Psychiatry and Mental health; Geriatrics and Gerontology; Clinical Psychology; General Neuroscience
Abstract :
[en] Background: Alzheimer’s disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA2-IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach. Objective: A cPLA2-IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy. Methods: We targeted the cPLA2-IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic acid dosage [AA], cPLA2-IVA cellular translocation) before being tested in vivo. We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA2-IVA itself, the NMDA receptor, AβPP and tau by IHC after i.v. injection in APP/PS1 mice. Results: Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA2-IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA2-IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation. Conclusions: cPLA2-IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD.
Research center :
CMMI - Centre de Recherche en Microscopie et Imagerie Médicale
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Andre, Séverine ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service de Chimie générale, organique et biomédicale
Verteneuil, Sébastien; General, Organic and Biomedical Chemistry Unit, NMR and Molecular Imaging Laboratory, University of Mons, Mons, Belgium
Ris, Laurence ; Université de Mons - UMONS > Faculté de Médecine et de Pharmac > Service de Neurosciences
Kahvecioglu, Zehra Cagla ; UMONS - Université de Mons [BE] > FMP > Service de Chimie Générale, Organique et Biomédicale
Nonclercq, Denis ; Université de Mons - UMONS > Faculté de Médecine et de Pharmac > Service d'Histologie
De winter, Julien ; Université de Mons - UMONS > Faculté des Science > Service de Synthèse et spectrométrie de masse organiques
Vander elst, Luce ; Université de Mons - UMONS > Faculté de Médecine et de Pharmacie > Service du Doyen de la Faculté de Médecine et Pharmacie
Laurent, Sophie ; Université de Mons - UMONS > Faculté de Médecine et de Pharmac > Service de Chimie générale, organique et biomédicale ; Center for Microscopy and Molecular Imaging, Gosselies, Belgium
Muller, Robert ; Université de Mons - UMONS > Faculté de Médecine et de Pharmac > Service du Doyen de la Faculté de Médecine et Pharmacie ; Center for Microscopy and Molecular Imaging, Gosselies, Belgium
Burtea, Carmen ; Université de Mons - UMONS > Faculté de Médecine et de Pharmac > Service de Chimie générale, organique et biomédicale
Language :
English
Title :
Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer’s Disease
M108 - Chimie générale, organique et biomédicale M119 - Neurosciences M118 - Histologie Organic Synthesis and Mass Spectrometry
Research institute :
R550 - Institut des Sciences et Technologies de la Santé R100 - Institut des Biosciences
Name of the research project :
3681 - FRMH 2016 BURTEA - Développement d'une stratégie moléculaire de traitement de la maladie d'Alzheimer via la modulation d'une isoforme de la phospholipase. - Sources privées 132 - ARC UMONS 5 - identification de nouveaux outils diagnostiques d'imagerie moléculaires basés sur la caractérisation de la réponse cellulaire aux signaux de mort - Fédération Wallonie Bruxelles 3256 - Fondation Rotary 2015 André - Development of a molecular strategy for Alzheimer's disease therapy by modulation of a phospholipase A2 isoform - Sources privées
Breijyeh Z, Karaman R (2020) Comprehensive review on Alzheimer’s disease: Causes and treatment. Mol Basel Switz 25, 5789.
Salomone S, Caraci F, Leggio GM, Fedotova J, Drago F (2012) New pharmacological strategies for treatment of Alzheimer’s disease: Focus on disease modifying drugs. Br J Clin Pharmacol 73, 504-517.
Graham WV, Bonito-Oliva A, Sakmar TP (2017) Update on Alzheimer’s disease therapy and prevention strategies. Annu Rev Med 68, 413-430.
Godyń J, Jończyk J, Panek D, Malawska B (2016) Therapeutic strategies for Alzheimer’s disease in clinical trials. Pharmacol Rep PR 68, 127-138.
Kudo I, Murakami M (2002) Phospholipase A2 enzymes. Prostaglandins Other Lipid Mediat 68-69, 3-58.
Angelova PR, Müller WS (2009) Arachidonic acid potently inhibits both postsynaptic-type Kv4.2 and presynaptic-type Kv1.4 IA potassium channels. Eur J Neurosci 29, 1943-1950.
Taylor AL, Bonventre JV, Uliasz TF, Hewett JA, Hewett SJ (2008) Cytosolic phospholipase A2 alpha inhibition prevents neuronal NMDA receptor-stimulated arachidonic acid mobilization and prostaglandin production but not subsequent cell death. J Neurochem 106, 1828-1840.
Zhu P, Genc A, Zhang X, Zhang J, Bazan NG, Chen C (2005) Heterogeneous expression and regulation of hippocampal prostaglandin E2 receptors. J Neurosci Res 81, 817-826.
Ross BM, Moszczynska A, Erlich J, Kish SJ (1998) Phospholipid-metabolizing enzymes in Alzheimer’s disease: Increased lysophospholipid acyltransferase activity and decreased phospholipase A2 activity. J Neurochem 70, 786-793.
Schaeffer EL, da Silva ER, Novaes B de A, Skaf HD, Gattaz WF (2010) Differential roles of phospholipases A2 in neuronal death and neurogenesis: Implications for Alzheimer disease. Prog Neuropsychopharmacol Biol Psychiatry 34, 1381-1389.
Shmelzer Z, Karter M, Eisenstein M, Leto TL, Hadad N, Ben-Menahem D, Gitler D, Banani S, Wolach B, Rotem M, Levy R (2008) Cytosolic phospholipase A2alpha is targeted to the p47phox-PX domain of the assembled NADPH oxidase via a novel binding site in its C2 domain. J Biol Chem 283, 31898-31908.
Zhu D, Lai Y, Shelat PB, Hu C, Sun GY, Lee JC-M (2006) Phospholipases A2 mediate amyloid-beta peptide-induced mitochondrial dysfunction. J Neurosci 26, 11111-11119.
Szaingurten-Solodkin I, Hadad N, Levy R (2009) Regulatory role of cytosolic phospholipase A2alpha in NADPH oxidase activity and in inducible nitric oxide synthase induction by aggregated Abeta1-42 in microglia. Glia 57, 1727-1740.
Hoshino T, Namba T, Takehara M, Nakaya T, Sugimoto Y, Araki W, Narumiya S, Suzuki T, Mizushima T (2009) Prostaglandin E2 stimulates the production of amyloid-beta peptides through internalization of the EP4 receptor. J Biol Chem 284, 18493-18502.
Sagy-Bross C, Kasianov K, Solomonov Y, Braiman A, Friedman A, Hadad N, Levy R (2015) The role of cytosolic phospholipase A2 in amyloid precursor protein induction by amyloid beta1-42: Implication for neurodegeneration. J Neurochem 132, 559-571.
Liang X, Wang Q, Hand T, Wu L, Breyer RM, Montine TJ, Andreasson K (2005) Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer’s disease. J Neurosci 25, 10180-10187.
Tang S-S, Wang X-Y, Hong H, Long Y, Li Y-Q, Xiang G-Q, Jiang L-Y, Zhang H-T, Liu L-P, Miao M-X, Hu M, Zhang T-T, Hu W, Ji H, Ye F-Y (2013) Leukotriene D4 induces cognitive impairment through enhancement of CysLT1 R-mediated amyloid- generation in mice. Neuropharmacology 65, 182-192.
Taniguchi T, Kawamata T, Mukai H, Hasegawa H, Isagawa T, Yasuda M, Hashimoto T, Terashima A, Nakai M, Mori H, Ono Y, Tanaka C (2001) Phosphorylation of tau is regulated by PKN. J Biol Chem 276, 10025-10031.
Arnaud LT, Myeku N, Figueiredo-Pereira ME (2009) Proteasome-caspase-cathepsin sequence leading to tau pathology induced by prostaglandin J2 in neuronal cells. J Neurochem 110, 328-342.
Cao L-L, Guan P-P, Liang Y-Y, Huang X-S, Wang P (2019) Cyclooxygenase-2 is essential for mediating the effects of calcium ions on stimulating phosphorylation of tau at the sites of Ser 396 and Ser 404. J Alzheimers Dis 68, 1095-1111.
Yokoyama U, Iwatsubo K, Umemura M, Fujita T, Ishikawa Y (2013) The prostanoid EP4 receptor and its signaling pathway. Pharmacol Rev 65, 1010-1052.
Joshi YB, Giannopoulos PF, Chu J, Sperow M, Kirby LG, Abood ME, Praticò D (2014) Absence of ALOX5 gene prevents stress-induced memory deficits, synaptic dysfunction and tauopathy in a mouse model of Alzheimer’s disease. Hum Mol Genet 23, 6894-6902.
Giannopoulos PF, Joshi YB, Chu J, Praticò D (2013) The 12-15-lipoxygenase is a modulator of Alzheimer’s-related tau pathology in vivo. Aging Cell 12, 1082-1090.
Sagy-Bross C, Hadad N, Levy R (2013) Cytosolic phospholipase A2 upregulation mediates apoptotic neuronal death induced by aggregated amyloid- peptide1-42. Neurochem Int 63, 541-550.
Kishida KT, Pao M, Holland SM, Klann E (2005) NADPH oxidase is required for NMDA receptor-dependent activation of ERK in hippocampal area CA1. J Neurochem 94, 299-306.
Sun GY, He Y, Chuang DY, Lee JC, Gu Z, Simonyi A, Sun AY (2012) Integrating cytosolic phospholipase A2 with oxidative/nitrosative signaling pathways in neurons: A novel therapeutic strategy for AD. Mol Neurobiol 46, 85-95.
Desbène C, Malaplate-Armand C, Youssef I, Garcia P, Stenger C, Sauvée M, Fischer N, Rimet D, Koziel V, Escanyé M-C, Oster T, Kriem B, Yen FT, Pillot T, Olivier JL (2012) Critical role of cPLA2 in A oligomer-induced neurodegenerationandmemorydeficit.NeurobiolAging33, 1123.e17-29.
Kriem B, Sponne I, Fifre A, Malaplate-Armand C, Lozac’hPillot K, Koziel V, Yen-Potin FT, Bihain B, Oster T, Olivier J-L, Pillot T (2005) Cytosolic phospholipase A2 mediates neuronal apoptosis induced by soluble oligomers of the amyloid-beta peptide. FASEB J 19, 85-87.
Williams RSB, Bate C (2016) An in vitro model for synaptic loss in neurodegenerative diseases suggests a neuroprotective role for valproic acid via inhibition of cPLA2 dependent signalling. Neuropharmacology 101, 566-575.
Kihara Y, Yanagida K, Masago K, Kita Y, Hishikawa D, Shindou H, Ishii S, Shimizu T (2008) Platelet-activating factor production in the spinal cord of experimental allergic encephalomyelitis mice via the group IVA cytosolic phospholipase A2-lyso-PAFAT axis. J Immunol 181, 5008-5014.
Hegen M, Sun L, Uozumi N, Kume K, Goad ME, Nickerson-Nutter CL, Shimizu T, Clark JD (2003) Cytosolic phospholipase A2alpha-deficient mice are resistant to collagen-induced arthritis. J Exp Med 197, 1297-1302.
Nagase T, Uozumi N, Ishii S, Kita Y, Yamamoto H, Ohga E, Ouchi Y, Shimizu T (2002) A pivotal role of cytosolic phospholipase A(2) in bleomycin-induced pulmonary fibrosis. Nat Med 8, 480-484.
Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F, Komagata Y, Maki K, Ikuta K, Ouchi Y, Miyazaki J, Shimizu T (1997) Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390, 618-622.
Hong KH, Bonventre JC, O’Leary E, Bonventre JV, Lander ES (2001) Deletion of cytosolic phospholipase A(2) suppresses Apc(Min)-induced tumorigenesis. Proc Natl Acad Sci U S A 98, 3935-3939.
Patel MI, Singh J, Niknami M, Kurek C, Yao M, Lu S, Maclean F, King NJC, Gelb MH, Scott KF, Russell PJ, Boulas J, Dong Q (2008) Cytosolic phospholipase A2-alpha: A potential therapeutic target for prostate cancer. Clin Cancer Res 14, 8070-8079.
Meyer AM, Dwyer-Nield LD, Hurteau GJ, Keith RL, O’Leary E, You M, Bonventre JV, Nemenoff RA, Malkinson AM (2004) Decreased lung tumorigenesis in mice genetically deficient in cytosolic phospholipase A2. Carcinogenesis 25, 1517-1524.
Sanchez-Mejia RO, Newman JW, Toh S, Yu G-Q, Zhou Y, Halabisky B, Cissé M, Scearce-Levie K, Cheng IH, Gan L, Palop JJ, Bonventre JV, Mucke L (2008) Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer’s disease. Nat Neurosci 11, 1311-1318.
Kalyvas A, David S (2004) Cytosolic phospholipase A2 plays a key role in the pathogenesis of multiple sclerosis-like disease. Neuron 41, 323-335.
Chuang DY, Simonyi A, Kotzbauer PT, Gu Z, Sun GY (2015) Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation throughthelipoxygenasepathway.JNeuroinflammation12, 199.
McKew JC, Lovering F, Clark JD, Bemis J, Xiang Y, Shen M, Zhang W, Alvarez JC, Joseph-McCarthy D (2003) Structure-activity relationships of indole cytosolic phospholipase A(2)alpha inhibitors: Substrate mimetics. Bioorg Med Chem Lett 13, 4501-4504.
Zhao Z, Liu N, Huang J, Lu P-H, Xu X-M (2011) Inhibition of cPLA2 activation by Ginkgo biloba extract protects spinal cord neurons from glutamate excitotoxicity and oxidative stress-induced cell death. J Neurochem 116, 1057-1065.
Weerasinghe GR, Rapoport SI, Bosetti F (2004) The effect of chronic lithium on arachidonic acid release and metabolism in rat brain does not involve secretory phospholipase A2 or lipoxygenase/cytochrome P450 pathways. Brain Res Bull 63, 485-489.
Solomonov Y, Hadad N, Levy R (2016) Reduction of cytosolic phospholipase A2 upregulation delays the onset of symptoms in SOD1G93A mouse model of amyotrophic lateral sclerosis. J Neuroinflammation 13, 134.
Liu H, Zuo F, Wu H (2017) Blockage of cytosolic phospholipase A2 alpha by monoclonal antibody attenuates focal ischemic brain damage in mice. Biosci Trends 11, 439-449.
André S, Larbanoix L, Verteneuil S, Stanicki D, Nonclercq D, Vander Elst L, Laurent S, Muller RN, Burtea C (2020) Development of an LDL receptor-targeted peptide susceptible to facilitate the brain access of diagnostic or therapeutic agents. Biology 9, 161.
Pitts MW (2018) Barnes maze procedure for spatial learning and memory in mice. Bio-Protoc 8, e2744.
functionalized imaging probe targeted to amyloid- and able to cross the blood-brain barrier. J Alzheimers Dis 60, 1547-1565.
Ansciaux E, Burtea C, Laurent S, Crombez D, Nonclercq D, Vander Elst L, Muller RN (2015) In vitro and in vivo characterization of several functionalized ultrasmall particles of iron oxide, vectorized against amyloid plaques and potentially able to cross the blood-brain barrier: Toward earlier diagnosis of Alzheimer’s disease by molecular imaging. Contrast Media Mol Imaging 10, 211-224.
Larbanoix L, Burtea C, Laurent S, Van Leuven F, Toubeau G, Vander Elst L, Muller RN (2010) Potential amyloid plaque-specific peptides for the diagnosis of Alzheimer’s disease. Neurobiol Aging 31, 1679-1689.
Perisic O, Fong S, Lynch DE, Bycroft M, Williams RL (1998) Crystal structure of a calcium-phospholipid binding domain from cytosolic phospholipase A2. J Biol Chem 273, 1596-1604.
Zhou P, Jin B, Li H, Huang S-Y (2018) HPEPDOCK: A web server for blind peptide-protein docking based on a hierarchical algorithm. Nucleic Acids Res 46, W443-W450.
Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu S-S (2004) Calcium, ATP, and ROS: A mitochondrial love-hate triangle. Am J Physiol Cell Physiol 287, C817-833.
Peper A (2009) Aspects of the relationship between drug dose and drug effect. Dose-Response Publ Int Hormesis Soc 7, 172-192.
Gray BP, Li S, Brown KC (2013) From phage display to nanoparticle delivery: Functionalizing liposomes with multivalent peptides improves targeting to a cancer biomarker. Bioconjug Chem 24, 85-96.
Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J (2000) Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction. J Biol Chem 275, 25616-25624.
Lane-Donovan C, Philips GT, Herz J (2014) More than cholesterol transporters: Lipoprotein receptors in CNS function and neurodegeneration. Neuron 83, 771-787.
Li Y, Cam J, Bu G (2001) Low-density lipoprotein receptor family: Endocytosis and signal transduction. Mol Neurobiol 23, 53-67.
Gawel K, Gibula E, Marszalek-Grabska M, Filarowska J, Kotlinska JH (2019) Assessment of spatial learning and memory in the Barnes maze task in rodents-methodological consideration. Naunyn Schmiedebergs Arch Pharmacol 392, 1-18.
Qu B, Gong Y, Gill JM, Kenney K, Diaz-Arrastia R (2017) Heterozygous knockout of cytosolic phospholipase A2 attenuates Alzheimer’s disease pathology in APP/PS1 transgenic mice. Brain Res 1670, 248-252.
Yarla NS, Bishayee A, Vadlakonda L, Chintala R, Duddukuri GR, Reddanna P, Dowluru KSVGK (2016) Phospholipase A2 isoforms as novel targets for prevention and treatment of inflammatory and oncologic diseases. Curr Drug Targets 17, 1940-1962.
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P (2005) Regulation of NMDA receptor trafficking by amyloid-. Nat Neurosci 8, 1051-1058.
Hardingham GE, Bading H (2010) Synaptic versus extrasynaptic NMDA receptor signalling: Implications for neurodegenerativedisorders.NatRevNeurosci11,682-696.
Wang Z-C, Zhao J, Li S (2013) Dysregulation of synaptic and extrasynaptic N-methyl-D-aspartate receptors induced by amyloid-. Neurosci Bull 29, 752-760.
Terwel D, Muyllaert D, Dewachter I, Borghgraef P, Croes S, Devijver H, Van Leuven F (2008) Amyloid activates GSK-3beta to aggravate neuronal tauopathy in bigenic mice. Am J Pathol 172, 786-798.
Metaxas A, Thygesen C, Kempf SJ, Anzalone M, Vaitheeswaran R, Petersen S, Landau AM, Audrain H, Teeling JL, Darvesh S, Brooks DJ, Larsen MR, Finsen B (2018) Tauopathy in the APPswe/PS1E9 mouse model of familial Alzheimer’s disease. bioRxiv 405647.
Kimura T, Ishiguro K, Hisanaga S-I (2014) Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci 7, 65.
Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: Evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13, 159-170.
Tan JZA, Gleeson PA (2019) The role of membrane trafficking in the processing of amyloid precursor protein and production of amyloid peptides in Alzheimer’s disease. Biochim Biophys Acta Biomembr 1861, 697-712.
Das U, Scott DA, Ganguly A, Koo EH, Tang Y, Roy S (2013) Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 79, 447-460.
Macklin L, Griffith CM, Cai Y, Rose GM, Yan XX, Patrylo PR (2017) Glucose tolerance and insulin sensitivity are impaired in APP/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline. Exp Gerontol 88, 9-18.
Jones PM, Burns CJ, Belin VD, Roderigo-Milne HM, Persaud SJ (2004) The role of cytosolic phospholipase A(2) in insulin secretion. Diabetes 53 Suppl 1, S172-178.
Strömberg K, Eketjäll S, Georgievska B, Tunblad K, Eliason K, Olsson F, Radesäter A-C, Klintenberg R, Arvidsson PI, von Berg S, Fälting J, Cowburn RF, Dabrowski M (2015) Combining an amyloid-beta (A) cleaving enzyme inhibitor with a -secretase modulator results in an additive reduction of A production. FEBS J 282, 65-73.
Fenili D, Brown M, Rappaport R, McLaurin J (2007) Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J Mol Med Berl Ger 85, 603-611.
Gervais F, Paquette J, Morissette C, Krzywkowski P, Yu M, Azzi M, Lacombe D, Kong X, Aman A, Laurin J, Szarek WA, Tremblay P (2007) Targeting soluble Abeta peptide with Tramiprosate for the treatment of brain amyloidosis. Neurobiol Aging 28, 537-547.
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, Dunstan R, Salloway S, Chen T, Ling Y, O’Gorman J, Qian F, Arastu M, Li M, Chollate S, Brennan MS, Quintero-Monzon O, Scannevin RH, Arnold HM, Engber T, Rhodes K, Ferrero J, Hang Y, Mikulskis A, Grimm J, Hock C, Nitsch RM, Sandrock A (2016) The antibody aducanumab reduces A plaques in Alzheimer’s disease. Nature 537, 50-56.
Ghantasala S, Pai MGJ, Biswas D, Gahoi N, Mukherjee S, Kp M, Nissa MU, Srivastava A, Epari S, Shetty P, Moiyadi A, Srivastava S (2021). Multiple reaction monitoring-based targeted assays for the validation of protein biomarkers in brain tumors. Front Oncol 11, 548243.
Fournier I, Mériaux C, Wisztorski M, Rakwal R, Salzet M (2011). MALDI imaging mass spectrometry for investigating the brain. In Sample Preparation in Biological Mass Spectrometry, Ivanov AR, Lazarev AV, eds. Springer, Dordrecht, pp 765-783.
