secretion and βA4 amyloid generation are not mutually exclusive

  1994cited by this paper
• The return of the cholinergic hypothesis.

  1994cited by this paper
• Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner.

  1994cited by this paper
• Overexpression of the high affinity choline transporter in cortical regions affected by Alzheimer's disease. Evidence from rapid autopsy studies.

  1994cited by this paper
• The release of Alzheimer's disease beta amyloid peptide is reduced by phorbol treatment.

  1994cited by this paper
• Cell biology of the amyloid beta-protein precursor and the mechanism of Alzheimer's disease.

  1994cited by this paper
• Antisense oligonucleotide strategies in neuropharmacology.

  1994cited by this paper
• The protein kinase C family for neuronal signaling.

  1994cited by this paper
• Normal and abnormal biology of the beta-amyloid precursor protein.

  1994cited by this paper
• NTera 2 Cells: A human cell line which displays characteristics expected of a human committed neuronal progenitor cell

  1993cited by this paper
• Signaling through G Proteins and G Protein-coupled Receptors during Platelet Activation

  1993cited by this paper
• Activation of protein kinase C inhibits cellular production of the amyloid beta-protein.

  1993cited by this paper
• New roles for G-protein (βγ-dimers in transmembrane signalling

  1993cited by this paper
• Muscarinic receptors--characterization, coupling and function.

  1993cited by this paper
• Alzheimer's pathology begins to yield its secrets.

  1993cited by this paper
• Alzheimer amyloid protein precursor complexes with brain GTP-binding protein Go

  1993cited by this paper
• Regulation by phorbol esters of amyloid precursor protein release from Swiss 3T3 fibroblasts overexpressing protein kinase C alpha.

  1993cited by this paper
• Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides.

  1993cited by this paper
• Secretion of β-amyloid precursor protein cleaved at the amino terminus of the β-amyloid peptide

  1993cited by this paper
• Fuel secretagogue stimulation of arachidonic acid accumulation in fresh and cultured pancreatic islets.

  1993cited by this paper
• Development of antisera selective for m4 and m5 muscarinic cholinergic receptors: distribution of m4 and m5 receptors in rat brain.

  1993cited by this paper
• Neurotransmitter receptors in Alzheimer disease.

  1993cited by this paper
• Analysis of Gz alpha by site-directed mutagenesis. Sites and specificity of protein kinase C-dependent phosphorylation.

  1993cited by this paper
• New roles for G-protein beta gamma-dimers in transmembrane signalling.

  1993cited by this paper
• Agonist activation of muscarinic acetylcholine receptors.

  1993cited by this paper
• Inositol trisphosphate and calcium signalling

  1993cited by this paper
• Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide.

  1993cited by this paper
• Release of excess amyloid beta protein from a mutant amyloid beta protein precursor.

  1993cited by this paper
• Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors.

  1992cited by this paper
• Inositol-lipid-specific phospholipase C isoenzymes and their differential regulation by receptors.

  1992cited by this paper
• Pure, postmitotic, polarized human neurons derived from NTera 2 cells provide a system for expressing exogenous proteins in terminally differentiated neurons

  1992cited by this paper
• Mutation of the β-amyloid precursor protein in familial Alzheimer's disease increases β-protein production

  1992cited by this paper
• Processing of the amyloid protein precursor to potentially amyloidogenic derivatives.

  1992cited by this paper
• Potentially amyloidogenic, carboxyl-terminal derivatives of the amyloid protein precursor.

  1992cited by this paper
• Production of the Alzheimer amyloid beta protein by normal proteolytic processing.

  1992cited by this paper
• Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor.

  1992cited by this paper
• The Seminal Role of β‐Amyloid in the Pathogenesis of Alzheimer Disease

  1992cited by this paper
• Diversity of structure, signaling and regulation within the family of muscarinic cholinergic receptors

  1992cited by this paper
• Amyloid β-peptide is produced by cultured cells during normal metabolism

  1992cited by this paper
• The seminal role of beta-amyloid in the pathogenesis of Alzheimer disease.

  1992cited by this paper
• Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids

  1992cited by this paper
• Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein.

  1992cited by this paper
• Carbachol stimulation of phospholipase A2 and insulin secretion in pancreatic islets.

  1992cited by this paper
• Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production.

  1992cited by this paper
• Amyloid beta-peptide is produced by cultured cells during normal metabolism.

  1992cited by this paper
• G-protein-regulated phospholipase C. Identification of component proteins.

  1992cited by this paper
• Evidence for a membrane defect in Alzheimer disease brain.

  1992cited by this paper
• Assays of phosphoinositide-specific phospholipase C and purification of isozymes from bovine brains.

  1991cited by this paper
• Expression patterns of beta-amyloid precursor protein (beta-APP) in neural and nonneural human tissues from Alzheimer's disease and control subjects.

  1991cited by this paper
• Identification of the subunits of GTP-binding proteins coupled to somatostatin receptors.

  1991cited by this paper
• Amyloid deposition as the central event in the aetiology of Alzheimer's disease.

  1991cited by this paper
• Distribution of m2 muscarinic receptors in rat brain using antisera selective for m2 receptors.

  1991cited by this paper
• Development of an antiserum against m3 muscarinic receptors: distribution of m3 receptors in rat tissues and clonal cell lines.

  1991cited by this paper
• Identification of Gz alpha as a pertussis toxin-insensitive G protein in human platelets and megakaryocytes.

  1991cited by this paper
• Subcellular distribution of the alpha subunit(s) of Gi: visualization by immunofluorescent and immunogold labeling.

  1991cited by this paper
• Production of antisera selective for m1 muscarinic receptors using fusion proteins: distribution of m1 receptors in rat brain.

  1991cited by this paper
• Regulation of polyphosphoinositide-specific phospholipase C activity by purified Gq.

  1991cited by this paper
• Aged Non‐Human Primates: An Animal Model of Age‐Associated Neurodegenerative Disease

  1991cited by this paper
• Mechanisms of receptor-mediated Ca2+ signaling in rat hepatocytes.

  1991cited by this paper
• Inositol phospholipids-specific phospholipase C: interaction of the gamma 1 isoform with tyrosine kinase.

  1991cited by this paper
• Seminars in medicine of the Beth Israel Hospital, Boston. beta-Amyloid and the pathogenesis of Alzheimer's disease.

  1991cited by this paper
• Diacylglycerol accumulation and microvascular abnormalities induced by elevated glucose levels.

  1991cited by this paper
• β-Amyloid and the pathogenesis of alzheimer's disease

  1991cited by this paper
• Expression patterns of β‐amyloid precursor protein (β‐APP) in neural and nonneural human tissues from alzheimer's disease and control subjects

  1991cited by this paper
• Inositol phospholipid-specific phospholipase C: interaction of the γ isoform with tyrosine kinase

  1991cited by this paper
• Diacylglycerol synthesis de novo from glucose by pancreatic islets isolated from rats and humans.

  1990cited by this paper
• Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation.

  1990cited by this paper
• Cleavage of amyloid beta peptide during constitutive processing of its precursor.

  1990cited by this paper
• Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing.

  1990cited by this paper
• Secretagogue-induced diacylglycerol accumulation in isolated pancreatic islets. Mass spectrometric characterization of the fatty acyl content indicates multiple mechanisms of generation.

  1989cited by this paper
• Interleukin‐1 inhibits glucose‐induced Ca2+ uptake by islets of Langerhans

  1989cited by this paper
• Studies of the Ca2+ requirements for glucose- and carbachol-induced augmentation of inositol trisphosphate and inositol tetrakisphosphate accumulation in digitonin-permeabilized islets. Evidence for a glucose recognition site in insulin secretion.

  1988cited by this paper
• Intracellular Ca2+ mobilization by arachidonic acid. Comparison with myo-inositol 1,4,5-trisphosphate in isolated pancreatic islets.

  1986cited by this paper
• Glucose-induced accumulation of inositol trisphosphates in isolated pancreatic islets. Predominance of the 1,3,4-isomer.

  1986cited by this paper

• The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player

  2025cites this paper
• New perspectives on the basal forebrain cholinergic system in Alzheimer's disease.

  2023cites this paper
• The Biology and Pathobiology of Glutamatergic, Cholinergic, and Dopaminergic Signaling in the Aging Brain

  2021cites this paper
• Polymorphism rs11867353 of Tyrosine Kinase Non-Receptor 1 (TNK1) Gene Is a Novel Genetic Marker for Alzheimer’s Disease

  2020cites this paper
• An adenoviral vector encoded with the GPx-1 gene attenuates memory impairments induced by β-amyloid (1-42) in GPx-1 KO mice via activation of M1 mAChR-mediated signalling

  2020cites this paper
• Novel Anti-Alzheimer's Therapeutic Molecules Targeting Amyloid Precursor Protein Processing

  2020cites this paper
• Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer’s disease

  2018cites this paper
• Machine Learning-based Virtual Screening and Its Applications to Alzheimer’s Drug Discovery: A Review

  2018cites this paper
• Cholinergic System and Post-translational Modifications: An Insight on the Role in Alzheimer’s Disease

  2017cites this paper
• Effects of phenothiazine-structured compounds on APP processing in Alzheimer's disease cellular model.

  2017cites this paper
• Cystatin C Shifts APP Processing from Amyloid-β Production towards Non-Amyloidgenic Pathway in Brain Endothelial Cells

  2016cites this paper
• Reduced Regional Cortical Thickness Rate of Change in Donepezil-Treated Subjects With Suspected Prodromal Alzheimer's Disease.

  2016cites this paper
• Drug Development in Alzheimer’s Disease: The Contribution of PET and SPECT

  2016cites this paper
• Substance P and Alzheimer's Disease: Emerging Novel Roles.

  2016cites this paper
• The selective positive allosteric M1 muscarinic receptor modulator PQCA attenuates learning and memory deficits in the Tg2576 Alzheimer's disease mouse model.

  2015cites this paper
• Calcium Channels in the Human NT2-N Cell Line Functional Expression of L-, N-, P/Q-, and R-Type

  2015cites this paper
• A Predictive In Vitro Model of the Impact of Drugs with Anticholinergic Properties on Human Neuronal and Astrocytic Systems

  2015cites this paper
• PPARα Activation Attenuates Amyloid-β-Dependent Neurodegeneration by Modulating Endo G and AIF Translocation

  2014cites this paper
• M1 muscarinic acetylcholine receptor in Alzheimer’s disease

  2014cites this paper
• Genetics of Alzheimer´S Disease

  2014cites this paper
• Trafficking regulation of proteins in Alzheimer’s disease

  2014cites this paper
• Lysophosphatidic acid induces increased BACE1 expression and Aβ formation.

  2013cites this paper
• Potential Therapeutic Strategies to Prevent the Progression of Alzheimer to Disease States

  2013cites this paper
• TRAFFICKING OF ALPHA SECRETASE ADAM10: NEW INSIGHTS INTO THE MOLECULAR MECHANISM OF MODULATION

  2012cites this paper
• Identification of the physiologically relevant α-secretase of the Alzheimer’s disease-related amyloid precursor protein and its relationship with β-secretase

  2012cites this paper
• Substance P activates ADAM9 mRNA expression and induces α-secretase-mediated amyloid precursor protein cleavage.

  2012cites this paper
• Evidence supporting the role of calpain in the α-processing of amyloid-β precursor protein.

  2012cites this paper
• Current therapeutic strategy in Alzheimer's disease.

  2012cites this paper
• Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors

  2012cites this paper
• Investigation of secreted amyloid precursor protein-α binding partners

  2012cites this paper
• Wnt Signaling: Role in Alzheimer Disease and Schizophrenia

  2012cites this paper
• Cholinergic modulation of amyloid precursor protein processing with emphasis on M1 muscarinic receptor: perspectives and challenges in treatment of Alzheimer’s disease

  2012cites this paper
• TRAFFICKING OF α-SECRETASE ADAM10: NEW INSIGHTS INTO THE MOLECULAR MECHANISM OF MODULATION

  2011cites this paper
• An MRI substudy of a donepezil clinical trial in mild cognitive impairment.

  2011cites this paper
• Investigational Medications for Treatment of Patients With Alzheimer Disease

  2010cites this paper
• P2Y2 Nucleotide Receptor-Mediated Responses in Brain Cells

  2010cites this paper
• Magnesium Modulates Amyloid-β Protein Precursor Trafficking and Processing

  2010cites this paper
• The secretases: enzymes with therapeutic potential in Alzheimer disease

  2010cites this paper
• To treat or not to treat? A meta-analysis of the use of cholinesterase inhibitors in mild cognitive impairment for delaying progression to Alzheimer’s disease

  2009cites this paper
• Fructose-derived carbohydrates from Alisma orientalis

  2009cites this paper
• M1 agonists as a potential disease-modifying therapy for Alzheimer's disease.

  2009cites this paper
• Fustin flavonoid attenuates β‐amyloid (1–42)‐induced learning impairment

  2009cites this paper
• Galantamine inhibits beta-amyloid aggregation and cytotoxicity.

  2009cites this paper
• Pharmacotherapeutic targets in Alzheimer's disease

  2008cites this paper
• Inhibiting gene expression of alpha3 nicotinic receptor in SH-SY5Y cells with the effects on APP metabolism and antioxidation in Alzheimer's disease.

  2008cites this paper
• Cortical Cholinergic Lesion Causes Aβ Deposition: Cholinergic-Amyloid Fusion Hypothesis

  2008cites this paper
• [Therapy of Alzheimer's disease: current status and future development].

  2008cites this paper
• Effects of TNFα-Converting Enzyme Inhibition on Amyloid β Production and APP Processing In Vitro and In Vivo

  2008cites this paper
• Cholinergic treatments with emphasis on M1 muscarinic agonists as potential disease-modifying agents for Alzheimer’s disease

  2008cites this paper
• Lítio e expressão gênica: implicações para a doença de Alzheimer.

  2008cites this paper
• Non-cholinergic Effects of Huperzine A: Beyond Inhibition of Acetylcholinesterase

  2008cites this paper
• Cholinergic Neurodegeneration in Alzheimer's Disease: Basis for Nerve Growth Factor Therapy

  2007cites this paper
• Release of β‐Amyloid from High‐Density Platelets

  2007cites this paper
• Release of beta-amyloid from high-density platelets: implications for Alzheimer's disease pathology.

  2007cites this paper
• M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer’s disease

  2007cites this paper
• M1 muscarinic agonists target major hallmarks of Alzheimer's disease--an update.

  2007cites this paper
• SPECIFIC MECHANISM FOR BLOOD INFLOW STIMULATION IN BRAIN AREA PRONE TO ALZHEIMER’S DISEASE LESIONS

  2007cites this paper
• Nicotinic component of galantamine in the regulation of amyloid precursor protein processing.

  2007cites this paper
• Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants.

  2007cites this paper
• Effects of β-amyloid protein on M1 and M2 subtypes of muscarinic acetylcholine receptors in the medial septum-diagonal band complex of the rat: relationship with cholinergic, GABAergic, and calcium-binding protein perikarya

  2007cites this paper
• M1 Muscarinic Agonists: A Comprehensive Therapy Against Major Hallmarks of Alzheimer's Disease

  2007cites this paper
• Sortilin, SorCS1b, and SorLA Vps10p sorting receptors, are novel γ-secretase substrates

  2006cites this paper
• Unique neuronal functions of cathepsin L and cathepsin B in secretory vesicles: biosynthesis of peptides in neurotransmission and neurodegenerative disease

  2006cites this paper
• Do cholinergic therapies have disease‐modifying effects in Alzheimer's disease?

  2006cites this paper
• Therapeutic approaches to Alzheimer's disease.

  2006cites this paper
• CXCL10‐induced cell death in neurons: role of calcium dysregulation

  2006cites this paper
• Acetylcholine receptors and tau phosphorylation.

  2006cites this paper
• Protease Pathways in Peptide Neurotransmission and Neurodegenerative Diseases

  2006cites this paper
• 5-HT3 and 5-HT4 Receptors as Targets for Drug Discovery for Dementia

  2006cites this paper
• P2Y2 Nucleotide Receptors Enhance α-Secretase-dependent Amyloid Precursor Protein Processing*

  2005cites this paper
• P2Y2 nucleotide receptors enhance alpha-secretase-dependent amyloid precursor protein processing.

  2005cites this paper
• β‐Amyloid Therapeutic Strategies for Alzheimer's Disease

  2005cites this paper
• Cortical Cholinergic Deafferentation Induces Aβ Deposition

  2005cites this paper
• Cysteine Proteases as beta-Secretases for Abeta Production in the Major Regulated Secretory Pathway of Neurons: Implications for Therapeutic Strategies in Alzheimer’s Disease

  2005cites this paper
• Searching for methods to detect, prevent, and treat Alzheimer's disease.

  2005cites this paper
• Direct involvement of G protein alpha(q/11) subunit in regulation of muscarinic receptor-mediated sAPPalpha release.

  2005cites this paper
• A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models.

  2005cites this paper
• Acetylcholinergic neurotransmission and the β-amyloid cascade: implications for Alzheimer’s disease

  2005cites this paper
• Relationship between Alzheimer’s disease clinical stage and Gq/11 in subcellular fractions of frontal cortex

  2005cites this paper
• Direct Involvement of G Protein αq/11n Subunit in Regulation of Muscarinic Receptor-Mediated sAPPα Release

  2005cites this paper
• Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer's disease?

  2005cites this paper
• Tumorigenicity Issues of Embryonic Carcinoma-derived Stem Cells: Relevance to Surgical Trials Using NT2 and hNT Neural Cells

  2005cites this paper
• The Role of Phospholipase D in Amyloid Precursor Protein Processing

  2005cites this paper
• Stimulation of beta-amyloid precursor protein alpha-processing by phorbol ester involves calcium and calpain activation.

  2004cites this paper
• Drugs that target muscarinic cholinergic receptors

  2004cites this paper
• Acetylcholinesterase inhibitors: novel activities of old molecules.

  2004cites this paper
• Differential expression of LMO4 protein in Alzheimer's disease

  2004cites this paper
• Downregulation of Amyloid Precursor Protein (APP) Expression following Post-Traumatic Cyclosporin-A Administration

  2004cites this paper
• Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents.

  2004cites this paper
• Stimulation of β-amyloid precursor protein α-processing by phorbol ester involves calcium and calpain activation

  2004cites this paper
• The serotonin 5-HT4 receptor and the amyloid precursor protein processing.

  2003cites this paper
• The pharmacology of amyloid precursor protein processing.

  2003cites this paper
• ADAMs family members as amyloid precursor protein alpha-secretases.

  2003cites this paper
• The secretases of Alzheimer's disease.

  2003cites this paper
• G-Protein Mediated Metabotropic Receptors Offer Novel Avenues in Neuronal and Vascular Cells for Cytoprotective Strategies

  2003cites this paper
• Up-regulation of soluble amyloid precursor protein fragment secretion in the rat retina in vivo by metabotropic glutamate receptor stimulation

  2003cites this paper
• Amyloid precursor protein processing in vivo--insights from a chemically-induced constitutive overactivation of protein kinase C in Guinea pig brain.

  2003cites this paper
• ADAMs family members as amyloid precursor protein α‐secretases

  2003cites this paper
• β-Amyloid and Cholinergic Neurons

  2003cites this paper
• Characterization of the effect of ganstigmine (CHF2819) on amyloid precursor protein metabolism in SH-SY5Y neuroblastoma cells

  2003cites this paper