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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2016

Open Access 01-12-2016 | Research article

Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo

Authors: Jonathan R. Fisher, Clare E. Wallace, Danielle L. Tripoli, Yvette I. Sheline, John R. Cirrito

Published in: Molecular Neurodegeneration | Issue 1/2016

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Abstract

Background

The aggregation of amyloid-β (Aβ) into insoluble plaques is a hallmark pathology of Alzheimer’s disease (AD). Previous work has shown increasing serotonin levels with selective serotonin re-uptake inhibitor (SSRI) compounds reduces Aβ in the brain interstitial fluid (ISF) in a mouse model of AD and in the cerebrospinal fluid of humans. We investigated which serotonin receptor (5-HTR) subtypes and downstream effectors were responsible for this reduction.

Results

Agonists of 5-HT4R, 5-HT6R, and 5-HT7R significantly reduced ISF Aβ, but agonists of other receptor subtypes did not. Additionally, inhibition of Protein Kinase A (PKA) blocked the effects of citalopram, an SSRI, on ISF Aβ levels. Serotonin signaling does not appear to change gene expression to reduce Aβ levels in acute timeframes, but likely acts within the cytoplasm to increase α-secretase enzymatic activity. Broad pharmacological inhibition of putative α-secretases increased ISF Aβ and blocked the effects of citalopram.

Conclusions

In total, these studies map the major signaling components linking serotonin receptors to suppression of brain ISF Aβ. These results suggest the reduction in ISF Aβ is mediated by a select group of 5-HTRs and open future avenues for targeted therapy of AD.
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Literature
1.
Seubert P, Oltersdorf T, Lee M, Barbour R, Blomquist C, Davis D, Bryant K, Fritz L, Galasko D, Thal L. Secretion of beta-amyloid precursor protein cleaved at the amino terminus of the beta-amyloid peptide. Nature. 1993;361:260–3.CrossRefPubMed
2.
Edbauer D, Winkler E, Regula JT, Pesold B, Steiner H, Haass C. Reconstitution of gamma-secretase activity. Nat Cell Biol. 2003;5:486–8.CrossRefPubMed
3.
Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Laass C, Fahrenholz F. Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A. 1999;96(March):3922–7.CrossRefPubMedPubMedCentral
4.
5.
Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee J-M, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011;14:750–6.CrossRefPubMedPubMedCentral
6.
Nelson RL, Guo Z, Halagappa VM, Pearson M, Gray AJ, Matsuoka Y, Brown M, Martin B, Iyun T, Maudsley S, Clark RF, Mattson MP. Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol. 2007;205:166–76.CrossRefPubMedPubMedCentral
7.
Reynolds GP, Mason SL, Meldrum A, De KS, Parnes H, Eglen M, Wong HF. 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue: distribution, pharmacology and effects of neurodegenerative diseases. Br J Pharmacol. 1995;114:993–8.CrossRefPubMedPubMedCentral
8.
Arjona A, Pooler AM, Lee RK, Wurtman RJ. Effect of a 5-HT(2C) serotonin agonist, dexnorfenfluramine, on amyloid precursor protein metabolism in guinea pigs. Brain Res. 2002;951:135–40.CrossRefPubMed
9.
Nitsch RM, Deng M, Growdon JH, Wurtman RJ. Serotonin 5-HT2a and 5-HT2c receptors stimulate amyloid precursor protein ectodomain secretion. J Biol Chem. 1996;271:4188–94.CrossRefPubMed
10.
Robert SJ, Zugaza JL, Fischmeister R, Gardier AM, Lezoualc’h F. The human serotonin 5-HT4 receptor regulates secretion of non-amyloidogenic precursor protein. J Biol Chem. 2001;276:44881–8.CrossRefPubMed
11.
Hashimoto G, Sakurai M, Teich AF, Saeed F, Aziz F, Arancio O. 5-HT4 receptor stimulation leads to soluble AβPPα production through MMP-9 upregulation. J Alzheimers Dis. 2012;32:437–45.PubMed
12.
Cirrito JR, Disabato BM, Restivo JL, Verges DK, Goebel WD, Sathyan A, Hayreh D, D’Angelo G, Benzinger T, Yoon H, Kim J, Morris JC, Mintun MA, Sheline YI. Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans. Proc Natl Acad Sci U S A. 2011;108:14968–73.CrossRefPubMedPubMedCentral
13.
Sheline Y, West T, Yarasheski K, Swarm R, Jasielec M, Fisher J, Ficker W, Yan P, Xiong C, Frederiksen C, Chott R, Bateman R, Morris J, Mintun M, Lee J, Cirrito J. An Antidepressant Decreases CSF Amyloid-beta Production in Healthy Individuals and in Transgenic Mice. Sci Transl Med. 2014;6:236re4.CrossRefPubMedPubMedCentral
14.
Tanaka KF, Samuels BA, Hen R. Serotonin receptor expression along the dorsal-ventral axis of mouse hippocampus. Philos Trans R Soc Lond B Biol Sci. 2012;367:2395–401.CrossRefPubMedPubMedCentral
15.
16.
Leone AM, Errico M, Lin SL, Cowen DS, Lione AM. Activation of extracellular signal-regulated kinase (ERK) and Akt by human serotonin 5-HT(1B) receptors in transfected BE(2)-C neuroblastoma cells is inhibited by RGS4. J Neurochem. 2000;75:934–8.CrossRefPubMed
17.
Francken BJ, Josson K, Lijnen P, Jurzak M, Luyten WH, Leysen JE. Human 5-hydroxytryptamine(5A) receptors activate coexpressed G(i) and G(o) proteins in Spodoptera frugiperda 9 cells. Mol Pharmacol. 2000;57:1034–44.PubMed
18.
Adayev T, Ray I, Sondhi R, Sobocki T, Banerjee P. The G protein-coupled 5-HT1A receptor causes suppression of caspase-3 through MAPK and protein kinase Cα. Biochim Biophys Acta - Mol Cell Res. 2003;1640:85–96.CrossRef
19.
Lairez O, Cognet T, Schaak S, Calise D, Guilbeau-Frugier C, Parini A, Mialet-Perez J. Role of serotonin 5-HT2A receptors in the development of cardiac hypertrophy in response to aortic constriction in mice. J Neural Transm. 2013;120:927–35.CrossRefPubMed
20.
Norum JH, Hart K, Levy FO. Ras-dependent ERK activation by the human G(s)-coupled serotonin receptors 5-HT4(b) and 5-HT7(a). J Biol Chem. 2003;278:3098–104.CrossRefPubMed
21.
Launay J, Birraux G, Bondoux D, Callebert J, Choi D, Loric S, Maroteaux L. Ras Involvement in Signal Transduction by the Serotonin 5-HT2B Receptor. J Biol Chem. 1996;271:3141–7.CrossRefPubMed
22.
Johnson-Farley NN, Kertesy SB, Dubyak GR, Cowen DS. Enhanced activation of Akt and extracellular-regulated kinase pathways by simultaneous occupancy of Gq-coupled 5-HT2A receptors and Gs-coupled 5-HT7A receptors in PC12 cells. J Neurochem. 2005;92:72–82.CrossRefPubMed
23.
Desdouits-Magnen J, Desdouits F, Takeda S, Syu LJ, Saltiel AR, Buxbaum JD, Czernik AJ, Nairn AC, Greengard P. Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade. J Neurochem. 1998;70:524–30.CrossRefPubMed
24.
Cirrito JR, Kang J-E, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008;58:42–51.CrossRefPubMedPubMedCentral
25.
Zhao J, Paganini L, Mucke L, Gordon M, Refolo L, Carman M, Sinha S, Oltersdorf T, Lieberburg I, McConlogue L. Beta-secretase processing of the beta-amyloid precursor protein in transgenic mice is efficient in neurons but inefficient in astrocytes. J Biol Chem. 1996;271:31407–11.CrossRefPubMed
26.
Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R, Point W. APP Processing and Synaptic Function. Neuron. 2003;37:925–37.CrossRefPubMed
27.
Cirrito JR, Yamada K, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005;48:913–22.CrossRefPubMed
28.
Cirrito JR, May PC, O’Dell M, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS, Bales KR, Paul SM, DeMattos RB, Holtzman DM. In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci. 2003;23:8844–53.PubMed
29.
Apparsundaram S, Stockdale DJ, Henningsen RA, Milla ME, Martin RS. Antidepressants Targeting the Serotonin Reuptake Transporter Act via a Competitive Mechanism. J Pharmacol Exp Ther. 2008;327:982–90.CrossRefPubMed
30.
Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins N, Copeland NG, Price DL, Sisodia SS. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron. 1997;19:939–45.CrossRefPubMed
31.
Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR. Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng. 2001;17:157–65.CrossRefPubMed
32.
Jankowsky JL, Slunt HH, Gonzales V, Jenkins NA, Copeland NG, Borchelt DR. APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1. Neurobiol Aging. 2004;25:885–92.CrossRefPubMed
33.
Cao C, Cirrito JR, Lin X, Wang L, Wang L, Verges DK, Dickson A, Mamcarz M, Zhang C, Mori T, Arendash GW, Holtzman DM, Potter H. Caffeine suppresses amyloid-beta levels in plasma and brain of Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2009;17:681–97.PubMedPubMedCentral
34.
Rodríguez JJ, Noristani HN, Verkhratsky A. The serotonergic system in ageing and Alzheimer’s disease. Prog Neurobiol. 2012;99:15–41.CrossRefPubMed
35.
Dalton GD, Smith FL, Smith P, Dewey WL. Alterations in brain Protein Kinase A activity and reversal of morphine tolerance by two fragments of native Protein Kinase A inhibitor peptide (PKI). Neuropharmacology. 2005;48:648–57.CrossRefPubMed
36.
37.
Gąska M, Kuśmider M, Solich J, Faron-Górecka A, Krawczyk MJ, Kułakowski K, Dziedzicka-Wasylewska M. Analysis of region-specific changes in gene expression upon treatment with citalopram and desipramine reveals temporal dynamics in response to antidepressant drugs at the transcriptome level. Psychopharmacology (Berl). 2012;223:281–97.CrossRef
38.
Verges DK, Restivo JL, Goebel WD, Holtzman DM, Cirrito JR. Opposing synaptic regulation of amyloid-β metabolism by NMDA receptors in vivo. J Neurosci. 2011;31:11328–37.CrossRefPubMedPubMedCentral
39.
Haring R, Fisher A, Marciano D, Pittel Z, Kloog Y, Zuckerman A, Eshhar, N, Heldman E. Mitogen-activated protein kinase-dependent and protein kinase C-dependent pathways link the m1 muscarinic receptor to beta-amyloid precursor protein secretion. J Neurochem. 1998;71:2094–103.CrossRefPubMed
40.
Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992;258:304–7.CrossRefPubMed
41.
Buxbaum JD, Liu K, Slack JL, Stocking KL, Peschon JJ, Johnson RS, Castner BJ, Cerretti DP, Black RA, Luo Y. Evidence That Tumor Necrosis Factor Alpha Converting Enzyme is Involved in Regulated alpha-Secretase Cleavage of the Alzheimer Amyloid Protein Precursor. J Biol Chem. 1998;273:27765–7.CrossRefPubMed
42.
Fragkouli A, Papatheodoropoulos C, Georgopoulos S, Stamatakis A, Stylianopoulou F, Tsilibary EC, Tzinia AK. Enhanced neuronal plasticity and elevated endogenous sAPPα levels in mice over-expressing MMP9. J Neurochem. 2012;121:239–51.CrossRefPubMed
43.
Kuhn P-H, Wang H, Dislich B, Colombo A, Zeitschel U, Ellwart JW, Kremmer E, Rossner S, Lichtenthaler SF. ADAM10 is the physiologically relevant, constitutive alpha-secretase of the amyloid precursor protein in primary neurons. EMBO J. 2010;29:3020–32.CrossRefPubMedPubMedCentral
44.
Suh J, Choi SH, Romano DM, Gannon MA, Lesinski AN, Kim DY, Tanzi RE. ADAM10 missense mutations potentiate β-amyloid accumulation by impairing prodomain chaperone function. Neuron. 2013;80:385–401.CrossRefPubMedPubMedCentral
45.
Tesseur I, Pimenova AA, Lo AC, Ciesielska M, Lichtenthaler SF, De Maeyer JH, Schuurkes JAJ, D’Hooge R, De Strooper B. Chronic 5-HT4 receptor activation decreases Aβ production and deposition in hAPP/PS1 mice. Neurobiol Aging. 2013;34:1779–89.CrossRefPubMed
46.
Giannoni P, Gaven F, de Bundel D, Baranger K, Marchetti-Gauthier E, Roman FS, Valjent E, Marin P, Bockaert J, Rivera S, Claeysen S. Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer’s disease. Front Aging Neurosci. 2013;5(December):96.PubMedPubMedCentral
47.
Gao Y, Nikulina E, Mellado W, Filbin MT. Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase. J Neurosci. 2003;23:11770–7.PubMed
48.
Yin K-J, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu F-F, Turk J, Xu J, Hsu CY, Mills JC, Holtzman DM, Lee J-M. Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci. 2006;26:10939–48.CrossRefPubMed
49.
Kojro E, Postina R, Buro C, Meiringer C, Gehrig-Burger K, Fahrenholz F. The neuropeptide PACAP promotes the alpha-secretase pathway for processing the Alzheimer amyloid precursor protein. FASEB J. 2006;20:512–4.PubMed
50.
Cisse M, Braun U, Leitges M, Fisher A, Pages G, Checler F, Vincent B. ERK1-independent α-secretase cut of β-amyloid precursor protein via M1 muscarinic receptors and PKCα/ε. Mol Cell Neurosci. 2011;47:223–32.CrossRefPubMed
51.
Gonzalez FA, Raden DL, Davis RJ. Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. J Biol Chem. 1991;266:22159–63.PubMed
52.
Yavari R, Adida C, Bray-Ward P, Brines M, Xu T. Human metalloprotease-disintegrin Kuzbanian regulates sympathoadrenal cell fate in development and neoplasia. Hum Mol Genet. 1998;7:1161–7.CrossRefPubMed
53.
Bard J, Zgombick J, Adham N, Vaysse P, Branchek T, Weinshank RL. Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem. 1993;268:23422–6.PubMed
54.
Prins NH, Akkermans LM, Lefebvre RA, Schuurkes JA. 5-HT(4) receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle. Br J Pharmacol. 2000;131:927–32.CrossRefPubMedPubMedCentral
55.
Rosenzweig-Lipson S, Beyer CE, Hughes ZA, Khawaja X, Rajarao SJ, Malberg JE, Rahman Z, Ring RH, Schechter LE. Differentiating antidepressants of the future: efficacy and safety. Pharmacol Ther. 2007;113:134–53.CrossRefPubMed
56.
Watts SW, Yang P, Banes AK, Baez M. Activation of Erk mitogen-activated protein kinase proteins by vascular serotonin receptors. J Cardiovasc Pharmacol. 2001;38:539–51.CrossRefPubMed
57.
Yan P, Bero AW, Cirrito JR, Xiao Q, Hu X, Wang Y, Gonzales E, Holtzman DM, Lee J-M. Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice. J Neurosci. 2009;29:10706–14.CrossRefPubMedPubMedCentral
58.
Savonenko AV, Xu GM, Price DL, Borchelt DR, Markowska AL. Normal cognitive behavior in two distinct congenic lines of transgenic mice hyperexpressing mutant APPSWE. Neurobiol Dis. 2003;12:194–211.CrossRefPubMed
59.
Peroutka SJ. Selective interaction of novel anxiolytics with 5-hydroxytryptamine1A receptors. Biol Psychiatry. 1985;20:971–9.CrossRefPubMed
60.
Rosenzweig-Lipson S, Zhang J, Mazandarani H, Harrison BL, Sabb A, Sabalski J, Stack G, Welmaker G, Barrett JE, Dunlop J. Antiobesity-like effects of the 5-HT 2C receptor agonist WAY-161503. Brain Res. 2006;1073–1074:240–51.CrossRefPubMed
61.
Yang D, Soulier JL, Sicsic S, Mathé-Allainmat M, Brémont B, Croci T, Cardamone R, Aureggi G, Langlois M. New esters of 4-amino-5-chloro-2-methoxybenzoic acid as potent agonists and antagonists for 5-HT4 receptors. J Med Chem. 1997;40:608–21.CrossRefPubMed
62.
Valentini V, Frau R, Bordi F, Borsini F, Di Chiara G. A microdialysis study of ST1936, a novel 5-HT6 receptor agonist. Neuropharmacology. 2011;60:602–8.CrossRefPubMed
63.
Brenchat A, Romero L, García M, Pujol M, Burgueño J, Torrens A, Hamon M, Baeyens JM, Buschmann H, Zamanillo D, Vela JM. 5-HT7 receptor activation inhibits mechanical hypersensitivity secondary to capsaicin sensitization in mice. Pain. 2009;141:239–47.CrossRefPubMed
64.
Gale JD, Grossman CJ, Whitehead JWF, Oxford AW, Bunce KT, Humphrey PPA. GR113808: a novel, selective antagonist with high affinity at the 5-HT4 receptor. Br J Pharmacol. 1994;111:332–8.CrossRefPubMedPubMedCentral
65.
Glass DB, Cheng HC, Kemp BE, Walsh DA. Differential and common recognition of the catalytic sites of the cGMP-dependent and cAMP-dependent protein kinases by inhibitory peptides derived from the heat-stable inhibitor protein. J Biol Chem. 1986;261:12166–71.PubMed
66.
Grobelny D, Poncz L, Galardy RE. Inhibition of human skin fibroblast collagenase, thermolysin, and Pseudomonas aeruginosa elastase by peptide hydroxamic acids. Biochemistry. 1992;31:7152–4.CrossRefPubMed
67.
Gadbois DM, Crissman HA, Tobey RA, Bradbury EM. Multiple kinase arrest points in the G1 phase of nontransformed mammalian cells are absent in transformed cells. Proc Natl Acad Sci U S A. 1992;89:8626–30.CrossRefPubMedPubMedCentral
68.
Linnanen T, Brisander M, Unelius L, Hacksell U, Johansson AM. Atropisomeric derivatives of 2’,6'-disubstituted (R) -11-phenylaporphine : selective serotonin 5-HT 7 receptor antagonists. J Med Chem. 2001;44:1337–40.CrossRefPubMed
69.
Esparza TJ, Zhao H, Cirrito JR, Cairns NJ, Bateman RJ, Holtzman DM, Brody DL. Amyloid-beta oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol. 2013;73:104–19.CrossRefPubMed
70.
Spandidos A, Wang X, Wang H, Seed B. PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res. 2010;38(Database issue):D792–9.CrossRefPubMed
71.
Spandidos A, Wang X, Wang H, Dragnev S, Thurber T, Seed B. A comprehensive collection of experimentally validated primers for Polymerase Chain Reaction quantitation of murine transcript abundance. BMC Genomics. 2008;9:633.CrossRefPubMedPubMedCentral
72.
Wang X, Seed B. A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res. 2003;31:154e–154.CrossRef
Metadata
Title
Redundant Gs-coupled serotonin receptors regulate amyloid-β metabolism in vivo
Authors
Jonathan R. Fisher
Clare E. Wallace
Danielle L. Tripoli
Yvette I. Sheline
John R. Cirrito
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2016
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-016-0112-5

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